Human brain activation in response to olfactory stimulation by intravenous administration of odorants

To identify the BOLD effects related to olfaction in humans, we recorded functional magnetic resonance imaging (fMRI) scans in response intravenously instilled thiamine propyl disulfide (TPD) and thiamine tetrahydrofurfuryl disulfide monohydrochloride (TTFD). TPD and TTFD evoked a strong and weak odor sensation, respectively. Since we did not spray the odor stimuli directly, this method is expected to reduce the effect caused by direct stimulation of the trigeminal nerve. For the analysis of fMRI data, statistical parametric mapping (SPM2) was employed and the areas significantly activated during olfactory processing were located. Both strong and weak odorants induced brain activities mainly in the orbitofrontal gyrus (Brodmann's area: BA 11) in the left hemisphere. TPD (a strong odorant) induced activity in the subthalamic nucleus in the left hemisphere and the precentral gyrus (BA 6) and insula in the right hemisphere. TTFD (a weak odorant) induced activity in the superior frontal gyrus (BA 11) in the right hemisphere. In both circumstances, there was an increase in blood flow at the secondary olfactory cortex (SOC) but not the primary olfactory cortex (POC), probably due to a habituation effect in the POC. From the present results, we found brain activity in not only odor-specific regions but also regions whose levels of activity were changed by an intensity difference of odor stimuli.     

Time course of odorant-induced activation in the human primary olfactory cortex

Paradoxically, attempts to visualize odorant-induced functional magnetic resonance imaging (fMRI) activation in the human have yielded activations in secondary olfactory regions but not in the primary olfactory cortex-piriform cortex. We show that odorant-induced activation in primary olfactory cortex was not previously made evident with fMRI because of the unique time course of activity in this region: in primary olfactory cortex, odorants induced a strong early transient increase in signal amplitude that then habituated within 30-40 s of odorant presence. This time course of activation seen here in the primary olfactory cortex of the human is almost identical to that recorded electrophysiologically in the piriform cortex of the rat. Mapping activation with analyses that are sensitive to both this transient increase in signal amplitude, and temporal-variance, enabled us to use fMRI to consistently visualize odorant-induced activation in the human primary olfactory cortex. The combination of continued accurate odorant detection at the behavioral level despite primary olfactory cortex habituation at the physiological level suggests that the functional neuroanatomy of the olfactory response may change throughout prolonged olfactory stimulation.     

Olfactometry in fMRI studies: odor presentation using nasal continuous positive airway pressure

We describe a method for generating and presenting olfactory stimuli in functional magnetic resonance imaging (fMRI) studies for humans. The olfactometer is based on principles of air dilution olfactometry and consists of a nasal mask and a nasal Continuous Positive Airway Pressure device, both normally used for patients suffering from obstructive sleep apnea syndrome. The system allows online monitoring and recording of the subject's breathing pattern. Switching between different olfactory conditions can easily be synchronized with the inhalation phase and be controlled by a computer. Besides, switching occurs rapidly and without any optical, acoustic, thermal, or tactile cues for the subject. As an example of implementation we present a fMRI trial of olfaction using pleasant and unpleasant odor stimuli to induce different affective states in healthy subjects. The relatively inexpensive olfactometer is reliable and permits constant odor concentrations during the inherently prolonged imaging studies.     

Appetitive learning of odours with different behavioural meaning in moths

Moth behaviour is to a great extent guided by olfactory stimuli with different relevance. We investigated whether olfactory learning of odours is influenced by the behavioural significance of the odorant. In proboscis extension conditioning experiments species-specific sex pheromones, which normally elicit an innate behaviour in males, and a flower odour were used as olfactory stimuli. After 10 conditioning trials, both sexes showed similar response levels to individual pheromone components and to the flower odour geraniol. However, when the female gland extract was used as conditioning stimulus, the response level was significantly lower than that for geraniol in both sexes. Significant learning nevertheless occurred in females, but not in males. Experiments with different numbers of training trials revealed that, in females, fewer learning trials with individual pheromone components were necessary for significant memory formation than in males.     

A dynamic fMRI study of illusory double-flash effect on human visual cortex

Functional MRI (fMRI) combined with the paired-stimuli paradigms (referred as dynamic fMRI) was used to study the “illusory double-flash” effect on brain activity in the human visual cortex. Three experiments were designed. The first two experiments aimed to examine the cross-modal neural interaction between the visual and auditory sensory systems caused by the illusory double-flash effect using combined auditory (beep sound) and visual (light flash) stimuli. The fMRI signal in the visual cortex was significantly increased in response to the illusory double flashes compared to the physical single flash when the inter-stimuli delay between the auditory and visual stimuli was 25 ms. This increase disappeared when the delay was prolonged to ~300 ms. These results reveal that the illusory double-flash effect can significantly affect the brain activity in the visual cortex, and the degree of this effect is dynamically sensitive to the inter-stimuli delay. The third experiment was to address the spatial differentiation of brain activation in the visual cortex in response to the illusory double-flash stimulation. It was found that the illusory double-flash effect in the human visual cortex is much stronger in the periphery than the fovea. This finding suggests that the periphery may be involved in high-level brain processing beyond the retinotopic visual perception. The behavioral measures conducted in this study indicate an excellent correlation between the fMRI results and behavioral performance. Finally, this work demonstrates a unique merit of fMRI for providing both temporal and spatial information regarding cross-modal neural interaction between different sensory systems.     

Rapid olfactory processing implicates subcortical control of an olfactomotor system

Sniffs are modulated in response to odor content. Higher concentrations of odor induce lesser-volume sniffs. This phenomenon implicates a neural feedback mechanism that measures sensory input (odor concentration) and modulates motor output (sniffing) accordingly. Here we used air-dilution olfactometry to probe the time course of this olfactomotor mechanism. A stainless-steel computer-controlled olfactometer, equipped with mass flow controllers, temperature and humidity control, and on-line photo-ionization detection, was coupled to a highly sensitive pneumatotachograph that measured nasal flow. The olfactometer was used to generate four ascending concentrations of the odorants propionic acid and phenethyl alcohol. Sniff volume was inversely related to odor concentration (P > 0.0001). Sniffs were uniform and concentration independent for the initial 150 ms but acquired a concentration-dependent flowrate as early as 160 ms following sniff onset for propionic acid (P > 0.05) and 260 ms for phenethyl alcohol (P > 0.05). Considering that odorant transduction takes around 150 ms and odorant-induced cortical evoked potentials have latencies of around 300 ms, the rapid motor adjustments measured here suggest that olfactomotor sniff feedback control is subcortical and may rely on neural mechanisms similar to those that modulate eye movements to accommodate vision and ear movements to accommodate audition.     

Optical recordings from the human nasal mucosa in response to olfactory stimulation

Using the intrinsic optical signal the present study aimed to investigate changes in blood flow at the nasal epithelium in response to specific olfactory stimulation. Recording equipment included an endoscope, a CCD camera, and a light source of 617 nm. Two concentrations of the specific olfactory stimulant H₂S (2.8 and 5.6 ppm), generated by a computer-controlled olfactometer, were used for olfactory stimulation. Eight healthy normosmic volunteers participated. Using 5.6 ppm H₂S stimuli, responses were typically recorded from the olfactory cleft, middle turbinate, and middle meatus while responses were less pronounced for 2.8 ppm H₂S stimuli. Response areas were significantly larger for the 5.6 ppm H₂S stimuli. While further experiments are needed, recordings of the intrinsic optical signal may be used to obtain responses from the nasal cavity to specific olfactory stimuli.     

Response properties of neurones in the rat olfactory bulb to various parameters of odour stimulation

Carbon fibre filled microelectrodes were used for extracellular recording of spikes discharges from 345 neurones of the lateral aspect of the left olfactory bulb of the rat under pentobarbitone anaesthesia. The identity of the neurones was determined by antidromic activation of the cell axons by electrical stimuli applied to the lateral olfactory tract (LOT) using collision blocking and twin stimuli. The bulbar units were classified as mitral (269) or tufted (16) cells; units in a third class were not identified (60). Application of stimuli (21) was made over a period of 15 s while slowly increasing the odorant concentration monitored by a flame ionization device (FID). The stimulating efficiency reached a maximum at a nasal flow of about 8 cm3 s-1. The response type excitation was seen in 12.0% and inhibition in 11.8% of the 7245 odour presentations. Each response type was subdivided into four classes according to the reactions to ramp stimulation. In the majority of cases the spike discharge remained constant or followed the odour concentration for the entire stimulation period. In 18% of the cases, the response adapted quickly towards the spontaneous activity level.     

Spatio–temporal dynamics of olfactory processing in the human brain: an event-related source imaging study

Although brain structures involved in central nervous olfactory processing in humans have been well identified with functional neuroimaging, little is known about the temporal sequence of their activation. We recorded olfactory event-related potentials (ERP) to H₂S stimuli presented to the left and right nostril in 12 healthy subjects. Topographic and source analysis identified four distinct processing steps between 200 and 1000 ms. Activation started ipsilateral to the stimulated nostril in the mesial and lateral temporal cortex (amygdala, parahippocampal gyrus, superior temporal gyrus, insula). Subsequently, the corresponding structures on the contralateral side became involved, followed by frontal structures at the end of the activation period. Thus, based on EEG-related data, current results suggest that olfactory information in humans is processed first ipsilaterally to the stimulated nostril and then activates the major relays in olfactory information processing in both hemispheres. Most importantly, the currently described techniques allow the investigation of the spatial processing of olfactory information at a high temporal resolution.     

Neural response to sustained affective visual stimulation using an indirect task

Event-related potentials were recorded from 30 subjects using sustained stimulation and an indirect task, two strategies which facilitate affective responses that are complete and free of cognitive interference. Stimuli were of three types: pleasant, unpleasant and neutral. A three-phase pattern was found. The first phase, an amplitude increase in response to negative stimuli higher than to neutral and pleasant stimuli, was produced at 160 ms after stimulus onset, the prefrontal cortex being the origin of this phase. The second phase, characterized by maximal amplitudes in response to positive stimuli, was produced at 400 ms, originating in the visual cortex. Finally, the third phase, another amplitude increase in response to negative stimuli, was produced at 680 ms, and its source was located in the left precentral gyrus. Present data show that the cortical response to sustained emotional visual stimulation presented within indirect tasks provides information on attention-, motivation- and motor-related biases that complement information obtained under other experimental conditions.     

Impairment of odor recognition in Parkinson's disease caused by weak activations of the orbitofrontal cortex

Olfactory dysfunction and abnormalities of olfactory brain structures are found in patients with Parkinson's disease (PD), and a number of studies have reported that olfactory dysfunction is caused by abnormalities of the central olfactory systems. We previously analyzed electroencephalograms (EEGs) and respiration simultaneously in normal subjects while testing for detection and recognition of odors. We identified changes in respiration pattern in response to odor stimuli and found inspiratory phase-locked alpha oscillations (I-alpha). The genesis of I-alpha were identified in olfactory-related areas including the entorhinal cortex, hippocampus, amygdale and orbitofrontal cortex with an EEG dipole tracing method. In the present study, we used the same protocol in PD patients and compared results of PD with those of age-matched controls. All PD patients detected odor, but 5 out of 10 showed impaired odor recognition. Changes in breathing pattern associated with emotional changes during exposure to odor stimuli were not observed in PD patients. I-alpha waveforms were not observed; however, positive waves followed by negative waves were identified approximately 100ms after inspiration onset. Dipoles of this component were localized in the entorhinal cortex for odor detection in all patients and in the entorhinal cortex and middle temporal gyrus for PD patients who could discriminate odors. Odor recognition in PD could be subserved by a different neural circuit from that of normal subjects, done through the temporal association cortex as a subsystem for recognizing the odor; however, the system may not be associated with the odor-induced emotions.     

Olfactory cortical adaptation facilitates detection of odors against background

Detection and discrimination of odors generally, if not always, occurs against an odorous background. On any given inhalation, olfactory receptor neurons will be activated by features of both the target odorant and features of background stimuli. To identify a target odorant against a background therefore, the olfactory system must be capable of grouping a subset of features into an odor object distinct from the background. Our previous work has suggested that rapid homosynaptic depression of afferents to the anterior piriform cortex (aPCX) contributes to both cortical odor adaptation to prolonged stimulation and habituation of simple odor-evoked behaviors. We hypothesize here that this process may also contribute to figure-ground separation of a target odorant from background stimulation. Single-unit recordings were made from both mitral/tufted cells and aPCX neurons in urethan-anesthetized rats and mice. Single-unit responses to odorant stimuli and their binary mixtures were determined. One of the odorants was randomly selected as the background and presented for 50 s. Forty seconds after the onset of the background stimulus, the second target odorant was presented, producing a binary mixture. The results suggest that mitral/tufted cells continue to respond to the background odorant and, when the target odorant is presented, had response magnitudes similar to that evoked by the binary mixture. In contrast, aPCX neurons filter out the background stimulus while maintaining responses to the target stimulus. Thus the aPCX acts as a filter driven most strongly by changing stimuli, providing a potential mechanism for olfactory figure-ground separation and selective reading of olfactory bulb output.     

A demonstration of classical conditioning of the human eyeblink to an olfactory stimulus.

While acquisition of the eyeblink conditioned response to a variety of stimuli has been widely studied, it has yet to be established that humans will demonstrate a conditioned response to an olfactory stimulus. In this study we present data to show that humans will demonstrate a classically conditioned eyeblink response to an olfactory stimulus. Ten participants were tested in a delay conditioning procedure with an olfactory stimulus presented in a heated, humidified stream of air via an olfactometer, allowing the precise control over stimulus duration necessary for delay conditioning. Trials on which odor alone was presented were administered to four additional participants. Establishing that humans will demonstrate an eyeblink conditioned response to an olfactory stimulus will allow further exploration of the pathways involved in classical conditioning and associative learning, as well as an analysis of conditioning pathways across sensory modalities.     

BOLD adaptation in vibrotactile stimulation: neuronal networks involved in frequency discrimination

The present functional magnetic resonance imaging (fMRI) study investigated human brain regions subserving the discrimination of vibrotactile frequency. An event-related adaptation paradigm was used in which blood-oxygen-level-dependent (BOLD) responses are lower to same compared with different pairs of stimuli (BOLD adaptation). This adaptation effect serves as an indicator for feature-specific responding of neuronal subpopulations. Subjects had to discriminate two vibrotactile stimuli sequentially applied with a delay of 600 ms to their left middle fingertip. The stimulus frequency was in the flutter range of 18-26 Hz. In half of the trials, the two stimuli possessed identical frequency (same), whereas in the other half, a frequency difference of +/-2 Hz was used (diff). As a result, BOLD adaptation was observed in the contralateral primary somatosensory cortex (S1), precentral gyrus, superior temporal gyrus (STG); ipsilateral insula as well as bilateral secondary somatosensory cortex and supplementary motor area. When statistically comparing the BOLD time courses between same and diff trials in these cortical areas, it was found that the vibrotactile BOLD adaptation is initiated in the contralateral S1 and STG simultaneously. These findings suggest that the cortical areas responsive to the frequency difference between two serially presented stimuli sequentially process the frequency of a vibrotactile stimulus and constitute a putative neuronal network underlying human vibrotactile frequency discrimination.     

Source Localization of Early Stages of Face Processing

Summary: Recent studies using ERPs in face recognition revealed that face processing starts around 100 ms after stimulus onset, 70 ms earlier than suggested before. While the neural sources of the N170 component have repeatedly been found to be localized in the gyrus fusiformis and the inferior occipital cortex, sources have not yet been investigated for the P100 component during face processing. Therefore, we measured the ERPs elicited by faces and control stimuli in 72 subjects in order to localize the neural sources of both the P100 and the N170 component. We observed significantly higher P100 and N170 amplitudes to faces compared to control stimuli. LORETA source localization revealed significantly higher brain activity in the left and right gyrus fusiformis for the N170 component, with additional regions of increased brain activation in a parieto-temporal-occipital network. For the P100, faces activated the left and right gyrus fusiformis significantly stronger than control stimuli. This study reveals that the first step of face processing (about 100 ms after stimulus presentation) is localized in the gyrus fusiformis. The second step of face processing around 170 ms involves the gyrus fusiformis, with additional activation in a more distributed network, including the occipital cortex.     

性相关视觉刺激对右脑Broca区不对称性兴奋的功能核磁共振研究

目的:了解与视觉性刺激相关的脑功能定位。方法:用张贴广告的形式征集到13例正常女性,通过功能核磁共振比较其观看普通影片和含有性内容图片时的大脑兴奋差异,确定差异有统计学意义的脑区。结果:与中性图片相比,涉性图片激发了广泛的大脑区域,包括侧枕叶皮质、中央后回、顶上小叶、枕叶梭状回、海马等。大部分脑区的兴奋都是左右半球对称的,只有额下回岛盖部(Z=3.64,P0.0001)和三角部(Z=3.42,P=0.003)为右脑优势。讨论:本文通过功能核磁共振方法发现,当女性受试在被呈示以与性相关的图片时,大脑右半球额下回岛盖部和三角部有显著的不对称兴奋。该脑区可能对性心理调控有重要意义。     

Ontogeny of olfaction: Development of the rats' sensitivity to urine and amyl acetate

Rat pups, 1 to 17 days of age, were tested for sensitivity to two olfactants, amyl acetate and adult rat urine. Biological and non-biological olfactory stimuli were generated by sparging and delivered to subjects via a dilution olfactometer. Unconditioned respiratory responses, odor-induced polypnea and sniffing, were used to measure detection of an odorant injected into a background stream of filtered air. Amyl acetate was presented in an ascending series of concentrations. Pups of all ages detected amyl acetate; chemosensitivity increased with age to all 3 concentrations of this nonbiological stimulus. Two concentrations of adult rat urine odor were equated to the strength of amyl acetate for 9-day-olds. Each normalized urine stimulus was then tested across the full range of age groups. Again, there was a dramatic age-related increase in chemosensitivity. Moreover, there was no indication of differential sensitivity to these biological and non-biological olfactants. These data were discussed within methodological and conceptual frameworks related to analyses of early olfactory and behavioral ontogenesis.     

Neural circuits subserving the retrieval and maintenance of abstract rules

Behavior is often governed by abstract rules or instructions for behavior that can be abstracted from one context and applied to another. Prefrontal cortex (PFC) is thought to be important for representing rules, although the contributions of ventrolateral (VLPFC) and dorsolateral (DLPFC) regions remain under-specified. In the present study, event-related fMRI was used to examine abstract rule representation in humans. Prior to scanning, subjects learned to associate unfamiliar shapes and nonwords with particular rules. During each fMRI trial, presentation of one of these cues was followed by a delay and then by sample and probe stimuli. Match and non-match rules required subjects to indicate whether or not the sample and probe matched; go rules required subjects to make a response that was not contingent on the sample/probe relation. Left VLPFC, parietal cortex, and pre-SMA exhibited sensitivity to rule type during the cue and delay periods. Delay-period activation in these regions, but not DLPFC, was greater when subjects had to maintain response contingencies (match, non-match) relative to when the cue signaled a specific response (go). In contrast, left middle temporal cortex exhibited rule sensitivity during the cue but not delay period. These results support the hypothesis that VLPFC interacts with temporal cortex to retrieve semantic information associated with a cue and with parietal cortex to retrieve and maintain relevant response contingencies across delays. Future investigations of cross-regional interactions will enable full assessment of this account. Collectively, these results demonstrate that multiple, neurally separable processes are recruited during abstract rule representation.     

Experience-dependent neural integration of taste and smell in the human brain

Flavor perception arises from the central integration of peripherally distinct sensory inputs (taste, smell, texture, temperature, sight, and even sound of foods). The results from psychophysical and neuroimaging studies in humans are converging with electrophysiological findings in animals and a picture of the neural correlates of flavor processing is beginning to emerge. Here we used event-related fMRI to evaluate brain response during perception of flavors (i.e., taste/odor liquid mixtures not differing in temperature or texture) compared with the sum of the independent presentation of their constituents (taste and/or odor). All stimuli were presented in liquid form so that olfactory stimulation was by the retronasal route. Mode of olfactory delivery is important because neural suppression has been observed in chemosensory regions during congruent taste-odor pairs when the odors are delivered by the orthonasal route and require subjects to sniff. There were 2 flavors. One contained a familiar/congruent taste-odor pair (vanilla/sweet) and the other an unfamiliar/incongruent taste-odor pair (vanilla/salty). Three unimodal stimuli, including 2 tastes (sweet and salty) and one odor (vanilla), as well as a tasteless/odorless liquid (baseline) were presented. Superadditive responses during the perception of the congruent flavor compared with the sum of its constituents were observed in the anterior cingulate cortex (ACC), dorsal insula, anterior ventral insula extending into the caudal orbitofrontal cortex (OFC), frontal operculum, ventral lateral prefrontal cortex, and posterior parietal cortex. These regions were not present in a similar analysis of the incongruent flavor compared with the sum of its constituents. All of these regions except the ventrolateral prefrontal cortex were also isolated in a direct contrast of congruent - incongruent. Additionally, the anterior cingulate, posterior parietal cortex, frontal operculum, and ventral insula/caudal OFC were also more active in vanilla + salty minus incongruent, suggesting that delivery of an unfamiliar taste-odor combination may lead to suppressed neural responses. Taken together with previous findings in the literature, these results suggest that the insula, OFC, and ACC are key components of the network underlying flavor perception and that taste-smell integration within these and other regions is dependent on 1) mode of olfactory delivery and 2) previous experience with taste/smell combinations.