Respiratory responses to olfactory stimuli in Parkinson's disease

There are many reports of olfactory impairment in patients with Parkinson's disease (PD) and the impairment can be observed before the appearance of typical PD symptom. Accordingly, olfactory screening tests may predict disease onset and indicates a need for early treatment before classic signs of the disease. Olfaction is dependent on inspiration, and activation of olfactory limbic areas are synchronized with the natural breathing cycle in animals and humans. Subconscious changes in respiratory pattern occur in response to odor stimulation. The use of olfactory stimuli to investigate respiratory pattern could be used to assess olfactory perception and serve as an index for olfactory limbic activation. In this study, we tested olfactory acuity in normal subjects and in patients with PD and recorded V(O2) and respiratory variables during pleasant and unpleasant odor presentation. All subjects were able to detect the odorants; however patients with PD were assigned to one of two groups, group that could recognize odors or the group with impaired odor recognition. Respiratory response toward unpleasant and pleasant odor recognition were weak in PD groups who could recognize odors than normal subject as well as emotional response to odor stimuli. PD group with impaired odor recognition showed no respiratory response toward odor stimuli. PD may experience difficulty in feeling positive emotions toward pleasant odors prior to the unpleasant odor because respiratory responses to pleasant odors may also be related to higher processes including intentional control of breathing pattern as a result of olfactory cortex processing and perceptions or emotions.     

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.     

Inspiratory phase-locked alpha oscillation in human olfaction: source generators estimated by a dipole tracing method

Olfactory perception and related emotions are largely dependent on inspiration. We acquired simultaneous respiration and electroencephalographic recordings during pleasant odour and unpleasant odour stimulation. We sought to identify changes in respiratory pattern, inspiratory-related potentials and location of dipoles estimated from the potentials. Electroencephalographic recording was triggered by inspiration onset. Respiratory frequency decreased at pleasant odour recognition, and it increased at unpleasant odour detection and recognition. O₂ consumption records showed that these changes were not due to metabolic demand. During olfactory stimulation, inspiratory phase-locked alpha oscillation (I-α) was found in the averaged potential triggered by inspiration onset. I-α was observed at both pleasant odour and unpleasant odour detection and recognition, but it was not seen in the inspiration-triggered potentials of normal air breathing. Electroencephalographic dipole tracing identified the location of dipoles from the I-α in the limbic area and the cortex; the entorhinal cortex, hippocampus, amygdala, premotor area and centroposterior orbitofrontal cortex subserve odour detection, and the rostromedial orbitofrontal cortex subserves odour recognition. We suggest that the I-α in our study originated from the olfactory cortex in the forebrain and was phase-locked to inspiration.     

Processing of autobiographical memory retrieval cues in borderline personality disorder

BACKGROUND: Affective dysregulation in borderline personality disorder (BPD) in response to both external stimuli and memories has been shown to be associated with functional alterations of limbic and prefrontal brain areas. This study aimed to examine neuronal networks involved in autobiographical memory retrieval using standardized stimuli that gain autobiographical significance by illustrating marked solitary and social situations of human life. METHODS: Using event-related functional Magnetic Resonance Imaging (fMRI), we examined the processing of pictures from the Thematic Apperception Test (TAT) in 14 BPD patients and 14 controls. RESULTS: In both groups, TAT stimuli activated brain areas known to be involved in autobiographical memory retrieval. BPD subjects lacked differential amygdala, orbitofrontal and cingulate activations for TAT versus neutral stimuli. In the TAT condition, compared to controls, BPD subjects displayed increased BOLD responses in the bilateral orbitofrontal and insular regions, in the left anterior cingulate and medial prefrontal cortex, as well as in the parietal and parahippocampal areas, consistent with a more aversive and arousing experience assessed by self-reports. CONCLUSIONS: Increased BOLD responses during TAT processing in BPD subjects were in line with previously reported changes in anterior cingulate and orbitofrontal cortices, which are known to be involved in memory retrieval. However, BPD subjects displayed hyperactivation in these areas for both TAT and neutral stimuli. The deficit of selective activation of areas involved in autobiographical memory retrieval suggests a general tendency towards a self-referential mode of information processing in BPD, or a failure to switch between emotionally salient and neutral stimuli.     

Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats

The objective of the present study was to investigate interactions between odor hedonic tone, perceived odor intensity, olfactory judgments and stimulated nostril laterality. Subjects were stimulated in the right and the left nostril separately, with two odors: vanillin (pleasant); and indole (unpleasant). They had two tasks to perform: an intensity judgment; and an affective judgment. Two concentrations (one strong and one weak) of each odor were presented. Odors were presented for a short period corresponding to one inhalation (about 1 s). The inter-stimulus interval was always 30 s. The nostril stimulated and task presentation order were counterbalanced according to a Latin square. Odor presentation order was randomized for each subject. Results indicated that response times for unpleasant odors were significantly shorter than for pleasant odors during affective judgment and right nostril stimulation, indicating greater right hemisphere efficiency for the decoding of unpleasant affects induced by odors.     

Remembering familiar people: the posterior cingulate cortex and autobiographical memory retrieval.

Most functional imaging studies of memory retrieval investigate memory for standardized laboratory stimuli. However, naturally acquired autobiographical memories differ from memories of standardized stimuli in important ways. Neuroimaging studies of natural memories may reveal distinctive patterns of brain activation and may have particular value in assessing clinical disorders of memory. This study used functional magnetic resonance imaging to investigate brain activation during successful retrieval of autobiographical memories elicited by name-cued recall of family members and friends. The caudal part of the left posterior cingulate cortex was the most strongly activated region and was significantly activated in all eight subjects studied. Most subjects also showed significant activation of the left anterior orbitomedial, anterior middle frontal, precuneus, cuneus, and posterior inferior parietal cortices, and the right posterior cingulate and motor cortices.Our findings are consistent with prior studies showing posterior cingulate cortex activation during autobiographical memory retrieval. This region is also consistently activated during retrieval of standardized memory stimuli when experimental designs emphasizing successful retrieval are employed. Our results support the hypothesis that the posterior cingulate cortex plays an important role in successful memory retrieval. The posterior cingulate cortex has strong reciprocal connections with entorhinal and parahippocampal cortices. Studies of early Alzheimer's disease, temporal lobectomy, and hypoxic amnesia show that hypometabolism of the posterior cingulate cortex is an early and prominent indicator of pathology in these patients. Our findings suggest that autobiographical memory retrieval tasks could be used to probe the functional status of the posterior cingulate cortex in patients with early Alzheimer's disease or at risk for that condition.     

Functional MRI correlates of the recall of unresolved life events in borderline personality disorder

BACKGROUND: Patients with borderline personality disorder (BPD) frequently report unresolved life events but it is still poorly understood, how these experiences are represented in the brain. Using functional magnetic resonance imaging (fMRI), the present study aimed at investigating the neural correlates of the recall of unresolved life events in patients with BPD and healthy controls. METHOD: Twenty female BPD patients and 21 healthy control subjects underwent fMRI. During measurement subjects recalled unresolved and resolved negative life events. Individual cue words were used to stimulate autobiographical memory. After scanning, subjects rated their emotional states during the recall of both types of memories. RESULTS: When contrasting unresolved and resolved life events, patients showed significant bilateral activation of frontotemporal areas including the insula, amygdala, and the anterior cingulate cortex, the left posterior cingulate cortex, right occipital cortex, the bilateral cerebellum and the midbrain. In healthy subjects, no differential brain activation was related to these conditions. The 2 x 2 factorial analysis (DeltaBPD - Deltacontrols) revealed similar results with bilateral activation of the frontal cortex including parts of the insula and of the orbitofrontal cortex, temporal activation including the amygdala, activation of the right occipital cortex, and parts of the cerebellum. Patients but not controls reported higher levels of anxiety and helplessness during the unresolved versus resolved memory condition. CONCLUSIONS: The activation of both, the amygdala and prefrontal areas, might reflect an increased effortful but insufficient attempt to control intensive emotions during the recall of unresolved life events in patients with BPD.     

Expiration: The moment we experience retronasal olfaction in flavor

Respiration is essential for smell perception. Previously we found that 8–12-Hz cortical rhythms were phase-locked to inspiration onset during the presentation of odor stimuli; this is referred to as inspiration phase-locked alpha band oscillation (I-α). Generators of I-α estimated with a dipole fitting model were found in the piriform, the entorhinal cortex (ENT), the amygdala (AMG), the hippocampus (HI) and the orbitofrontal cortex (OFC). Such olfactory perception is said to occur via the orthonasal olfaction route. Another route is the retronasal olfaction route. In this study, we investigated the link between respiration phase and retronasal olfactory perception. Electroencephalograph (EEG) and respiratory flows (separately measured with mouth and nose) were simultaneously recorded during stimulation of subjects’ tongues with liquids of chocolate, sucrose and water. The percentage of subjects correctly identifying the chocolate taste was higher when subjects were asked to breathe through the nose than when they were breathing through the mouth. In the averaged EEGs triggered by the onset of expiration measured from the flow through the nose, a 8–12-Hz oscillation was observed. Generators of this potential were found in the left ENT, HI, AMG and OFC in the order of milliseconds after expiration onset. Perception of retronasal olfaction is dependent on expiration, and combining retronasal olfactory information with gustatory information and somatosensation enable us to identify flavors when drinking and feeding.     

Estrous odors and sexually conditioned neutral odors activate separate neural pathways in the male rat

Olfactory stimuli play important roles in sexual behavior. Previous studies have demonstrated that both estrous odors and initially neutral odors paired with copulation influence the sexual behavior of male rats. The present study examines the pattern of neural activation as revealed by Fos immunoreactivity (Fos-IR) following exposure to bedding scented with either a neutral odor (almond) paired previously with copulation, estrous odors or no odor. Following exposure to estrous odors Fos-IR increased in the accessory olfactory bulb, medial amygdala, medial bed nucleus of the stria terminalis, medial preoptic area, ventromedial hypothalamus, ventral tegmental area, and both the nucleus accumbens core and shell. Conversely, following exposure to the sexually conditioned odor Fos-IR increased in the piriform cortex, basolateral amygdala, nucleus accumbens core, and the anterior portion of the lateral hypothalamic area. In addition, following exposure to almond odor Fos-IR increased in the main olfactory bulb independent of its pairing with copulation. These patterns of Fos-IR following exposure to estrous or sexually conditioned odors were not influenced by either the addition or omission of the other type of odor. These findings demonstrate that estrous and sexually conditioned odors are processed by distinct neural pathways and converge in the nucleus accumbens core, suggesting that this structure has a unique role in processing sexual stimuli of both pheromonal and olfactory natures.     

Orbital cortex neuronal responses during an odor-based conditioned associative task in rats

Neuronal activity in the rat orbital cortex during discrimination of various odors [five volatile organic compounds (acetophenone, isoamyl acetate, cyclohexanone, p-cymene and 1,8-cineole), and food- and cosmetic-related odorants (black pepper, cheese, rose and perfume)] and other conditioned sensory stimuli (tones, light and air puff) was recorded and compared with behavioral responses to the same odors (black pepper, cheese, rose and perfume). In a neurophysiological study, the rats were trained to lick a spout that protruded close to its mouth to obtain sucrose or intracranial self-stimulation reward after presentation of conditioned stimuli. Of 150 orbital cortex neurons recorded during the task, 65 responded to one or more types of sensory stimuli. Of these, 73.8% (48/65) responded during presentation of an odor. Although the mean breadth of responsiveness (entropy) of the olfactory neurons based on the responses to five volatile organic compounds and air (control) was rather high (0.795), these stimuli were well discriminated in an odor space resulting from multidimensional scaling using Pearson's correlation coefficients between the stimuli. In a behavioral study, a rat was housed in an equilateral octagonal cage, with free access to food and choice among eight levers, four of which elicited only water (no odor, controls), and four of which elicited both water and one of four odors (black pepper, cheese, rose or perfume). Lever presses for each odor and control were counted. Distributions of these five stimuli (four odors and air) in an odor space derived from the multidimensional scaling using Pearson's correlation coefficients based on behavioral responses were very similar to those based on neuronal responses to the same five stimuli. Furthermore, Pearson's correlation coefficients between the same five stimuli based on the neuronal responses and those based on behavioral responses were significantly correlated.The results demonstrated a pivotal role of the rat orbital cortex in olfactory sensory processing and suggest that the orbital cortex is important in the manifestation of various motivated behaviors of the animals, including odor-guided motivational behaviors (odor preference).     

Orbital cortex neuronal responses during an odor-based conditioned associative task in rats

Neuronal activity in the rat orbital cortex during discrimination of various odors [five volatile organic compounds (acetophenone, isoamyl acetate, cyclohexanone, p-cymene and 1,8-cineole), and food- and cosmetic-related odorants (black pepper, cheese, rose and perfume)] and other conditioned sensory stimuli (tones, light and air puff) was recorded and compared with behavioral responses to the same odors (black pepper, cheese, rose and perfume). In a neurophysiological study, the rats were trained to lick a spout that protruded close to its mouth to obtain sucrose or intracranial self-stimulation reward after presentation of conditioned stimuli. Of 150 orbital cortex neurons recorded during the task, 65 responded to one or more types of sensory stimuli. Of these, 73.8% (48/65) responded during presentation of an odor. Although the mean breadth of responsiveness (entropy) of the olfactory neurons based on the responses to five volatile organic compounds and air (control) was rather high (0.795), these stimuli were well discriminated in an odor space resulting from multidimensional scaling using Pearson's correlation coefficients between the stimuli. In a behavioral study, a rat was housed in an equilateral octagonal cage, with free access to food and choice among eight levers, four of which elicited only water (no odor, controls), and four of which elicited both water and one of four odors (black pepper, cheese, rose or perfume). Lever presses for each odor and control were counted. Distributions of these five stimuli (four odors and air) in an odor space derived from the multidimensional scaling using Pearson's correlation coefficients based on behavioral responses were very similar to those based on neuronal responses to the same five stimuli. Furthermore, Pearson's correlation coefficients between the same five stimuli based on the neuronal responses and those based on behavioral responses were significantly correlated. The results demonstrated a pivotal role of the rat orbital cortex in olfactory sensory processing and suggest that the orbital cortex is important in the manifestation of various motivated behaviors of the animals, including odor-guided motivational behaviors (odor preference).     

Hedonic-specific activity in piriform cortex during odor imagery mimics that during odor perception

Although it is known that visual imagery is accompanied by activity in visual cortical areas, including primary visual cortex, whether olfactory imagery exists remains controversial. Here we asked whether cue-dependent olfactory imagery was similarly accompanied by activity in olfactory cortex, and in particular whether hedonic-specific patterns of activity evident in olfactory perception would also be present during olfactory imagery. We used functional magnetic resonance imaging to measure activity in subjects who alternated between smelling and imagining pleasant and unpleasant odors. Activity induced by imagining odors mimicked that induced by perceiving real odorants, not only in the particular brain regions activated, but also in its hedonic-specific pattern. For both real and imagined odors, unpleasant stimuli induced greater activity than pleasant stimuli in the left frontal portion of piriform cortex and left insula. These findings combine with findings from other modalities to suggest activation of primary sensory cortical structures during mental imagery of sensory events.     

Odors modulate pain perception: a gender-specific effect

Odors naturally provoke emotions that are pleasant or unpleasant. Prior studies have demonstrated the effects of pleasing odors on cognition and mood perception, but no studies have reported if they influence pain perception. In the present study, we measured the effect of, and relationship between, different odors on mood and experimental pain perception. Results show that odors significantly influence mood in both women and men. Compared to a neutral odor, pleasant odors produced a positive mood while unpleasant odors produced a negative mood. However, the effect of odor on pain was gender specific, as only women experienced the effects of odor on pain perception. Because no relationship was found between mood and pain perception, it could suggest that different mechanisms are involved in the emotional aspects of mood and pain perception. These results and their potential clinical implications are discussed.     

Amygdala activity related to enhanced memory for pleasant and aversive stimuli

Pleasant or aversive events are better remembered than neutral events. Emotional enhancement of episodic memory has been linked to the amygdala in animal and neuropsychological studies. Using positron emission tomography, we show that bilateral amygdala activity during memory encoding is correlated with enhanced episodic recognition memory for both pleasant and aversive visual stimuli relative to neutral stimuli, and that this relationship is specific to emotional stimuli. Furthermore, data suggest that the amygdala enhances episodic memory in part through modulation of hippocampal activity. The human amygdala seems to modulate the strength of conscious memory for events according to emotional importance, regardless of whether the emotion is pleasant or aversive.     

Representation of pleasant and aversive taste in the human brain

In this study, the representation of taste in the orbitofrontal cortex was investigated to determine whether or not a pleasant and an aversive taste have distinct or overlapping representations in this region. The pleasant stimulus used was sweet taste (1 M glucose), and the unpleasant stimulus was salt taste (0.1 M NaCl). We used an ON/OFF block design in a 3T fMRI scanner with a tasteless solution delivered in the OFF period to control for somatosensory or swallowing-related effects. It was found that parts of the orbitofrontal cortex were activated (P < 0.005 corrected) by glucose (in 6/7 subjects) and by salt (in 6/7 subjects). In the group analysis, separate areas of the orbitofrontal cortex were found to be activated by pleasant and aversive tastes. The involvement of the amygdala in the representation of pleasant as well as aversive tastes was also investigated. The amygdala was activated (region of interest analysis, P < 0.025 corrected) by the pleasant taste of glucose (5/7 subjects) as well as by the aversive taste of salt (4/7 subjects). Activation by both stimuli was also found in the frontal opercular/insular (primary) taste cortex. We conclude that the orbitofrontal cortex is involved in processing tastes that have both positive and negative affective valence and that different areas of the orbitofrontal cortex may be activated by pleasant and unpleasant tastes. We also conclude that the amygdala is activated not only by an affectively unpleasant taste, but also by a taste that is affectively pleasant, thus providing evidence that the amygdala is involved in effects produced by positively affective as well as by negatively affective stimuli.     

‘When an old rat smells a cat’: A decline in defense-related, but not accessory olfactory, Fos expression in aged rats

Comparisons were made between young (3-6 months) and aged (20-30 months) Wistar rats on locomotor activity, emergence, social interaction and cat odor avoidance. Aged rats were less active and spent less time in the open field during the emergence test than younger rats. Older rats also showed fewer contacts with a novel conspecific in the social interaction test, although total duration of interaction did not differ. There were very few behavioral differences between male and female rats. Older rats were less reactive than younger rats in a test of cat odor avoidance. However, they expressed similar amounts of cat odor-induced Fos in the posterior accessory olfactory bulb, a critical region for processing the predator odor stimulus. Older rats had reduced Fos expression in several defense-related brain regions that are normally activated by predator odors such as the medial amygdala and dorsal premammillary nucleus. These results indicate that aged rats are less reactive than younger rats to predator odors due to decreased responsiveness in defense-related but not necessarily olfactory circuits.     

Startle reflex modulation during exposure to pleasant and unpleasant odors

The eyeblink component of the startle response to acoustic probes was measured while subjects smelled pleasant odors, unpleasant odors, or no odor. Peak electromyogram (EMG) 20–90 ms after probe onset was greater during unpleasant than during no odor conditions; EMGs for pleasant odors did not differ from those for no odor. Base tension in orbicularis oculi muscles was also higher during unpleasant odors. The results for unpleasant odors parallel those found in previous studies that have used a variety of methods for producing negatively valenced experiences. The results for pleasant odors diverge from those of most previous studies, which have found startle attenuation during positively valenced experiences. However, the results may be compatible with the suggestion (Lang, Bradley, & Cuthbert, 1992) that the motivational state that modulates startle involves both valence and arousal. Pleasant odors may require appropriate contexts to produce the positive motivational state required for startle attenuation.     

Odor-driven activity in the olfactory cortex of an in vitro isolated guinea pig whole brain with olfactory epithelium

We developed a new technique to isolate a whole guinea pig brain with an intact olfactory epithelium (OE) that enables us to access the ventral surface of the brain including olfactory areas with ease during natural odor stimulation. We applied odorants to OE and confirmed that odor-induced local field potentials (LFPs) could be induced in olfactory areas. In the olfactory bulb (OB) and the piriform cortex (PC), odor-induced LFPs consisted of a phasic initial component followed by a fast activity oscillation in the beta range (20 Hz). To understand the neural mechanisms of odor-induced responses especially in the anterior PC, we analyzed odor-induced LFPs, together with unit activity data. We confirmed that the initial component of odor-induced response has a characteristic temporal pattern, generated by a relatively weak direct afferent input, followed by an intra-cortical associative response, which was associated with a phasic inhibition. The beta oscillation might be formed by the repetition of these network activities. These electrophysiological data were consistent with the results of previous studies that used slice or in vivo preparations, suggesting that the olfactory neural network and activities of the brain are preserved in our new in vitro preparation. This study provides the basis for clarifying the sequence of neural activities underlying odor information processing in the brain in vitro following natural olfactory stimulation.     

The role of cognitive and affective processing in a transgenic mouse model of cortical-limbic neuropotentiated compulsive behavior

Obsessive compulsive disorder (OCD) may involve abnormal cortical-limbic processing or responsiveness. Mice with behaviors resembling the symptoms of OCD and related disorders were made by expression of a neuropotentiating cholera toxin (CT) transgene in cortical-limbic D1 receptor-expressing neurons. Because these D1CT mice express CT in the piriform cortex and amygdala (major cognitive and affective olfactory processing areas) it was tested whether abnormal odor perception, discrimination, or responsiveness facilitates their compulsion-like behavior. The mice exhibited normal olfactory discriminative capability. An anxiogenic odor potentiated their abnormal repetitive leaping, but novel or familiar nonthreatening odors did not. These data suggest that compulsions can be triggered not by impaired cortical-limbic processing but by increased cortical-limbic responsiveness, particularly to sensory or cognitive stimuli with affective properties.     

Regional brain responses to pleasant and unpleasant IAPS pictures: different networks

Purpose: The purpose of this study was to investigate the brain circuitry involved in the processing of both positive and negative emotions in normal healthy subjects. Method: we have recruited 15 healthy volunteers (9 males and 6 females, age range 30-60). In this block-design fMRI study, we compared the blood oxygen level dependant (BOLD) signal change as response to pleasant and unpleasant IAPS pictures, each compared to a neutral condition. Results: Pleasant pictures versus neutral condition contrast demonstrated significant activation (p(FDRcorrected) <0.05) in bilateral pre-frontal cortex (PFC), anterior and posterior cingulate gyri and temporal lobe. Unpleasant pictures relative to neutral condition exhibit significant activation (p(FDRcorrected) <0.05) in amygdala, hippocampus, parahippocampal gyri, temporal lobe, visual cortex, fusiform gyri, PFC and anterior cingulate gyrus. Conclusion: Amygdala is mainly involved in the processing of negative emotions. Although an overlap in regions involved in the processing of pleasant and unpleasant IAPS pictures exists, the neural network for each is unique.