Small postage stamp sized regions of superior aspect of each nasal cavity and upper portion of the nasal septum contain the olfactory epithelium. Within this region, specialized G-protein coupled olfactory receptors bind to inhaled volatile chemicals that have dissolved in the olfactory mucosa. Once odorants are bound to receptors, action potentials are initiated and are transmitted to the brain via the olfactory nerves. Axons project through fenestrations within the cribriform plate of the ethmoid bone and synapse on neurons (mitral and tufted cells) within the olfactory bulb. From here, signals project predominantly through the lateral olfactory tract to the primary olfactory cortex (including the piriform and entorhinal cortices, part of the amygdala and the olfactory tubercule). Collaterals from these axons project to the anterior olfactory nucleus. A minority of fibres project via the medial olfactory tract and cross, via the anterior commissure, to the contralateral olfactory bulb. However, the vast majority of olfactory projections are ipsilateral[10].

The olfactory system is unique among the senses as it projects initially to cortical regions, rather than thalamic nuclei. Thalamic connections occur post-cortically, along with projections from piriform cortex to other limbic regions, such as the hypothalamus and hippocampus. Projections to the orbitofrontal cortex can be either direct from primary olfactory cortex, or indirect via the dorsomedial nucleus of the thalamus[11].

A further differentiating factor that separates the olfactory system from other senses is that the signals from primary sensory receptors to higher processing regions are predominantly sent ispilaterally, rather than having a contralateral representation. This fact allows for the assessment of the relative contribution of each hemisphere to the processing of olfactory stimuli. If stimulus presentation is restricted to one nostril only, the ipsilateral hemisphere will be preferentially (initially) engaged. This anatomic detail has been exploited by some research groups and lateralized findings have been reported[12,13].

Olfactory dysfunction can occur as a result of damage at any level of the olfactory system, from destruction of the olfactory receptors due to exposure to inhaled chemical toxins, to deficits in olfactory detection threshold as a result of olfactory nerve/tract damage during closed head injury, to distinct higher level olfactory deficits (e.g., olfactory agnosia) as a result of lesions to secondary olfactory cortex[14,15].

Between 1%-3% of the population suffers from non-affective psychotic disorders, with schizophrenia being the most common form[16]. These disorders are associated with a diverse range of abnormal mental phenomena, including hallucinations, delusions, unusual thought content, anhedonia, social withdrawal and alterations in cognitive domains such as memory, attention, language and executive function. The typical age of onset of these disorders is relatively early, with most individuals presenting with their first psychotic episode in late adolescence or early adulthood. For many, the course of illness is one of waxing and waning of symptomatology; few make a full recovery after one episode.

The issue of whether olfactory sensitivity (detection threshold/acuity) is impaired in schizophrenia has not yet been resolved, with some studies showing normal acuity[17,18], others impaired[19,20] and still others demonstrating enhanced sensitivity[21,22]. As well, the issue of whether olfactory hedonics are abnormal in patients with psychotic disorders continues to be debated[19,23-27]. There is evidence that pleasantness ratings differ by sex[28,29] and are likely related to symptom presentation[30,31]. More consistent findings have emerged when olfactory discrimination (same as/different) and olfactory memory/familiarity are assessed. Patients with psychotic disorders appear to be impaired on both of these functions[26,32,33]. Odour intensity ratings, however, appear to be intact in patients with psychotic disorders[26].

The most robust difference between patients with psychotic disorders and control subjects has been noted in studies examining olfactory identification ability. In these investigations, consistently abnormal olfactory identification has been shown in psychosis patients[7,9,18,30,34]. Olfactory identification deficits do not appear to be influenced by age of illness onset[17,34], smoking history[17,35], exposure to antipsychotic medications[13,17,32] or cannabis use[7]. Olfactory identification deficits, however, are thought to correlate with measures of verbal memory function[36,37], and negative (but not positive) psychotic symptoms[7,9,34].

Recent research has shown that olfactory compromise may be a marker for poorer outcome. Good et al[8] examined symptomatic outcome in a group of patients who were antipsychotic drug naive at initial olfactory testing. Poorer negative and cognitive symptom outcome was associated with a lower baseline olfactory identification (UPSIT) test score. This same group prospectively followed a group of first episode patients for 4 years[9]. Those with poorer olfactory scores at initial assessment had worse symptom outcome and reduced functional outcome at follow up. Additionally, individuals who are at risk for developing a psychotic disorder (by virtue of having a first degree relative with the disorder and/or showing attenuated psychotic symptoms), having lower olfactory test scores appears to be related to the conversion to a true psychotic disorder[6]. Taken together, these findings suggest that not only may olfactory deficits predict transition to illness, but that subgroups may be identified, early in the course of illness, who may be at risk for a more severe illness course.

That patients with psychotic disorders have olfactory dysfunction is not surprising given the overlap between olfactory processing regions and areas of the brain that have been consistently noted as abnormal in these patients. Abnormalities in medial temporal regions, including the hippocampus, amygdala and parahippocampal gyrus have been observed in patients with psychotic disorders. For a review, see[38,39]. Moreover, orbitofrontal and dorsomedial nucleus of thalamus have also been found to be both structurally and functionally abnormal[40,41]. Left sided abnormalities are more commonly reported[42].

Brain regions that are activated after presentation of odours when subjects are instructed not to sniff or nor consciously process the odorants include areas associated with primary olfactory cortex [piriform cortex (however, see above), amygdala, hippocampus, entorhinal cortex] and secondary olfactory regions (thalamus, orbitofrontal cortex, cingulate and insula)[46-49]. These regions can be thought of as “core” olfactory regions. When olfactory-cognitive load is increased, other ancillary regions are also engaged.

As previously mentioned, the piriform cortex may be activated solely in the presence of active “sniffing” or nasal airflow[43,50]. A more recent positron emission tomography (PET) study, however, did not confirm these results[44].

Odour hedonics: Humans are particularly poor at naming odours de novo (see section below). However, odours can evoke very strong emotional reactions, even without conscious awareness. Consequently, the primary dimension by which humans characterize odorants is according to the odour’s pleasantness, and particularly when odorants are difficult to name[51]. Researchers have capitalized on this aspect of olfactory processing in imaging studies; but unfortunately, mixed findings have resulted. The data is clear on one point: pleasant and unpleasant odorants invoke activation in similar neural networks, (primary and secondary cortices). However, intensities and degree of engagement may differ and some unique brain regions may also be invoked[52], particularly for unpleasant/aversive odorants. Both pleasant and unpleasant odorants activate the bilateral piriform/amygdala[45,53,54] but see also[55], right[49] and bilateral insula[45,56], and orbitofrontal cortex[49,53,54,57,58]. Most contrasts between pleasant (P) and unpleasant (UP) odorants have shown a greater degree of activation in the UP-P subtraction, rather than the other way around (P-UP). To this end, aversive or unpleasant odorants appear to further engage orbitofrontal cortex[54] - but only when subjects are engaged in a hedonic estimation task, and the activation seems to be concentrated in the lateral aspect rather than medial subdivisions[58]. Moreover, the left insula[45,52], but see also[56] who showed insular activity predominantly during pleasant odour stimulation), the anterior cingulate[45,52,58], brainstem/hypothalamus[52], and piriform/amygdala[45] activation has been noted after unpleasant odor presentation over and above that demonstrated during pleasant odorant stimulation.

Odour familiarity: Determining whether an odour is familiar requires an implicit set of memory processes; the perceptual input needs to be compared with semantic odour associations[59]. The smeller must recollect prior exposure without the exact autobiographical context and also without naming. Only few studies have examined this aspect of olfactory processing. In 1999, Royet et al[60] examined, among other aspects of olfactory processing, odour familiarity in healthy subjects. In this study, they demonstrated right orbitofrontal cortex activation during odour familiarity ratings, suggesting a lateralization of secondary olfactory cortical function. In a later study by this same group, Royet et al[57] noted a larger network of olfactory brain regions associated with odour familiarity. Bilateral orbitofrontal cortex (OFC), anterior cingulate along with left superior and right middle frontal gyri were all active during a PET scan during which an odour familiarity task was compared to control activation (presentation of odorless air). When compared with odour detection, left superior and left inferior frontal gyri engagement was noted, suggesting a hierarchical process, with odour familiarity ratings at higher levels of processing. This group suggested that the lateral frontal activation may represent accessing stored representations.

Odour intensity: A further dimension of odour processing is that of rating odour intensity. Odour pleasantness ratings change as a function of an odour’s perceived intensity. For example, the rose-like odorant (phenyl ethanol) tends to be perceived as pleasant at lower concentrations, but less pleasant at higher concentrations[61]. In many studies assessing olfactory hedonics, the intensity of presented odorants was not controlled. In order to dissociate intensity and valence, Anderson et al[54] focused on the amygdala and the orbitofrontal cortex. The amygdala has been reliably shown to activate during presentation of aversive stimuli[62]. The orbitofrontal cortex, as mentioned previously, appears to be invoked in higher order processing of olfactory stimuli. By presenting two different odorants at two different concentrations (high intensity-unpleasant, high intensity-pleasant, low intensity-unpleasant, low intensity-pleasant), Anderson et al[54] noted that that the orbitofrontal cortex engaged in relation to the valence of the odorant while the amygdala was preferentially engaged according to the intensity of the odorant. No ratings were performed during the scan; rather, subjects were only instructed to “sniff” for the duration of a presented message and respond if an odour was detected. A more recent study lent some further explanation to this unexpected finding. Winston et al[63] replicated the Anderson et al[54] study, but included both high- and low-intensity neutral odours for comparison. In this study, the amygdala was engaged predominantly with both the pleasant and unpleasant high-intensity odors, but not the high intensity neutral odour (nor any of the low intensity odours either). A more parsimonious explanation was suggested by these researchers in that the amygdala is engaged when odours are encountered that may be relevant for survival. High intensity pleasant or unpleasant odours are more likely to be behaviorally salient than are neutral odours (or low intensity odours along the hedonic spectrum).

Olfactory identification: Odor naming, particularly when potential exemplars are not provided, is a difficult task for humans[64,65]. By providing a multiple-choice format, such as the University of Pennsylvania Smell Identification Test (UPSIT), performance is improved significantly[61].

In a recent study, Kjelvik et al[47] examined whether there were any differences in activation patterns when individuals were successful in naming odorants vs when they incorrectly named the odours. Odorants were presented to subjects (only women) during an FMRI scan. Post scanning, subjects were presented with these same odours and were instructed to spontaneously name them (no exemplars provided). Brain activation patterns differed between correctly identified odours vs those not correctly identified in left entorhinal cortex, bilateral temporal poles, orbitofrontal cortex (right moreso than left), right thalamus and left insula. Other, non-olfactory areas (e.g., putamen, primary visual and auditory cortices, premotor cortex, SII and cerebellum, inferior frontal, and fusiform area) were also activated more during identified vs non-identified odours. When specifically examining the medial temporal regions, left entorhinal cortex, and bilateral posterior parahippocampal gyri were engaged. The data suggested that the entorhinal cortex and the hippocampus are more attuned to identifying odours.

Sex differences: Many of the studies mentioned above (e.g.,[47,55]) examined only female subjects as women reliably outperform men on olfactory detection, memory and identification tasks[66-68]. Three different research groups have examined whether this female olfactory superiority translates into enhanced brain activity. In an early FMRI study, Yousem et al[69] noted that female brains had significantly more active voxels in the perisylvian and inferior frontal regions during odour presentation. Levy et al[53], using a ratio of pixel activated to the number of pixels in a region, also showed sex differences; However, their findings were in the opposite direction (males > females). In contrast, Bengtsson et al[70] were unable to detect any male/female differences in brain activation during passive perception of odours. This group suggested that males and females engage similar networks during low level processing of olfactory stimuli. However, due to methodological inconsistencies, the intensity of activation was not examined in this PET study, making comparisons with other papers data difficult. In contrast, Royet et al[45] found that women activated the left orbitofrontal cortex over and above what was noted in male brains. The differences again may prove to be related to methodological differences, or rather due to the processing demands placed on the subjects during olfactory scanning (for part of the study, subjects in the Royet et al[45], study were asked to make an hedonic judgment regarding the odours presented while Bengtsson et al[70] were examining olfactory processing during passive administration). Nevertheless, these data taken as a whole, suggest that sex differences should be taken into account when examining olfactory brain activations.

As the ability to perceive odours deteriorates with age, do functional alterations in brain regions associated with the sense of smell also accompany these changes A study published by Wang et al[71] noted that there were significant differences in the processing of olfactory stimuli when comparing young and older subjects. Although for both groups, the same regions were activated by odorants, lower cluster volumes and intensities were noted in the aged group when compared to the younger group. This finding suggests that age should be taken into consideration when examining neural activation to olfactory stimuli (Table 2).

Odour activation patterns are similar between patients with psychotic disorders and control subjects during passive odour administration[25]. However, there are some differences regarding the intensity or cluster volume in these regions between patients and control subjects. Plailly et al[25] examined olfactory detection (passive odour administration), hedonics and familiarity using PET. A moderately sized sample of patients with schizophrenia and healthy controls were presented with odours during the scan and were instructed to press a button when they detected an odour (for the detection condition), if the odour was pleasant (for the hedonic condition) and if it was familiar (for the familiarity condition). For the detection condition, this group noted that the piriform cortex and the orbitofrontal cortex (inferior frontal) were activated in both groups. However, small clusters remained in these two regions when a subtraction analysis (HC-SZ) was performed. So, although both primary and secondary cortices were activated in both groups, patients with psychotic disorders appeared to show less robust activity in these two regions. Our group has recently examined passive odour administration in a group of patients with non-affective psychosis (Good et al, under review). We noted that patients and controls had similar activation patterns in amygdala, OFC and left thalamus, but the subtraction analysis (HC-SZ) showed slightly greater activation in OFC and left thalamus. In contrast, controls, but not patients, activated right thalamus, caudate (bilateral), cingulate, middle temporal gyrus and frontal pole (Figure 1).

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Figure 1 Neural activation for passive smelling in controls-patients. For both locations (thalamus and right orbitofrontal), controls showed significant activation relative to psychosis patients that was unrelated to sex. A: Thalamus; B: Right orbitofrontal. From Good et al (under review).

In contrast to passive odour administration, other aspects of olfactory processing appear to engage different brain regions between patients and control subjects. As previously mentioned, rating the pleasantness of odorants is an automatic process and may have survival significance, particularly if the odour is intense. As described above, in patients with psychotic disorders, their ability to rate odour pleasantness may be abnormal. In imaging studies, significant patient/control differences have emerged and show some contrasting findings. For instance, in the PET study published by Crespo-Facorro et al[72], patients were impaired on rating the pleasantness of pleasant odours, but no differences were noted between patients and control in neural processing of these same odours. In contrast, patients did not differ from control subjects on ratings of unpleasant odours; however, neural activation did differ. Control subjects engaged the left anterior insula, left parahippocampal gyrus, left superior temporal gyrus, lingual gyrus (bilateral) and left cerebellar vermis along with right accumbens when contrasted with unpleasant vs pleasant odorants, while patients did not. Interestingly, patients demonstrated higher metabolic rates in other brain regions relative to the controls, suggesting that patients invoked compensatory structures during processing. These regions included a number of right hemisphere regions (dorsolateral, lateral and parahippocampal gyrus) and left hemisphere activations (dorsolateral, medial and lateral frontal along with posterior cingulate). In a more recent PET study[25], where both positively and negatively valenced odorants were compared together, greater regional cerebral blood flow (rCBF) was noted in the left insula and left inferior orbitofrontal regions in control subjects relative to patients (Figure 2).

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Figure 2 Figure showing difference between hedonic processing and baseline (air) for patients with psychotic disorders and control subjects. Differences in activation were noted between patients and control subjects in anterior insula and inferior frontal gyrus. Controls had enhanced activation in both sites for the hedonicity condition (relative to baseline) while for the anterior insula, patients showed no increase and for inferior frontal regions patients saw a statistically significant decrease in regional cerebral blood flow (H-B). Reprinted with permission from Plailly et al[25]. ^aP < 0.05, ^bP < 0.001.

In an FMRI study, hypoactivity of right middle temporal and right middle frontal (BA 46) cortices in patients with psychotic disorders relative to controls during the presentation of a negatively valenced odorant; a relative hyperactivity was also seen in the middle frontal gyrus (in BA 9) and right anterior cingulate in patients. During presentation with a pleasant odorant, left thalamic hypoactivation was noted in patients relative to controls. In the presentation of both types of odorants, insular hypoactivation just missed statistical significance. Unfortunately, unpleasant and pleasant odours were never compared to each other in this study[27].

Taken together, despite different methodology and analytic techniques, the data presented suggest that dysfunction in secondary olfactory cortices and perhaps the insula may account for the olfactory hedonics dysfunction in patients with psychotic disorders. As no group noted differences in amygdala and piriform cortex activations suggest that primary olfactory cortices may be normally activated in these patients.

The neural underpinnings of processing odour intensity have not been contrasted between patients and control subjects. But as mentioned previously, no differences between these two groups have been noted on odour intensity ratings. Nevertheless, future research should examine this dimension of olfactory processing.

Determining whether an odorant has been experienced before appears to further engage frontal brain regions (see above). When patients with psychotic disorders were compared with control subjects on a familiarity task, hypoactivity of piriform cortex, orbitofrontal and superior temporal gyrus (all on the left) was observed[25]. This study also noted that patients rated odours as less familiar than did healthy controls. It was suggested that impaired familiarity ratings may be accounted for by temporolimbic/orbitofrontal dysfunction.

The neural underpinnings of olfactory identification have not been adequately examined in patients with psychotic disorders, despite the fact that olfactory identification deficits are the most robust finding in this patient group. Malaspina et al[33] were the first to examine olfactory identification using SPECT. In this study, a small sample of patients with psychotic disorders and controls were scanned while engaging in a forced-choice odour identification test and a comparator picture matching test. Differences in rCBF between the two tasks included hypometabolism in patients in inferior frontal, superior temporal and supramarginal/angular gyri (on the right). Controls, but not patients engaged right fusiform gyrus and bilateral hippocampi during the odour activation task relative to the control task. The right-sided deficits are consistent with lesion data showing more severe deficits in odour identification after rights than left sided lesions. However, the data is not entirely consistent with the majority of neuropathological studies of schizophrenia showing a predominance of left sided structural abnormalities. Moreover, there was no examination of the differences in odour activation according to the correctness of identification of the odorants.

As it appears that only a proportion of patients demonstrate abnormalities on olfactory identification testing, dividing the groups of patients into those who are impaired vs those who have normal olfactory function, may have merit. Clark et al[73] examined glucose metabolism in three groups of subjects: a group of patients with olfactory agnosia (impaired olfactory identification ability and normal olfactory detection), a group of patients with normal sense of smell (normosmic) and healthy controls (age matched). PET scanning occurred in the absence of any olfactory stimulation (resting state). In all brain regions, the agnosia patient group had the lowest metabolic rates compared to the other two groups, followed by the normosmic patients and then controls. Controls had higher rCBF than both patient groups in bilateral frontal and parietal regions. The two patient groups differed from each other on right thalamus and basal ganglia metabolism (olfactory agnosia group lower than normal olfactory group). The results of this study are consistent with earlier reports of structural and functional abnormalities in thalamic and basal ganglia. As no olfactory task was presented, these data suggest an underlying hypofunction in regions of the brain that subserve olfactory processing, rather than a processing abnormality. Nevertheless, the heterogeneity of schizophrenia should be taken into account, or at least acknowledged, when examining the neural underpinnings of olfactory function in patients with psychotic disorders. Further investigation is required.

Not only do patients with psychotic disorders exhibit abnormalities in olfactory processing, but their unaffected first-degree relatives also demonstrate mildly abnormal brain activation patterns when contrasted to non-related controls[27]. When presented with an unpleasant odour, patients’ unaffected brothers demonstrated reduced frontal activation (relative to the healthy control group) and increased activation in anterior cingulate, but during the presentation of a pleasant odorant, no differences were noted. This group suggested that hypofrontality may be a genetic trait that is expressed to a lesser degree in the non-affected brothers.

Despite age being considered an important factor to consider in olfactory neuroimaging research[71], to date, no studies have examined the difference in olfactory neural processing between young and older patients with psychotic disorders. In all studies presented in this literature review, the age of the patients and that of control subject have been well matched and also relatively young (Mean ages < 35 years). Further research may be informative in this regard.