This chapter provides an overview of the anatomy of the primary olfactory system, the olfactory mucosa and olfactory bulb. A notable feature of olfactory bulb anatomy is the convergence of feedback from higher centres whose axons project onto the interneurons at the granule and periglomerular levels. The chapter shows how the chemical properties of odorant molecules are encoded into neural activity. It covers the consequences of this neural activity and how it defines the regions of the human brain involved in olfactory perception. The olfactory system is characterised by relatively direct connections to brain structures implicated in memory and emotion such as the hippocampus, thalamus, and frontal cortex. With the development of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), it is possible to reveal large-scale activation patterns associated with particular cognitive processes, allowing the identification of the neural networks specifically activated by chemosensory stimuli.

This chapter illustrates how information from functional neuroimaging complements and extends the knowledge one has gained about olfaction from studying disorders of the temporal lobes. Such integration of approaches and findings promises to broaden the understanding of the 'Olfactory brain'. Olfactory functioning has been studied in various patient groups whose lesions involved the temporal lobes. Temporal lobe epilepsy (TLE) has been one of the commonly used models for the study of this relationship, because the olfactory system comprises some of the structures that are a frequent source of epileptogenic activity. Two studies showed a change in the functional neuroanatomy of the olfactory response over time. A unique feature of the olfactory system is that perception itself involves limbic structures, including the amygdala. Odour-induced activations have been reported less often in the entorhinal cortex than in the piriform cortex or the amygdala.

Disgust has a characteristic facial expression which is recognised across all cultures. Functional neuroimaging studies have provided an evidence for the role of the insula and the basal ganglia in the identification of facial expressions of disgust. This chapter discusses the involvement of the insula in the perception of disgust and in the processing of smells. It explores the insula, its connections, and its functions in more detail. Insula activation has been demonstrated in human neuroimaging studies in response to both odours and tastes. The insula is ideally located to integrate information from different sensory modalities and from the autonomic system, and could therefore be involved in both the perception of disgust from various sensory modalities and the subjective experience of disgust. The chapter focuses on two psychiatric disorders which have been linked to both abnormal processing of disgust and to olfactory deficits: obsessive-compulsive disorder (OCD) and schizophrenia.

This chapter analyzes the nature of olfactory memory in an attempt to understand its uniqueness and richness. It summarises neurobiological underpinnings of olfactory memory before discussing specific issues pertaining to components of the olfactory memory system. The chapter also presents a discussion of the nature of olfactory memory encoding and retrieval in relation to semantic processes and an assessment of the relationship between emotion and olfactory memories. The memory studies probe explicit memory for odours. However, olfaction plays an important role in the implicit and unconscious component of memory. The olfactory memory system may rely upon cross-modal integration, and incongruent cues could attenuate olfactory memory retrieval. Olfactory perceptual qualities, such as hedonics and familiarity, are autonomic in nature and influence olfactory stimulus encoding. The context in which olfactory stimuli are encoded is likely to influence olfactory memory retrieval.

This chapter outlines a programme of research that examined olfactory neuroepithelium in schizophrenia as an example of the heuristic value of this research. The neurodevelopmental hypothesis of schizophrenia proposes that genetic and epigenetic factors alter early brain development, leaving the affected individual at increased risk of developing schizophrenia. The favoured model for neurodevelopment is the adult olfactory epithelium, which provides access to developing neural tissue in living patients. The olfactory neuroepithelium is capable of regeneration and there is a continual renewal of the sensory neuron. Properties of olfactory neuroepithelium cultures of individuals with psychotic disorders may have heuristic value with respect to unravelling functions related to both early brain development and even with respect to current brain function, given the continuing neurogenesis now known to occur in adult brain. In schizophrenia, olfactory epithelium has also been exploited to reveal evidence in support of neurodevelopmental aetiology for this disorder.

This chapter reviews the limited available data about the maturation of olfactory function in the context of the emergence of disorders of neurodevelopment. It explores how the neurobiology of each of the disorders may lead to the observed deficits in olfactory abilities. The chapter discusses the relationship between olfactory memory and limbic/emotional processes. Understanding the normal maturation of olfactory abilities is relevant to understanding the nature and timing of the disturbances in neuropsychiatric disorders. The chapter also discusses the implications of these principles to disorders of childhood and adolescence. The nature and degree of deficit may also be informative about the nature of any proposed neural compromise. To date, the available studies to inform these hypotheses are limited and further work should focus on longitudinal studies of olfactory abilities from childhood to adulthood in individuals at high risk for various disorders of neurodevelopment.

This chapter shows how olfactory testing could be applied to investigations of orbitofrontal cortex (OFC) function and related behavioural outcomes. It discusses how tasks such as olfactory identification may offer insights into the development and maintenance of substance use disorders (SUD). Although imaging and neuropsychological studies demonstrate abnormalities in OFC function within addicted populations, it is unclear whether these deficits are related to premorbid vulnerability, a direct consequence of chronic exposure to addictive substances, or a combination of both. In humans, there is growing evidence that an earlier onset age of substance abuse may be related to more marked neurobiological and cognitive deficits. Adolescence is a developmental period associated with increased risk-taking and experimentation with drugs, and is also a time of increased vulnerability to the development of SUD. Experimentation with drugs also occurs during a period of substantial brain development and remodelling.

This chapter examines the evidence of olfactory regression over the course of primate evolution with the aim of understanding the human sense of smell in an evolutionary context. It discusses the evolutionary morphology of primate olfaction, including the taxonomic variability of the main and accessory olfactory systems. Mammals possess a number of paranasal sinuses, which emanate from the nasal fossae and excavate the surrounding cranial bones. Sinus development occurs in two stages: primary and secondary pneumatisation. Major evolutionary modifications of the nasal fossae differentiate haplorhines from strepsirrhines and all other mammals. Human olfactory mucosa is typically described as limited to the posterosuperior nasal fossae, covering part of the superior nasal concha and the facing wall of the septum. Based on comparisons of the relative size of olfactory structures, some authors have assigned mammals to different categories of olfactory ability. These categories include highly acute (macrosmatic), diminished (microsmatic) or absent (anosmatic).

This chapter examines the evidence from family or genetic high-risk studies in schizophrenia, an example of a highly heritable, complex neuropsychiatric disorder for which the aetiology and pathophysiology remain elusive. It discusses a rationale for using family/genetic high-risk studies and the concept of endophenotypes. Emphasising applications in schizophrenia research, Gottesman and Gould provide compelling evidence to suggest that further study and identification of endophenotypes hold tremendous promise for clarifying the aetiology and pathophysiology of schizophrenia, and improving its treatment. In addition to the endophenotypes, measurement of olfactory functioning is independent of diagnosis and hence provides a feasible approach, both practically and economically, for assessing abnormal brain function and genetic vulnerability to schizophrenia. Continued investigations of the olfactory system and related abnormalities, and particularly its role as an endophenotype, may aid in unravelling the mysteries of the molecular and genetic underpinnings of schizophrenia and other complex neuropsychiatric diseases.

This chapter reviews the literature on sex differences in olfactory ability and describes the current state of knowledge on this subject. Sex differences in olfactory function have been observed on virtually all olfactory measures examined. These include detection threshold, sensitivity, discrimination, identification, naming, memory and hedonics. The chapter outlines methodological shortcomings in published reports, and offers some hypotheses in order to explain the male/female difference in olfactory function. The consistent behavioural differences between males and females on olfactory psychophysical testing support the argument that it is imperative that 'sex' be taken into account when designing olfactory neuroimaging studies. There is a widely held belief that women are differentially sensitive to odours over the course of the menstrual cycle. The effects of sex on odour processing are not limited to sexually relevant odours, as is evidenced by sex differences in odour detection threshold for sexually irrelevant odorants.

This chapter traces the evolution of chemical communication in animals and considers how mammals, and humans in particular, use odours in their daily activities. Comparative anatomy provides a record of how evolutionary processes have moulded tissues and organs, just as the Antarctic ice core provides a clear record of past climates, or mitochondrial DNA records the evolutionary past of a species. The science of comparative anatomy of animals teaches important facts about the common origin of the olfactory system and the anterior part of the pituitary. The chapter examines the pheromones, the chemical messengers that pass between individuals much as hormones pass messages within the individual's body. It outlines some parallels between the nose and the immune system, since both systems function to discriminate between the internal and external milieus of an organism. Finally, the chapter describes the controversial vomeronasal system, which is the secondary olfactory system.

This chapter relates the neurobiology of olfactory processing to social functioning in humans, with a focus on schizophrenia to highlight the understanding of compromise of these processes. Olfaction may be a sensory modality that evolved early in order to process social information. This sensory modality is comprised of two intricately interwoven olfactory systems in mammals, the accessory and main olfactory systems. Both olfactory systems may also be relevant to social affiliation and reproduction, including through pheromones. Olfactory regions and the hypothalamus are central to the circuitry of human emotions. Motivated behaviour is intertwined with olfactory processing through overlap in neural circuitry, including the limbic system, temporal and frontal lobes, and thalamus. Motivational aspects of odours arise from the hypothalamus, deriving from input from the amygdala and midbrain. Odour identification deficits are robustly described in schizophrenia. Social deficits represent a significant component of disease expression in schizophrenia.

Although some patients initially present with a frank complaint of a smell disturbance, others are unaware of their dysfunction or are extremely inaccurate in assessing its magnitude, pointing to the need for routine quantitative olfactory assessment. Olfactory threshold measures have been the most common means for assessing smell function quantitatively. Unlike threshold tests, suprathreshold tests employ clearly discernible stimuli. Among such tests are those of odour identification, recognition, discrimination, memory and attribute scaling; the latter employs, for example, rating scales and magnitude estimation procedures. In the case of olfactory threshold measures, tests based upon forced-choice procedures are more reliable than those based upon non-forced-choice procedures. As with educational and psychological tests, the reliability of an olfactory threshold test is generally a function of test length, with greater reliability occurring the more frequently the threshold region is sampled.

This chapter describes the functional neuroanatomical components of olfaction, and summarises the findings in various neurological and psychiatric disorders. The functional significance of the components of the olfactory cortex have been determined from experiments in animals, human lesion studies neurological disorders and, more recently from work using newer brain imaging techniques, such as positron emission tomography (PET), and both structural and functional magnetic resonance imaging (fMRI). Independence of function of olfactory abilities has been suggested by studies in neurological patients with lesions in various parts of the olfactory system. Deficits in olfactory identification are often associated with lack of awareness of olfactory dysfunction, and are related to injury severity. Examination of olfactory disturbances may provide early markers of impending neurological or psychiatric illness and, in some disorders including Alzheimer's Disease (AD), attention deficit hyperactivity disorder (ADHD) and schizophrenia, may be trait markers of the condition.

The olfactory system is damaged to varying degree in the presence of clinically evident Parkinsonism. This chapter focuses on idiopathic Parkinson's disease (IPD) and familial Parkinsonism, as well as the known variants, Guam PD-dementia complex; Lewy body disease (LBD); multiple system atrophy (MSA), progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD), drug induced PD (DIPD), vascular Parkinsonism (VP) and X-linked dystonia-Parkinsonism ('Lubag'). Patients with IPD have a profound disorder of olfactory function. This observation is based on pathological abnormality, psychophysical tests and evoked potential studies. Normal olfaction would favour essential tremor with the proviso that females with tremor-dominant IPD might also have a normal result. Degenerative syndromes with smell impairment may be split into two major categories that is, IPD, LBD, MSA where there is disorder of α-synuclein (alpha-synucleinopathy) and those with more normal olfaction that is, Alzheimer's disease, CBD and PSP where there is disorder of tau protein (tauopathy).

Neuropsychological, structural and functional imaging studies have broken new ground in demonstrating the existence of physiological and anatomical abnormalities in the olfactory system in schizophrenia. Since the pioneering psychophysical studies of odour recognition memory in patients with schizophrenia by Australian researchers Campbell and Gregson, a number of investigators have reported that schizophrenia patients exhibit olfactory dysfunction. In a 10-year longitudinal study, the presence of deviant olfactory experiences was found to significantly predict the development of future psychosis. The causes of olfactory impairments are numerous, including chemical, infectious, traumatic, metabolic and hormonal disturbances. Recent years have brought rapid expansion of structural and functional imaging technologies, including high-resolution structural magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission tomography (SPECT) and event-related potential (ERP). To characterise more directly the functional status of the olfactory system, ERPs have been employed to assess the physiological brain response to odour stimuli.

This chapter reviews the literature on olfactory hallucinations and discerns any characteristics of olfactory hallucinations which allow those of organic aetiology to be distinguished from those of functional origin, such as those related to schizophrenia. Olfactory hallucinations/auras are rare in patients with epilepsy but may be more common when the epilepsy type is restricted to temporal lobe epilepsy (TLE). The prevalence of olfactory hallucinations in psychiatric populations has varied widely. Olfactory hallucinations have been described in patients with differing diagnoses including schizophrenia, affective disorders, eating disorders and hysteria. Olfactory hallucinations are observed in patients with schizophrenia but usually in combination with the other symptoms of schizophrenia and with hallucinations in other modalities. There are no clear-cut qualitative differences between the olfactory hallucinations described by patients with schizophrenia compared to patients with 'organic states', though the presence of continuous olfactory hallucinations is more suggestive of a psychiatric diagnosis.

The olfactory reference syndrome (ORS) is an under-recognised type of delusional disorder that has been described for more than a century. This chapter discusses ORS's history, clinical features, prevalence, treatment response, possible pathogenesis, nosological status and relationship to other psychiatric disorders, including mood disorders, schizophrenia, social phobia, and obsessive compulsive disorder (OCD). ORS can be associated with significant academic, occupational and most frequently social impairment. Impairment has been noted to result from the large amount of time spent thinking about the odour and engaging in behaviours aimed at diminishing the smell. The distress caused by ORS has been reported to lead to psychiatric hospitalisation, depression, suicidal ideation, suicide attempts and completed suicide. Most reports on medications for ORS focus on antipsychotics or antidepressants. A range of psychological approaches have been adopted in treating ORS, including individual psychotherapy, analytic psychotherapy, relaxation, paradoxical intention and behavioural therapy, such as exposure.