Scents and nonsense: olfactory dysfunction in schizophrenia

Abstract

Among the sensory modalities, olfaction is most closely associated with the frontal and temporal brain regions that are implicated in schizophrenia and most intimately related to the affective and mnemonic functions that these regions subserve. Olfactory probes may therefore be ideal tools through which to assess the structural and functional integrity of the neural substrates that underlie disease-related cognitive and emotional disturbances. Perhaps more importantly, to the extent that early sensory afferents are also disrupted in schizophrenia, the olfactory system-owing to its strategic anatomic location-may be especially vulnerable to such disruption. Olfactory dysfunction may therefore be a sensitive indicator of schizophrenia pathology and may even serve as an "early warning" sign of disease vulnerability or onset. In this article, we review the evidence supporting a primary olfactory sensory disturbance in schizophrenia. Convergent data indicate that structural and functional abnormalities extend from the cortex to the most peripheral elements of the olfactory system. These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression. With the opportunity to obtain olfactory neural tissue from live patients through nasal epithelial biopsy, the peripheral olfactory system offers a uniquely accessible window through which the pathophysiological antecedents and sequelae of schizophrenia may be observed. This could help to clarify underlying brain mechanisms and facilitate identification of clinically relevant biomarkers.

Fig. 1.

Left: Primary olfactory receptor neurons originate in the superior nasal cavity and project axons through the cribriform plate into the cranium, where they terminate in the overlying olfactory bulb (Patrick J. Lynch, medical illustrator; C. Carl Jaffe, MD, cardiologist. http://creativecommons.org/licenses/by/2.5/). Right: Ventral surface of the brain, showing the olfactory bulbs (arrows) and olfactory tracts projecting to the ipsilateral medial temporal lobe.

Fig. 2.

Performance on the University of Pennsylvania Smell Identification Test. Both patients and unaffected first-degree relatives have significant bilateral impairments.

Fig. 3.

Left: High-resolution sagittal MRI scan of the olfactory bulb (arrows). Right: Mean bulb volumes for patients, unaffected family members, and control subjects. Asterisks indicate significant volume reductions relative to controls (adapted from Turetsky et al76).

Fig. 4.

Left: Coronal MRI scan indicating the olfactory bulbs (arrows) and the overlying olfactory sulci (white lines), through which the olfactory tracts project to the ventromedial temporal lobe. Right: Mean sulcal depth measurements for patients, controls, and family members, indicating bilateral depth reductions in patients.

Fig. 5.

Top: Experimental setup for recording olfactory evoked potentials, illustrating the olfactometer (left) and hose used for odor delivery (right). Bottom: Biphasic olfactory chemosensory evoked potential elicited by an odorant. Amplitude of patient response is significantly reduced.

Fig. 6.

Left: Experimental setup for recording electro-olfactogram (EOG). Wire recording electrode is inserted into the nasal cavity and held in position on the epithelial surface by an adjustable clip mechanism attached to a pair of glasses strapped to the head (reproduced from Turetsky et al99). Right: EOG response to a 100 ms odor pulse. Olfactory receptor neuron depolarization is significantly larger in patients.

Fig. 7.

Ligand stimulation of dopamine receptors activates signaling pathways in human olfactory epithelial cultures. Cells were preincubated with either sch23390 (D1 receptor antagonist) or sulpiride (D2 receptor antagonist), followed by stimulation with 1 μM dopamine. Isoform specific activation of G-proteins was assessed for Gαs/olf, Gαi, Gαo, and Gαq/11. Asterisks indicate significant effects of dopamine antagonists (adapted from Borgmann-Winter et al116).