REVIEW Olfactory Dysfunction in Schizophrenia: A Review of Neuroanatomy and Psychophysiological Measurements An D. Nguyen, MD, Martha E. Shenton, PhD, and James J. Levitt, MD Olfactory processing is thought to be mediated via the frontal and temporolimbic brain regions, both of which, as well as olfactory dysfunction, are implicated in schizophrenia. Likewise, several empiri- cal studies of olfactory dysfunction—in particular, olfactory deficits in identification, odor detection threshold sensitivity, and odor memory, along with associated brain structural changes—have been conducted to illuminate the pathophysiology of schizophrenia. These anomalies have been investi- gated, more recently, as possible biological markers of that disabling illness. This article summarizes recent research on neuroimaging changes associated with olfactory impairments in schizophrenia patients and on related functional changes in psychophysiological measurements (e.g., odor iden- tification, odor discrimination, odor detection threshold, and odor memory). The possible role of these changes as biological markers of the disorder will be discussed, as will potentially productive directions for future research. (HARV REV PSYCHIATRY 2010;18:279–292.) Keywords: MRI, neuroimaging, olfaction, olfactory function, schizophrenia Schizophrenia is a severe and disabling brain disorder that is associated with social withdrawal, problems with attention, difficulties making decisions, and perceptual dis- From Harvard Medical School; VA Boston Healthcare System, Brockton, MA; and Neuroimaging Laboratory, Department of Psy- chiatry, Brigham and Women’s Hospital, Boston, MA. Supported, in part, by VA Merit Awards (Drs. Levitt and Shenton) and grants from the VA Schizophrenia Center, National Institute of Mental Health (K05: no. MH 070047, and R01: no. MH 50740), and National Institutes of Health Mental Health Center for Clinical Interventional Development and Applied Research (P50: no. MH 080272) (Dr. Shenton). Original manuscript received 29 May 2009; revised manuscript re- ceived 15 January 2010, accepted for publication 18 February 2010. Correspondence: James J. Levitt, MD, VA Boston Healthcare System, Brockton Campus, 116A4, 940 Belmont St., Brockton, MA 02301. Email: james levitt@hms.harvard.edu  c 2010 President and Fellows of Harvard College DOI: 10.3109/10673229.2010.511060 turbances. Olfactory disturbances in the identification, dis- crimination, memory, and detection of odors are all associ- ated with male patients diagnosed with schizophrenia. 1−4 Of interest, brain abnormalities in schizophrenia and olfactory processing involve overlapping neuroanatomic structures. Thus, it is not surprising that olfactory function has been shown to be abnormal in schizophrenia. 5−9 For example, pri- mary olfactory cortex (located in the medial temporal lobe) and the olfactory association cortex (located in limbic struc- tures such as parts of the amygdala, the hippocampus, and the orbitofrontal cortex) are neural structures that have all been found to be abnormal in schizophrenia. 10 Given that such olfactory abnormalities are found in schizophrenia, it suggests that schizophrenia patients with more severe deficits in olfaction may have more severe abnormalities in these specific brain regions. Furthermore, it has been suggested that poor olfactory function may predict a more severe form of schizophrenia with lower IQ, more negative symptoms, and a deficit syndrome. 11,12 Moreover, olfactory function is a useful feature to examine in schizophrenia as it may represent more of a trait than a state symptom. For example, psychometric research has shown that olfac- tory deficits in odor identification are not associated with medication use, smoking, olfactory hallucinations, or 279