scents and nosense

7/30/2019 Scents and Nosense

1/15

Scents and Nonsense: Olfactory Dysfunction in Schizophrenia

Bruce I. Turetsky1,2, Chang-Gyu Hahn2, Karin Borgmann-Winter2,3, and Paul J. Moberg2

2Department of Psychiatry, 10th Floor, Gates Building, Universityof Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104;3Department of Psychiatry, Childrens Hospital of Philadelphia,Philadelphia, PA

Among the sensory modalities, olfaction is most closelyassociated with the frontal and temporal brain regionsthat are implicated in schizophrenia and most intimately

related to the affective and mnemonic functions thatthese regions subserve. Olfactory probes may thereforebe ideal tools through which to assess the structuraland functional integrity of the neural substrates that un-derlie disease-related cognitive and emotional disturban-ces. Perhaps more importantly, to the extent that earlysensory afferents are also disrupted in schizophrenia,the olfactory systemowing to its strategic anatomiclocationmay be especially vulnerable to such disruption.Olfactory dysfunction may therefore be a sensitive indica-tor of schizophrenia pathology and may even serve asan early warning sign of disease vulnerability or onset.In this article, we review the evidence supporting a primaryolfactory sensory disturbance in schizophrenia. Conver-gent data indicate that structural and functional abnor-malities extend from the cortex to the most peripheralelements of the olfactory system. These reflect, in part,a genetically mediated neurodevelopmental etiology.Gross structural and functional anomalies are mirroredby cellular and molecular abnormalities that suggestdecreased or faulty innervation and/or dysregulation ofintracellular signaling. A unifying mechanistic hypoth-esis may be the epigenetic regulation of gene expression.With the opportunity to obtain olfactory neural tissuefrom live patients through nasal epithelial biopsy, the

peripheral olfactory system offers a uniquely accessiblewindow through which the pathophysiological ante-cedents and sequelae of schizophrenia may be observed.This could help to clarify underlying brain mecha-nisms and facilitate identification of clinically relevantbiomarkers.

Key words: neurodevelopment/genetics/biomarkers/evoked potentials/olfactory receptor neurons/olfactorybulb

Introduction

Neuropsychological and neuroimaging studies offer con-vergent evidencethat schizophrenia patients haveselectiveimpairments in the functional domains of memory, atten-tion, executive planning, and affect regulation1,2 and have

neuroanatomical and physiological abnormalities in thetemporolimbic andfrontal lobe regions that underlie thesebehavioral domains.3 Among the sensory modalities, ol-faction is most closely associated withtheseneuroanatom-ical regions andmost intimatelyrelated to theaffectiveandmnemonic functions that they subserve. Olfactory probesmay therefore be ideal tools through which to assess thestructural and functional integrity of the neural substratesunderlyingdisease-relatedcognitive and emotional distur-bances.46 Perhaps more importantly, to the extent thatearly sensory afferents are disrupted in schizophrenia,the olfactory systemowing to its strategic anatomic

locationmaybeespeciallyvulnerabletosuchdisruption.As such, olfactorydysfunction maybe a sensitive indicatorof schizophrenia pathology and, perhaps, may even serveasanearlywarningsignofdiseasevulnerabilityoronset.In thisarticle,we reviewthe evidence supportinga primaryolfactory sensory disturbance in schizophrenia, with par-ticular emphases on (1) the specific neuroanatomicalsubstrates that may be involved, (2) the likely neurodeve-lopmental etiology of this disturbance, and (3) the cellularand molecular mechanisms that may be implicated.This growing body of evidence, along with the uniqueopportunity to obtain olfactory neural tissue from livepatients through nasal epithelial biopsy, suggests that

the peripheral olfactory system may be a promising entrypoint for understanding the brain mechanisms underlyingschizophrenia pathology.7

Neuroanatomy of the Olfactory System

We begin with a description of the olfactory system, high-lighting several unusual features that make it especiallyin-formative. The olfactory system is the only sensorymodality that does not utilize the thalamus as a central

1To whom correspondence should be addressed; tel: 215-615-3607, fax: 215-662-7903, e-mail: [email protected].

Schizophrenia Bulletin vol. 35 no. 6 pp. 11171131, 2009doi:10.1093/schbul/sbp111Advance Access publication on September 30, 2009

The Author 2009. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.For permissions, please email: [email protected].

1117


2/15

relaystation.8 Primary olfactory neurons arising in the na-sal epithelium project unmyelinated afferent fibersthrough the cribriform plate into the brain cavity, wherethey terminate on mitral and tufted cells whose dendritesare clustered in glomeruli in the ipsilateral olfactory bulb(OB) (figure 1, left). Axons from these second-order OBneurons form the olfactory tracts, which project to the ip-silateral pyriform and entorhinal cortices (figure1, right).9

Olfactory information passes, in turn, from these primaryrecipient zones to the amygdala, hippocampus, thalamus,and orbitofrontal cortex.10 It also passes through the an-terior commissure to olfactory cortical areas in the contra-lateral hemisphere,facilitating the integration of olfactoryinputs to left and right nostrils. With only 2 synapses be-tween olfactory receptors and secondary cortical and sub-cortical targets,9 the olfactory system provides the mostdirect environmental access to the neuroanatomical sub-strates that have been implicated in schizophrenia.

The olfactory system is also unique in that it retainsplasticity and exhibits robust neurodevelopment through-out life. The olfactory epithelium regenerates approxi-mately every 23 months.11 Basal stem cells divide to

give rise to new immature neurons that migrate towardthe epithelial surface. These neurons differentiate intomature olfactory receptor neurons (ORNs) that projectnew axons back to re-innervate the glomeruli of the OBand form new synapses with target neurons. The olfactorysystem thus offers an unparalleled opportunity to observethe developmental processes of neurogenesis, axon guid-ance, and synapse formation that are no longer evidentto any significant extent in other adult brain areas. Giventhe growing clinical and postmortem evidence implicatingabnormal neurodevelopment in the pathogenesis ofschizophrenia, the olfactory system may therefore hold

special promise for understanding neurodevelopmentalcontributions to schizophrenia pathophysiology.

Developmental Neurobiology of Olfaction

Morphological differentiation of the human olfactorysystem occurs early in embryonic development.12 Thenasal placodes begin to invaginate to form nasal pitsat about the sixth week of gestation, and the nasal cavitiesare fully sculpted by week 11.13 ORN axons reach thebulb by the end of the first trimester and there is evidenceof mitral cell synapse formation by the 17th week ofgestation. The olfactory system is believed to be func-tional in the late fetus, and newborns can discriminateamong a wide variety of odorants. Consistent with itsearly development, the olfactory system is vulnerableto disruption, in utero, by physical and chemical terato-gens.12 The evidence that such disruptions may also playa role in the etiology of schizophrenia is now clear. Ahistory of gestational or perinatal complications, includ-ing second trimester influenza infection,14 rhesus andABO blood-type incompatibility,15 and perinatal anoxic

birth injury,16 all increase the risk of illness. A neurode-velopmental etiology is also supported by findings ofreduced cranial size17 and, in particular, minor midlinephysical anomalies (eg, reduced palate height and cleftpalate) that arise from the same embryological processesthat produce the olfactory structures.18 It is plausible,therefore, that early developmental abnormalities inthe structure, growth, or functioning of olfactory neuronswould not only result in olfactory deficits but wouldalso be representative of neurodevelopmental abnormal-ities that were more diffusely extant in the brain duringgestation.

Fig. 1. Left: Primary olfactory receptor neurons originate in thesuperiornasal cavityand project axons through thecribriform plate into thecranium, 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 tractsprojecting to the ipsilateral medial temporal lobe.

B. I. Turetsky et al.

1118
http://creativecommons.org/licenses/by/2.5/http://creativecommons.org/licenses/by/2.5/http://creativecommons.org/licenses/by/2.5/http://creativecommons.org/licenses/by/2.5/


3/15

Behavioral Evidence of Olfactory Impairment

Abnormalities in Schizophrenia Patients

Since the pioneering psychophysical studies of olfactoryrecognition memory in patients with schizophrenia byCampbell and Gregson,19 a number of investigatorshave reported that schizophrenia patients exhibit

olfactory dysfunction [See Moberg et al20 for a review].Inanearlystudy,Bradley21reportedthatpsychoticpatients,most notablyschizophrenic men, were hypersensitiveto theodorant 5a-16-androsten-3-one. However, more recentstudies have not confirmed this hypersensitivity, withsome studies finding intact olfactory sensitivity 2224 andothers demonstrating decreased sensitivity.25,26 With onlyone exception 27 deficits in odor identification,23,24,26,2838

odor detection threshold sensitivity25,26 and odor memory19,38,39 have all been reported.

Despite the increasing interest in olfactory abnormal-ities in patients with schizophrenia, very few studies

have explored the relative severity of different olfactorydeficits (ie, identification, threshold, memory, and inten-sity/hedonics). Given the presumed differences in neuro-anatomical loci for these different olfactory domains, itmay be expected that they would be differentiallyimpaired in the disorder. In addition, the effects ofpotential moderator variables, such as gender, medica-tion, and smoking history, have not been consistentlyassessed across studies. However, a comprehensivemeta-analytic review of the literature pertaining toolfactory function in schizophrenia20 revealed that (1)comparable deficits are seen for all psychophysicalmeasures (odor detection, identification, and memory);

(2) no differences exist between male and femalepatients, except as they reflect more general genderdifferences in olfaction; (3) there are no significanteffects of antipsychotic medications on olfactory perfor-mance; and (4) patient deficits persist after accountingfor the effects of smoking.

Family and At-Risk Studies

Responses to odorants often appear to be instinctual, andhighly consistent responses are observed across individ-uals within a species. This reflects the fact that there are

important genetic contributions to the development ofthe olfactory system.40 So, it is reasonable to considerwhether the olfactory abnormalities observed in schizo-phrenia might also be genetically mediated. There havenow been several studies of olfactory performance in un-affected family members of patients.4143 Althoughresults have been inconsistent, some deficits have beenfound. In one of the most compelling studies, Kopalaand colleagues42 examined 19 probands, 27 nonpsychoticfamily members, and 43 healthy controls using the Uni-versity of Pennsylvania Smell Identification Test(UPSIT) and an ascending staircase odor detection

threshold test. They found that the UPSIT performanceof the nonpsychotic family members was intermediate tothat of the patient probands and the healthy controls.Fifty-eight percent of the probands and 34% of the non-psychotic family members performed in the microsmicrange, compared with only 9% of healthy comparisonsubjects.

Roalf et al43 expanded on these earlier efforts by testingschizophrenia patients, unaffected family members, andhealthy comparison subjects unirhinally (ie, each nostrilseparately) rather than birhinally. In addition to exposingpotentially important laterality differences, unirhinaltesting eliminates the effects of birhinal facilitation,whereby olfactory performance is improved through sec-ondary integration of the separate left and right nostrilafferent inputs. Unirhinal testing is therefore a purertest of the integrity of primary olfactory afferents.Odor identification and detection threshold sensitivitymeasures were acquired from 22 Diagnostic and Statisti-

cal Manual of Mental Disorder (Fourth Edition) diag-nosed schizophrenia patients, 30 nonill first-degreefamily members, and 45 healthy comparison subjects,who did not differ with regard to age, sex, or level of ed-ucation. This study provided the first description of uni-rhinal olfactory function in a relatively large sample ofschizophrenia patients and their unaffected family mem-bers. Both patients and first-degree relatives showedsignificant deficits in their ability to correctly identifyodorants. Mean scores of family members were nomi-nally intermediate to those of patients and controls.However, family members odor identification scoreswere not statistically different from those of patients.Patients were also impaired in their ability to simply de-tect the presence of a low concentration odorant, relativeto healthy controls. In contrast, there were no significantdifferences in detection threshold between healthy partic-ipants and family members or between patients andfamily members. These results have now been replicatedin a larger sample (figure 2). The finding of comparableodor identification deficits in patients and nonill first-degree relatives suggests that this is likely to be a geneticmarker of vulnerability to the illness, rather than a man-ifestation of the disease itself. The presence of both iden-tification and threshold sensitivity deficits in patients, but

only identification deficits in the nonill family members,may indicate dissociation between olfactory deficitsthat represent genetically mediated vulnerability factorsand deficits that are manifestations of the overt diseaseprocess.

Consistent with the hypothesis that at least some olfac-tory abnormalities denote a genetic vulnerability toschizophrenia, olfactory performance deficits have alsobeen reported in individuals with schizotypal personalitydisorder,44 who are thought to share the same geneticvulnerability as patients with schizophrenia. Studies ofpsychosis-prone individuals, who do not meet criteria

1119

Olfactory Dysfunction in Schizophrenia


4/15

for any disorder but score high on measures of perceptualaberration, physical anhedonia, and magical ideation,have similarly shown that these subclinical symptomsare correlated both with increases in deviant olfactoryexperiences (eg, misperceptions and hallucinations).4547

The relationship between olfaction and aberrant cogni-tive and perceptual experiences extends beyond mere cor-relation. In a 10-year longitudinal study,48 the presence ofsuch deviant olfactory experiences was found to signifi-cantly predict the development of future psychosis. Moreimportantly, a similar investigation49 examining actualpsychophysical olfactory deficits, as opposed to aberrantolfactory experiences, found that odor identification per-formance was significantly impaired in those high-riskindividuals who subsequently developed schizophreniabut not in those who went on to develop affective psycho-ses or remained symptom free. This finding has been re-cently replicated in a sample of 26 well-characterizedadolescents with early onset psychosis.50 Results revealedthat deficits in odor identification existed across youthswith psychotic disorder and were specifically related totypical characteristics of schizophrenia, such as negative

symptoms and lower intelligence, but not to features ofbipolar disorder.

Diagnostic Specificity

The causes of olfactory impairments are numerous, in-cluding chemical, infectious, traumatic, metabolic, andhormonal disturbances. Within the realm of neuropsychi-atry, several neurodegenerative disorders have beenshown to compromise olfaction, including Alzheimersdisease, Downs syndrome, Huntingtons disease, Par-kinsons disease, and multiple sclerosis.51 Among these,

the relationship of olfaction to Alzheimers disease isperhaps of greatest interest because the anterior medialtemporal lobe areas that receive afferents from the OBare among the earliest to exhibit the characteristic neuro-pathology of that disorder. It has therefore beensuggested that olfactory deficits may be an early indicatorof disease onset, prior to the development of clinically

observable memory loss. The question of diagnostic spec-ificity or lack thereof is much less certain with respect tothe major psychiatric disorders. For reasons that are notclear, there have been only a few studies of olfaction inaffective illnesses, and the data that do exist are inconsis-tent. Patients with major depression or seasonal affectivedisorder have variously been reported to exhibit in-creased,52,53 decreased,54 and normal55 olfactory acuity,as well as normal27,33 and reduced26 olfactory identifica-tion ability.

There is even less information concerning bipolar af-fective disorder (BPD) patients. One early study30 found

no impairments in either acuity or identification amongBPD patients being treated with antipsychotic medica-tions. A subsequent investigation56 found that affectivedisorder patients were indistinguishable from schizophre-nia patients on olfactory identification performance.However, those affective disorder patients with psychoticsymptoms also performed significantly worse than thosewithout evidence of psychosis. Most recently, a study ofheterogeneous first-episode psychosis patients57 reportedno difference, across the diagnostic subgroups, in thelevel of odor identification impairment. The authorsconcluded that olfactory deficits exist at the onset ofpsychotic illness, but they are not specific to schizophre-nia or schizophreniform disorder. The accumulatingevidence from these studies, and from the high-risk stud-ies cited above, indicate that olfactory deficits arerelatively specific to psychotic disorders, as distinctfrom nonpsychotic psychiatric conditions. However,the specificity to schizophrenia, as opposed to BPDwith psychosis, is less clear. The finding cited above,49,50

that olfactory impairments during the prodromal phasesignificantly predict a subsequent diagnosis of schizo-phrenia, supports the hypothesis that this is a truedisease-specific vulnerability marker.

Summary and Limitations

These investigations indicate that (1) olfactory abilitiesare impaired in schizophrenia; (2) similar impairmentsare evident in individuals who are symptom free but ge-netically at risk; (3) these deficits may be diagnosticallyspecific for schizophrenia as opposed to other major psy-chiatric conditions; and (4) they may be predictive ofthose high-risk individuals who will develop overt illness.However, it is important to emphasize that these findingswere all based on behavioral performance measures,which rely upon a subjects cooperation, motivation,

Fig. 2. Performance on the University of Pennsylvania Smell

Identification Test. Both patients and unaffected first-degreerelatives have significant bilateral impairments.

1120



5/15

attention, and cognitive capacity to ensure accurate as-sessment. It remains unclear, therefore, whether olfactorydeficits denote a primary disturbance within the olfactoryneural substrate or whether these are merely reflections ofmore diffuse cognitive and/or affective impairment. Withfew exceptions, prior studies have not included structuralor physiological assessments of the integrity of the olfac-

tory system. Structural and functional measures that donot rely upon nonspecific factors such as motivation orattention are likely to be more sensitive to differential def-icits across diagnostic groups and more specific in local-izing abnormalities to discrete neural substrates. Weconsider, below, the neurobiological evidence supportingspecific disruptions in each of the 3 components of theafferent olfactory systemthe primary olfactory cortex,the bulbs and tracts, and the nasal cavity.

Structural Abnormalities

Olfactory Cortex

There have been a vast number of quantitative magneticresonance imaging (MRI) studies in schizophrenia.58

Areas of the temporal lobe, including the superior tem-poral gyrus, hippocampus, and amygdala, have beenamong the most extensively studied. Interest in these par-ticular regions stems from their association with the ver-bal, cognitive memory, and affective symptoms that areprominent in the disorder. Primary olfactory brainregions, in contrast, have been virtually ignored. How-ever, a growing number of studies have now examinedthe entorhinal cortex (Brodmann area 28),5965 whichfunctions as a critical relay between the hippocampusand cortical association areas and, importantly, alsoreceives direct afferent inputs from the OB. Patient dec-rements were identified in 6 of 7 studies, including 2 thatfocused exclusively on neuroleptic-naive first-episodepatients.63,64 In one of these,63 however, a small sampleof nonschizophrenic psychotic patients also exhibited re-duced entorhinal cortical volumes, raising a question re-garding the diagnostic specificity of this volumereduction.

Only 2 studies have specifically assessed the perirhinalcortex (Brodmann areas 35 and 36), which receives most

of the afferent inputs from the OB.61,65 Both found vol-ume decrements in this region. However, a similar abnor-mality was not observed in the first-degree relatives ofschizophrenia patients (B.I. Turetsky, MD, unpublisheddata, 2003). Importantly, Turetsky et al61 also found thatthis volume decrement was specific to the primary olfac-tory cortex and did not extend into the adjacent tempor-opolar cortex (Brodmann area 38), which is functionallydistinct and does not receive any olfactory afferents. Thisfinding of intact temporal pole morphology in schizo-phrenia has since been independently replicated.66 Em-bryologically, the temporal pole develops separately

from the olfactory system and it is one of the last corticalregions to emerge.67 Selective changes in olfactory corti-cal regions may therefore point to a developmental dis-turbance occurring during the late first or early secondtrimester of gestation, preceding the development ofthe temporopolar cortex but coincident with the emer-gence of the olfactory sensory apparatus. If this develop-

mental hypothesis is correct, then we might expect to seesimilar abnormalities in more peripheral elements of theolfactory system that develop in association with the cor-tex in an integrated manner over the same time course.

Olfactory Bulb and Tract

Although MRI studies of the OBs have been conductedin the context of normal fetal development, congenitaland acquired anosmias, Parkinsons disease, and Kall-manns syndrome,6874 only 2 such studies have been con-ducted in schizophrenia patients.75,76 In an initial study

of 26 schizophrenia patients and 22 healthy comparisonsubjects, Turetsky et al75 reported a 23% volume reduc-tion, bilaterally, in patients. In healthy individuals, therewas a strong association between OB volume and odordetection threshold sensitivity, but this normal struc-tural-functional relationship was disrupted in schizo-phrenia. A second study by the same investigators76

examined bulb volumes in an independent patient sam-ple, as well as a sample of unaffected first-degree relativesof patients. This investigation replicated the finding ofreduced bilateral bulb volumes in schizophrenia patients.It also revealed volume reductions of the right, but notthe left, OB among genetically at-risk family members(figure 3). The presence of a bulb abnormality in thefamily members supports the hypothesis of a geneticallymediated vulnerability factor affecting primary sensorycomponents of the olfactory system. These 2 studiesare the first demonstration of such a deficit in any sensorymodality, in either schizophrenia patients or theirfamily members. The restriction of the deficit to the rightbulb, in relatives, may be related to the well-establishedfinding that the right hemisphere is better adapted toprocessing olfactory inputs than the left.77 This func-tional asymmetry presumably extends to the level ofthe bulb and recent studies have demonstrated larger

right OBs as a consequence of normal development indiverse species.78,79 Right bulb development may there-fore be more susceptible to developmental disruptionor genetic mediation.

There are no volumetric studies of the olfactory tracts,as opposed to the bulbs, and such studies would likelyshed little light on the status of these white matter fiberbundles. Diffusion tensor imaging, however, has beenshown to be extremely sensitive to disruptions of olfac-tory tract integrity in early Parkinsons disease.80

It is likely that this approach would prove to be simi-larly sensitive to such disruptions in schizophrenia.

1121



6/15

Unfortunately, these studies have yet to be conducted.Indirect inferences regarding the developmental integrityof the olfactory tracts can, however, be obtained by ex-amining the olfactory sulcus. This sulcus, which resides inthe basal forebrain directly overlying the olfactory tracts,is among the earliest to develop in utero and is identifi-able in the fetal forebrain around week 16 of gestation.81

The depth of the olfactory sulcus is a measure thatappears to be directly linked to embryonic developmentof both the olfactory system and the cerebral cortex. Itdevelops in association withthe projectionof the olfactorytract from the OB to the olfactory cortex and it appears tobe dependent upon the integrity of this afferent fiber tract

for its own development. In developmental disorders suchas Kallmanns syndrome or isolated congenital anosmiathat are characterized by dysgenesis of the OB and tract,the olfactory sulcus tends to be unusually shallow oreven completely absent.82,83 Olfactory sulcal depth may,

therefore, be a pathognomonic marker for aberrant devel-opment of both the forebrain and olfactory sensory affer-ents during the first half of pregnancy. We recentlymeasuredthe depthsof theolfactory sulci in 36schizophre-nia patients and 28 comparison subjects, matched for ageand gender distribution.84 The olfactory sulci were shal-lower, bilaterally, in patients. A separate sample of 31 un-affected family members had sulcal depths that wereintermediate between those of patients and controls butnot significantly different from control subject values (fig-ure 4). Interestingly, consistent with the right hemispherebias for olfactory functioning and the larger volume of theright OB, noted above, olfactory sulcal depth was also sig-

nificantlygreater on the right side acrossgroups. Most im-portantly, the depth of the H-shaped orbital sulcus,which sits adjacent to the olfactory sulcus on the ventralforebrain, wasnot shallowerin patients.The orbital sulcusdoes notbegin todevelopuntilweek28 ofgestation.Hence,

Fig. 3. Left: High-resolution sagittal MRI scan of the olfactory bulb (arrows). Right: Mean bulb volumes for patients, unaffected familymembers, and control subjects. Asterisks indicate significant volume reductions relative to controls (adapted from Turetsky et al 76).

Fig. 4. Left: Coronal MRI scan indicating the olfactory bulbs (arrows) and the overlying olfactory sulci (white lines), through which theolfactory tracts project to the ventromedial temporal lobe. Right: Mean sulcal depth measurements for patients, controls, and familymembers, indicating bilateral depth reductions in patients.

1122



7/15

it is relatively immune to the effects of early intrauterineinsultsthat caninfluencedevelopment of the olfactory sul-cus.85Schizophreniapatients,therefore,aresimilartoindi-viduals with other diagnoses who have known disruptionsofearlyforebrainembryogenesisandexhibitcongenitalol-factory impairments, rather than individuals with postde-velopmental forebrain atrophy.82,83

Nasal Cavity

Macroscopic examination of the structures underlying ol-faction can be extended even more peripherally to includeevaluation of the nasal cavities. To this end, acousticrhinometry can be employed. This simple bedside tech-nique uses ultrasound technology to derive cross-sec-tional area measurements of the cavity from the tip ofthe nose posteriorly toward the nasopharynx. Fromthese, volumes of individual segments of the left and rightnasal cavities can be easily computed. Auxiliary measures

include the minimum cross-sectional area and airflow re-sistance. These allow volume reductions resulting frommucosal engorgement or nasal congestion, which wouldcompromise airflow, to be distinguished from deforma-tions of the underlying cartilaginous structure.

There have been 2 studies of nasal cavity volume inschizophrenia. The initial investigation, which includedonly men, found that male patients had reduced posteriornasal cavity volumes relative to male controls and thatthis could not be explained by differences in stature,smoking, or vascular engorgement of the nasal tissue.86

The second larger study included both male and femalepatients (n = 85) and controls (n = 66), as well as unaf-fected first-degree relatives of both genders (n = 25).87

This study replicated the initial finding of reduced poste-rior nasal cavity volume in male schizophrenia patients.However, female patients did not differ from female con-trols and unaffected first-degree relatives of either sex didnot differ from same-sex control subjects. These findingspersisted after covarying for height and smoking historyand were unrelated to clinical symptomatology or anti-psychotic medication usage.

Embryologically, the nasal cavities develop through in-vagination of the nasal placodes, which are derived fromneural crest tissue. This occurs between the 6th and 11th

weeks of embryogenesis, in conjunction with palatal andnasal septal fusion. Although subsequent developmentresults in overall enlargement, there is no substantialreshaping of the cavities.88 The time course of nasal cavitydevelopment thus coincides with the period of substan-tially increased embryological risk for schizophrenia.8991

Thissuggeststhatposteriornasalcavityvolumedecrementmay be a specific craniofacial dysmorphology marker ofearly embryological developmental disturbance in maleswith schizophrenia. Although the explanation for the gen-der specificity of this finding is unknown, the fact thatschizophrenia manifests as a more severe illness in men

is well documented.92 This measure may be an indicatorof this increased male vulnerability.

Functional Abnormalities

Olfactory Cortex

Physiological studies of olfactory sensory processing sup-port the findings from structural imaging by providingconvergent evidence that the functional integrity of theafferent olfactory system is compromised at the levelof the cortex. Evoked potentials (EPs), with their exqui-site temporal resolution, have the ability to parse physi-ological responses into early obligate afferent responsesand later contextual processes. Their use in olfactory re-search has been limited due to the technical difficultiesassociated with odor stimulus delivery. Recent advancesin olfactometry equipment have alleviated this problem.It is now possible to present precisely timed pulses of

odorants of specified concentrations, without transientchanges in temperature, humidity, or pressure. This per-mits the olfactory nerve (cranial nerve I) to be stimulatedwithout concomitant trigeminal nerve (cranial nerve V)stimulation. This has given rise to a growing body of che-mosensory EP data.

Initialstudiesemployingthismethodologyconfirmedthechemosensory specificity of the method and the absence ofcross-modalcontamination. Subjectswith congenital anos-mia, eg, had intact EP responses to chemosensory agentsthat stimulate the trigeminal nerve but no response topure olfactory stimulants.93 Olfactory EPs were alsofound to be sensitive to both gender differences and thefunctional decline in olfactory ability that occurs with nor-mal aging.94 Applying this methodology to the study ofschizophrenia, Turetsky et al95characterizedthe physiolog-ical EP response elicited by passive smelling of 3 differentconcentrations of hydrogen sulfide in 21 patients and 20healthy controls. Figure 5 illustrates the characteristicbiphasic olfactory EP waveform. Note that the N1and P2 components seen here are delayed by 200300 msrelative to typical auditory or visual EP waveforms.This reflects the additional time required in olfaction,compared with audition or vision, for molecules of anodorant to bind to chemoreceptors in the olfactory

epithelium.Patients exhibited dose-dependent reductions in the

amplitudes of both N1 and P2, with associated P2 latencyprolongation. Patient deficits were more prominent withincreasing odor concentration, with the magnitude of thecortical response exhibiting an abnormal ceiling effect.The olfactory systems of these patients were essentiallyoverwhelmed by the stronger stimuli, becomingmore dysfunctional as they tried to respond to the in-creased stimulus load. These physiological measureswere directly related to psychophysical performancemeasures: N1 amplitude, which specifically denotes

1123



8/15

primary olfactory cortex activity,96 was related to im-paired odor detection threshold sensitivity; P2 amplitude,which reflects secondary sensory integrative processes,was related to impaired odor identification. These dataprovide the first direct evidence for a physiological im-pairment in the olfactory cortex in patients with schizo-phrenia. It is important to emphasize that thisabnormality reflects an obligate physiological responseelicited by repetitive stimulation of the first cranial nerve,

in the absence of any attentional or cognitive processingdemands. Although odor concentration varied, the stim-uli were neither qualitatively distinctive nor task salient.It is unlikely, therefore, that this reflects other nonspecificfactors that might alter brain function.

To assess the possible role of a genetic vulnerabilityfactor in this physiological EP deficit, a second identicalstudy was conducted in a sample of 15 healthy familymembers and matched controls.97 A profile of abnormal-ities was seen in the family members that preciselymatched what was observed in patients. That is, therewere dose-dependent deficits in N1 amplitude, P2 ampli-

tude, and P2 latency. There are 2 important features tonote concerning this physiological deficit. First, thesefamily members were not impaired on psychophysicaltests of olfactory ability. This likely reflects a thresholdphenomenon, in which overt behavioral impairmentsmay not be observed until the underlying anatomic sub-strate abnormality rises above some critical threshold.Such nonlinear structure-function relationships are wellestablished in many organ systems. The underlying sub-

strate was, nevertheless, compromised, as indicated bythe abnormal EP responses. This confirms the expectationthat such physiological measures are more sensitive todetecting subtle deficits. Second, contrary to what hasbeen reported in virtually all previous studies of familialabnormalities in schizophrenia, the relatives in this studydid not show an intermediate deficit (ie, a deficit whosemagnitude was between that of patients and controls).Rather, the relatives deficit was equal to that of patients.This implies a much greater genetic contribution to, andless environmental modification of, this neural responseie, greater heritabilityindicating that it could be a more

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 significantlyreduced.

1124



9/15

useful endophenotypic marker of neurodevelopmental

vulnerability.

Olfactory Bulb and Tract

Unfortunately, the small size of the OBs, along with theirlocation deep in the midline below the ventral forebrain,makes it extremely difficult to record isolated bulbresponses in vivo in humans. To our knowledge, thereare no electrophysiological or functional imaging studiesof OB activity in humans, let alone in schizophreniapatients. However, high-resolution magnetic resonancespectroscopy techniques may, in the future, provide in-formation concerning bulb composition and activity.

Nasal Epithelium

The functional integrity of the ORNs located in the ep-ithelial lining of the posterior nasal cavity can also beassessed via the electro-olfactogram (EOG).98 TheEOG represents the summed multicellular membrane de-polarization of ORNs in response to a chemosensoryodorant stimulus. This depolarization response can berecorded in vivo by a thin wire electrode inserted intothe nasal cavity and positioned adjacent to the olfactoryepithelium, allowing a direct examination of the physio-logical responsiveness of these peripheral sensory neu-

rons. In contrast to scalp-recorded EPs, which haveamplitudes on the order of 110 lv, the EOG responseis several hundred microvolts in amplitude. This makesit possible to record responses to individual odor stimuliand to appreciate its exquisite sensitivity to odor concen-tration and exposure duration.

In a recent study of 21 patients and 18 controlstheonly such study of its kind in schizophreniapatientsexhibited significantly larger EOG responses (figure 6).99

This increased excitability in patients was evident acrossall odor concentrations and durations. It was also evidentfollowing both left and right nostril stimulation, although

the group difference was greater for the right nostril. The

patient-control difference could not be explained by dif-ferences in age, gender, smoking, or use of antipsychoticmedications. This study provides unequivocal evidence ofa peripheral olfactory sensory impairment, although theexplanation for this seemingly paradoxical findingremains unclear. There appear to be at least 3 differentpossibilities: (1) the absolute number of olfactory neu-rons is greater in schizophrenia patients, hence the ob-served EOG response is more robust; (2) there is a lossof specificity of olfactory receptor expression in schizo-phrenia, such that the number of neurons that respondto a particular odorant is increased even if the absolutenumber of neurons is not; and (3) the magnitude of themembrane depolarization current of individual ORNs isincreased, so that the recorded EOG response is greatereven if the number of responding neurons is unchanged.These alternative mechanisms should not be consideredmutually exclusive. There is, in fact, some indirect evi-dence to support each of them.

As previously noted, ORNs undergo continuing neu-rogenesis, including proliferation and differentiation ofneural precursors, axon growth, and synapse formation.At any given moment (including the instant of death), ex-amination of the olfactory epithelium offers a snapshot ofthese regenerative processes, revealing cells in different

stages of differentiation and migration. Using postmor-tem tissue, Arnold et al100 observed a decrease in p75-immunoreactive basal cells and an increase in the numberof immature ORNs, suggesting dysregulated prolifera-tion and differentiation of neuronal precursors in schizo-phrenia. In addition, in vitro olfactory epithelial culturesobtained through nasal epithelial biopsy of still-livingpatients exhibited increased rates of mitosis and greatercellular proliferation.101 Gene expression profiling ofolfactory epithelial tissue also found increased expressionof multiple genes related to cell proliferation, differenti-ation, and neurogenesis in schizophrenia.102 Collectively,

Fig.6. Left:Experimentalsetupfor recordingelectro-olfactogram(EOG).Wire recording electrodeis insertedinto thenasal cavity andheld inpositionon theepithelial surface by an adjustable clipmechanism attachedto a pairof glasses strappedto thehead (reproducedfrom Turetskyet al99). Right: EOG response to a 100 ms odor pulse. Olfactory receptor neuron depolarization is significantly larger in patients.

1125



10/15

these findings suggest dysregulated processes of olfactoryepithelial neurodevelopment in schizophrenia. The ob-servation of increased EOG amplitude could, therefore,reflect altered cellular composition secondary to dysregu-lated neurodevelopment.

This process may also be exacerbated by a loss of selec-tivity of olfactory neurons. Normally, a given olfactory

neuron expresses only one olfactory receptor on its mem-brane surface, restricting its response to a specific odorantmolecule configuration.103 There is evidence, however,that such selectivity can be altered, as in the case of the al-teration of olfactory function with normal human ag-ing.104 Perhaps more importantly, electrophysiologicalstudies of olfactory development indicate that the olfac-toryepitheliumofimmatureanimalsishighlynonselective,withindividual olfactory neurons responding to many dif-ferent odorants.105 Selectivity appears to be acquired onlylaterindevelopment.Becausethebasicfindingofthesecel-lular studies is an increase in the turnover rate and density

of immature rather than mature neurons, this could trans-late into an increased number of neurons that respondmore nonselectively to any given odorant.

Another possibility is that the magnitude of the EOG re-sponse is increased at the level of the individual neuronie,thattherearealterations in theintracellular signal trans-duction pathways that lead to increased membrane de-polarization. The binding of an odorant to an olfactoryreceptor results in increased levels of intracellular cyclicAMP (cAMP). cAMP functions as a second messenger,causing cyclic nucleotide-gated ion channels to open andcations to enter the cell. There is a strong correlationbetween the magnitude of this transmembrane current,which produces the observed EOG response, and thelevels of adenylyl cyclase activation and cAMP accumu-lation within olfactory neurons.106 There is increasingevidence to suggest that this intracellular signaling cas-cade may be dysregulated in schizophrenia. An earlystudy, using B-lymphocytes,107 found increased adenylylcyclase activity and cAMP accumulation in cells fromschizophrenia patients following stimulation with for-skolin, which binds to a high-affinity site on the catalyticsubunit of adenylyl cyclase. More recently it has beenshown that DISC1, the schizophrenia susceptibilitygene located on chromosome 1q42, acts intracellularly

to sequester phosphodiesterase, the enzyme responsiblefor the degradation of cAMP and to release it in re-sponse to elevated levels of cAMP.108 Alterations ofthe quantity or function of the DISC1 protein will there-fore necessarily alter the regulation of cAMP levels.Similarly, a polymorphism of the GNAS1 gene on chro-mosome 20q13, which codes for the a-subunit of theG-protein that stimulates adenylyl cyclase, has been as-sociated with deficit syndrome schizophrenia.109 Altera-tions of this protein would affect the production, ratherthan the degradation, of cAMP following stimulation.Alterations in cAMP levels could also be a secondary

effect of either glutamatergic110 or dopaminergic111 dys-regulation, both of which have been implicated inschizophrenia pathophysiology. While these associationssupport the idea that cAMP signaling is disrupted inschizophrenia, the status of olfactory signal transductionin this disorder has yet to be examined.

A recent behavioral study112 tested the hypothesis that

dysregulation of the cAMP-mediated signaling cascadecontributed to olfactory dysfunction in schizophrenia.Turetsky et al measured odor detection threshold sensitiv-ity to 2 different odors in 30 patients, 25 control subjects,and 19 unaffected family members. The specific odorants,citralva and lyral, were selected because, although they arequalitativelysimilarfloralscents,theydifferedintheextentto which they activatedintracellular adenylyl cyclase in theORNtoproducecAMP.Citralvaproducesalargeincreasein adenylyl cyclase and a robust EOG depoloarization re-sponse, while lyral elicits only a minimal response.106,113

On testing, control subjects did not exhibit any differences

in their ability to detect the presence of these 2 odors. Bothpatients and family members, however, exhibited signifi-cant impairments in their ability to detect lyral but not cit-ralva.Thisevidenceofanodor-specifichyposmiaindicatesthat the mechanisms underlying olfactory dysfunction inschizophrenia are not global ones that disrupt all aspectsof sensory processing. It also implicates a genetically reg-ulated disruption of cAMP-mediated signal transductionin peripheral ORNs as one specific mechanism underlyingthis dysfunction. While not dispositive in the absence ofmore direct physiological biochemical assessments, theresults of this study provide strong inferential supportfor this hypothesis.

Olfactory Epithelial Biopsy

There is compelling preliminary evidence to suggest thatthe structural and functional impairments detailed aboveare mirrored by cellular and molecular abnormalitiesconsistent with faulty cellular proliferation and innerva-tion and/or dysregulated intracellular signaling.100102

The fact that ORNs exhibit continuous neurodevelop-mental proliferation and can be harvested, in living sub-

jects, through olfactory epithelial biopsy offers thepossibility of testing putative mechanisms underlying

the developmental neuropathology of the disorder exvivo. Such a model also offers the opportunity to examinetissues at specific stages of the illness and to capture neu-robiological changes associated with different phases ofthe illness. Recent work using explant cultures derivedfrom epithelial biopsy material has demonstrated thatthe course of neuronal differentiation and maturationcan be tracked over time, from neuronal precursorsthrough immature to fully mature functional olfactoryneurons.114 A proportion of the cell lines derived fromthese explant cultures exhibit odor responsiveness and ex-press neuronal protein markers.115 Cultured cells also

1126



11/15

express receptors for different neurotransmitters, includ-ing serotonin 5HT2A and 5HT2C, dopamine D2R, andN-methyl-D-aspartate (NMDA) NR1 and NR2A/2B.116

These receptors are functionally active and respond toappropriate ligands. The functional competence of differ-ent receptor classes can therefore be assessed by measur-ing G-protein activation116 and/or calcium influxfollowing ligand stimulation (figure 7).117 This allowsspecific hypotheses, such as NMDA receptor hypofunc-tion or altered cAMP-mediated signaling, to be tested di-rectly using cultured neurons derived from clinicallycharacterized patients or individuals at risk for disease.This work is still in its earliest stages. However, initialresults suggest that there are robust disease-specificchanges in both NMDA receptor function and ligand-in-duced G-protein activation in schizophrenia patients(C.G. Hahn, MD, PhD, unpublished data, 2009).

Making Sense of the Nonsense: An Attempt at Integration

Collectively, these research findings provide compellingevidence that schizophrenia patients exhibit structural

and functional abnormalities of the olfactory systemthat extend from the cortex to the periphery. The pres-ence of olfactory deficits in unaffected first-degree rela-tives of patients implicates, at least in part, a geneticetiology. Similarly, the presence of structural abnormal-ities associated with midline craniofacial and forebrainmorphogenesis implicates an early embryonic develop-mental etiology. Importantly, there is an emerging pat-tern of relative dissociation between these genetic anddevelopmental markers. Individuals who carry an in-creased genetic risk have functional olfactory deficits,as indicated by behavioral and electrophysiological meas-

ures. However, they do not exhibit the structural abnor-malities that are most indicative of an early gestationaldisturbance (ie, reduced nasal cavity volume and shallowolfactory sulcus). Although data regarding other minorphysical anomalies are somewhat contradictory,118122

these olfactory findings are in agreement with studies in-dicating that physical anomalies can distinguish monozy-

gotic twins discordant for schizophrenia,120 areprominent in sporadic but not familial schizophrenia,120

and are not found in unaffected family members.121,122 Itthus appears that structural and functional deficits mayrepresent 2 relatively independent sets of measures thatcan be used to track, respectively, intrauterine environ-mental and genetic contributions to schizophrenia vul-nerability. Of course, this dissociation is not absoluteand this is not to suggest that genetic factors do not con-tribute to morphological abnormalities. Rather, it sug-gests that these structural measures may be especiallysensitive to the environmental factors that influence em-

bryonic development, while functional olfactory deficitsmay be more sensitive endophenotypic markers of an un-derlying genetic vulnerability.

This has important implications for the use of thesemeasures as potential biomarkers, particularly in the con-text of longitudinal studies of individuals who are eitherat genetic risk due to a family history of schizophrenia orexhibiting behavioral changes consistent with a schizo-phrenia prodrome. As noted above, olfactory identifica-tion impairments predicted subsequent conversion toschizophrenia among ultrahigh-risk individualswho either were exhibiting subthreshold psychotic symp-toms or had a family history of psychosis and a significantdecline in functioning.49 While it still remains to be dem-onstrated, a composite measure that incorporates bothstructural and functional elements would presumablyhave greater sensitivity and specificity for predictingschizophrenia in this case than a functional measurealone. Also, the ultrahigh-risk research strategy doesnot address the question of how to identify, prior tothe onset of prodromal symptoms, those individualswith a family history of schizophrenia that are likelyto develop the illness. In this case, the presence of bothstructural and functional olfactory abnormalities maybe a critical distinguishing feature. Future longitudinal

studies, therefore, should include the concurrent assess-ment of both sets of measures.

Although we cannot, at this point, identify the specificmechanisms that underlie these olfactory impairments,we can speculate about some of the broader processesthat may be involved. Developmental abnormalities inmidline craniofacial and forebrain morphogenesis sug-gest a disturbance in the cell-cell signaling mechanismsthat regulate embryonic mesenchymal/epithelial tissueinteractions.123 Mesenchymal/epithelial induction duringthe first trimester of embryogenesis gives rise to the entirefrontonasal region, including the olfactory epithelium,

Fig.7. Ligand stimulation of dopaminereceptors activatessignalingpathways in human olfactory epithelial cultures. Cells werepreincubated with either sch23390 (D1 receptor antagonist) orsulpiride (D2 receptor antagonist), followed by stimulation with1 lM dopamine. Isoform specific activation of G-proteins wasassessed for Gas/olf, Gai, Gao, and Gaq/11. Asterisks indicatesignificant effects of dopamine antagonists (adapted fromBorgmann-Winter et al116).

1127



12/15

OB and rudimentary forebrain.124 This set of complex tis-sue interactions is regulated by a group of molecules (in-cluding retinoic acid, sonic hedgehog, Notch4, and FGF)that control gene expression, and any dysregulation ofthis process could produce minor anomalies. Amongthese regulatory molecules, retinoic acid may be of par-ticular interest. Retinoids have been previously impli-

cated in the pathophysiology of schizophrenia125,126

and vitamin A deficiency is a prenatal nutritional factorthat both increases the risk of illness and produces con-genital malformations that resemble the stigmata ofschizophrenia.127 Importantly,retinoic acid also regulatesthe expression of multiple schizophrenia candidate genesand target molecules, including dysbindin,128 dopamineand dopamine receptors, NMDA receptors, nicotinereceptors, GABA receptors,129 and elements of the G-pro-teincAMPprotein kinase A intracellular signalingpathway.130 The integrity of the olfactory system mayalso be maintained, in the adult brain, by retinoic acid-me-

diated regulation of neurogenesis.131

It remains to be de-termined whether retinoids are specifically implicated inthe etiology of schizophrenia olfactory deficits. We wouldemphasize, though, that an epigenetic regulatory mecha-nism of this sort offers a plausible unifying explanationfor thismultitiered array of structural, functional, genetic,developmental, inter-,and intracellularabnormalities.Wewould also note, in this context, that there is a growingap-preciation of the potential importance of epigenetic mech-anisms in the pathophysiology of schizophrenia.132

Conclusions

The olfactory system offers an integrated translationalresearch model that can bridge multiple levels anddomains of inquiry. The fact that olfactory dysfunctionprecedes the development of acute schizophrenia symp-tomatology indicates that early developmental changesin other central nervous system regions are mirroredin this relatively simple sensory system. With the oppor-tunity to obtain olfactory neural tissue from live patientsthrough nasal epithelial biopsy, the peripheral olfactorysystem offers a uniquely accessible window throughwhich to observe the pathophysiological antecedentsand sequelae of schizophrenia. An in-depth longitudinal

characterization of olfactory neuronal dysfunction uti-lizing convergent in vivo and in vitro methods may allowus to observe, in the context of ongoing brain develop-ment, the development of functional dysregulations thatare correlated with molecular and cellular changes. Suchan approach may not only facilitate the identification ofpreclinical biomarkers but also link these to specific dis-ease mechanisms.

Funding

National Institutes of Health (MH59852 to B.I.T.,MH63381 to P.J.M, MH80194 to C.G.H.); NARSAD

Yound Investigator Award to K.B.W; Childrens Hospi-tal of Philadelphia Institutional Development Funds toK.B.W.

References

1. Saykin AJ, Shtasel DL, Gur RE, et al. Neuropsychological

deficits in neuroleptic naive patients with first-episodeschizophrenia. Arch Gen Psychiatry. 1994;51:124131.

2. Turetsky BI, Kohler CG, Indersmitten T, Bhati MT,Charbonnier D, Gur RC. Facial emotion recognition inschizophrenia: when and why does it go awry? SchizophrRes. 2007;94:253263.

3. Turetsky B, Cowell PE, Gur RC, Grossman RI, Shtasel DL,Gur RE. Frontal and temporal lobe brain volumes in schizo-phrenia. Relationship to symptoms and clinical subtype.Arch Gen Psychiatry. 1995;52:10611070.

4. Schneider F, Habel U, Reske M, Toni I, Falkai P, Shah NJ.Neural substrates of olfactory processing in schizophreniapatients and their healthy relatives. Psychiatry Res.2007;155:103112.

5. Seckinger RA, Goudsmit N, Coleman E, et al. Olfactoryidentification and WAIS-R performance in deficit and non-deficit schizophrenia. Schizophr Res. 2004;69:5565.

6. Pause BM, Hellmann G, Goder R, Aldenhoff JB, Ferstl R.Increased processing speed for emotionally negative odors inschizophrenia. Int J Psychophysiol. 2008;70:1622.

7. Sawa A, Cascella NG. Peripheral olfactory system for clini-cal and basic psychiatry: a promising entry point to the mys-tery of brain mechanism and biomarker identification inschizophrenia. Am J Psychiatry. 2009;166:137139.

8. Price J. The central olfactory and accessory olfactory sys-tems. In: Finger TE, Silver WL, eds. Neurobiology of Tasteand Smell. New York, NY: Wiley; 1987:179203.

9. Eslinger PJ, Damasio AR, Van Hoesen GW. Olfactory dys-

function in man: anatomical and behavioral aspects. BrainCogn. 1982;1:259285.

10. Tanabe T, Yarita H, Iino M, Ooshima Y, Takagi SF. An ol-factory projection area in orbitofrontal cortex of the mon-key. J Neurophysiol. 1975;38:12691283.

11. Takagi S. Degeneration and regeneration of the sensory neu-ron: studies on the olfactory epithelium. Shinkei Kenkyu NoShimpo. 1969;13:152163.

12. Farbman A. Developmental Neurobiology of the OlfactorySystem. New York, NY: Raven Press; 1991.

13. Larsen WJ. Human Embryology. New York, NY: ChurchillLivingstone; 2001.

14. Mednick SA, Machon RA, Huttunen MO, Bonett D. Adultschizophrenia following prenatal exposure to an influenzaepidemic. Arch Gen Psychiatry. 1988;45:189192.

15. Hollister JM, Laing P, Mednick SA. Rhesus incompatibilityas a risk factor for schizophrenia in male adults. Arch GenPsychiatry. 1996;53:1924.

16. Cannon TD, Rosso IM, Hollister JM, Bearden CE, SanchezLE, Hadley T. A prospective cohort study of genetic andperinatal influences in the etiology of schizophrenia. Schiz-ophr Bull. 2000;26:351366.

17. Gur RE, Mozley PD, Shtasel DL, et al. Clinical subtypes ofschizophrenia: differences in brain and CSF volume. Am JPsychiatry. 1994;151:343350.

18. OCallaghan E, Larkin C, Kinsella A, Waddington JL. Fa-milial, obstetric, and other clinical correlates of minor

1128



13/15

physical anomalies in schizophrenia. Am J Psychiatry.1991;148:479483.

19. Campbell I, Gregson RAM. Olfactory short term memory innormal, schizophrenic and brain-damaged cases. Aust J Psy-chol. 1972;24:179185.

20. Moberg PJ, Agrin R, Gur RE, Gur RC, Turetsky BI, DotyRL. Olfactory dysfunction in schizophrenia: a qualitativeand quantitative review. Neuropsychopharmacology.1999;21:325340.

21. Bradley EA. Olfactory acuity to a pheromonal substanceand psychotic illness. Biol Psychiatry. 1984;19:899905.

22. Geddes J, Huws R, Pratt P. Olfactory acuity in the positiveand negative syndromes of schizophrenia. Biol Psychiatry.1991;29:774778.

23. Kopala LC, Clark C, Hurwitz T. Olfactory deficits in neuro-leptic naive patients with schizophrenia. Schizophr Res.1993;8:245250.

24. Kopala L, Clark C, Hurwitz TA. Sex differences in olfactoryfunction in schizophrenia. Am J Psychiatry. 1989;146:13201322.

25. Isseroff R, Stoler M, Ophir D, Lancet D, Sirota P. Olfactorysensitivity to androstenone in schizophrenic patients. BiolPsychiatry. 1987;22:922925.

26. Serby M, Larson P, Kalkstein D. Olfactory sense in psycho-ses. Biol Psychiatry. 1990;28:830.

27. Warner MD, Peabody CA, Csernansky JG. Olfactory func-tioning in schizophrenia and depression. Biol Psychiatry.1990;27:457458.

28. Brewer WJ, Edwards J, Anderson V, Robinson T, Pantelis C.Neuropsychological, olfactory, and hygiene deficits in menwith negative symptom schizophrenia. Biol Psychiatry.1996;40:10211031.

29. Houlihan DJ, Flaum M, Arnold SE, Keshavan M, Alliger R.Further evidence for olfactory identification deficits in schizo-phrenia. Schizophr Res. 1994;12:179182.

30. Hurwitz T, Kopala L, Clark C, Jones B. Olfactory deficits inschizophrenia. Biol Psychiatry. 1988;23:123128.

31. Kopala L, Good K, Martzke J, Hurwitz T. Olfactory deficitsin schizophrenia are not a function of task complexity.Schizophr Res. 1995;17:195199.

32. Kopala LC, Good K, Honer WG. Olfactory identificationability in pre- and postmenopausal women with schizophre-nia. Biol Psychiatry. 1995;38:5763.

33. Kopala LC, Good KP, Honer WG. Olfactory hallucinationsand olfactory identification ability in patients with schizo-phrenia and other psychiatric disorders. Schizophr Res.1994;12:205211.

34. Malaspina D, Wray AD, Friedman JH, et al. Odor discrim-ination deficits in schizophrenia: association with eye move-

ment dysfunction. J Neuropsychiatry Clin Neurosci.1994;6:273278.

35. Moberg PJ, Doty RL, Turetsky BI, et al. Olfactory identifi-cation deficits in schizophrenia: correlation with duration ofillness. Am J Psychiatry. 1997;154:10161018.

36. Seidman LJ, Oscar-Berman M, Kalinowski AG, et al. Experi-mental and clinical neuropsychological measures of prefrontaldysfunction in schizophrenia. Neuropsychology. 1995;9:481490.

37. Seidman LJ, Goldstein JM, Goodman JM, et al. Sex differ-ences in olfactory identification and Wisconsin Card Sortingperformance in schizophrenia: relationship to attention andverbal ability. Biol Psychiatry. 1997;42:104115.

38. Wu J, Buchsbaum MS, Moy K, et al. Olfactory memory inunmedicated schizophrenics. Schizophr Res. 1993;9:4147.

39. Dunn TP, Weller MP. Olfaction in schizophrenia. PerceptMot Skills. 1989;69:833834.

40. Barinaga M. Olfaction. Smells course is predetermined. Sci-ence. 2001;294:12691271.

41. Kopala LC, Good KP, Torrey EF, Honer WG. Olfactoryfunction in monozygotic twins discordant for schizophrenia.Am J Psychiatry. 1998;155:134136.

42. Kopala LC, Good KP, Morrison K, Bassett AS, Alda M,Honer WG. Impaired olfactory identification in relativesof patients with familial schizophrenia. Am J Psychiatry.2001;158:12861290.

43. Roalf DR, Turetsky BI, Owzar K, et al. Unirhinal olfactoryfunction in schizophrenia patients and first-degree relatives.J Neuropsychiatry Clin Neurosci. 2006;18:389396.

44. Park S, Schoppe S. Olfactory identification deficit in relationto schizotypy. Schizophr Res. 1997;26:191197.

45. Mohr C, Rohrenbach CM, Laska M, Brugger P. Unilateralolfactory perception and magical ideation. Schizophr Res.2001;47:255264.

46. Mohr C, Hubener F, Laska M. Deviant olfactory experien-ces, magical ideation, and olfactory sensitivity: a study with

healthy German and Japanese subjects. Psychiatry Res.2002;111:2133.

47. Becker E, Hummel T, Piel E, Pauli E, Kobal G, Hautzinger M.Olfactory event-related potentials in psychosis-prone subjects.Int J Psychophysiol. 1993;15:5158.

48. Kwapil TR, Chapman JP, Chapman LJ, Miller MB. Devi-ant olfactory experiences as indicators of risk for psychosis.Schizophr Bull. 1996;22:371382.

49. Brewer WJ, Wood SJ, McGorry PD, et al. Impairment of ol-factory identification ability in individuals at ultra-high riskfor psychosis who later develop schizophrenia. Am J Psychi-atry. 2003;160:17901794.

50. Corcoran C, Whitaker A, Coleman E, et al. Olfactory defi-cits, cognition and negative symptoms in early onset psycho-sis. Schizophr Res. 2005;80:283293.

51. Doty RL. Olfactory system. In: Getchell TV, BartoshukLM, Doty RL, Snow JB, eds. Smell and Taste in Healthand Disease. New York, NY: Raven Press; 1991:175203.

52. Postolache TT, Wehr TA, Doty RL, et al. Patients with sea-sonal affective disorder have lower odor detection thresholdsthan control subjects. Arch Gen Psychiatry. 2002;59:11191122.

53. Gross-Isseroff R, Luca-Haimovici K, Sasson Y, Kindler S,Kotler M, Zohar J. Olfactory sensitivity in major depressivedisorder and obsessive compulsive disorder. Biol Psychiatry.1994;35:798802.

54. Pause BM, Miranda A, Goder R, Aldenhoff JB, Ferstl R.Reduced olfactory performance in patients with major de-pression. J Psychiatr Res. 2001;35:271277.

55. Amsterdam JD, Settle RG, Doty RL, Abelman E, WinokurA. Taste and smell perception in depression. Biol Psychiatry.1987;22:14811485.

56. Striebel KM, Beyerstein B, Remick RA, Kopala L, HonerWG. Olfactory identification and psychosis. Biol Psychiatry.1999;45:14191425.

57. Brewer WJ, Pantelis C, Anderson V, et al. Stability of ol-factory identification deficits in neuroleptic-naive patientswith first-episode psychosis. Am J Psychiatry. 2001;158:107115.

58. Shenton ME, Dickey CC, Frumin M, McCarley RW. A re-view of MRI findings in schizophrenia. Schizophr Res.2001;49:152.

1129



14/15

59. Pearlson GD, Barta PE, Powers RE, et al. Ziskind-Somer-feld Research Award 1996. Medial and superior temporalgyral volumes and cerebral asymmetry in schizophrenia ver-sus bipolar disorder. Biol Psychiatry. 1997;41:114.

60. Nasrallah HA, Sharma S, Olson SC. The volume of the ento-rhinal cortex in schizophrenia: a controlled MRI study. ProgNeuropsychopharmacol Biol Psychiatry. 1997;21:13171322.

61. Turetsky BI, Moberg PJ, Roalf DR, Arnold SE, Gur RE.Decrements in volume of anterior ventromedial temporallobe and olfactory dysfunction in schizophrenia. Arch GenPsychiatry. 2003;60:11931200.

62. Baiano M, Perlini C, Rambaldelli G, et al. Decreased ento-rhinal cortex volumes in schizophrenia. Schizophr Res.2008;102:171180.

63. Prasad KM, Patel AR, Muddasani S, Sweeney J, KeshavanMS. The entorhinal cortex in first-episode psychotic disor-ders: a structural magnetic resonance imaging study. Am JPsychiatry. 2004;161:16121619.

64. Joyal CC, Laakso MP, Tiihonen J, et al. A volumetric MRIstudy of the entorhinal cortex in first episode neuroleptic-na-ive schizophrenia. Biol Psychiatry. 2002;51:10051007.

65. Sim K, DeWitt I, Ditman T, et al. Hippocampal and para-hippocampal volumes in schizophrenia: a structural MRIstudy. Schizophr Bull. 2006;32:332340.

66. Crespo-Facorro B, Nopoulos PC, Chemerinski E, Kim JJ,Andreasen NC, Magnotta V. Temporal pole morphologyand psychopathology in males with schizophrenia. Psychia-try Res. 2004;132:107115.

67. Fogliarini C, Chaumoitre K, Chapon F, et al. Assessment ofcortical maturation with prenatal MRI. Part I: normal cor-tical maturation. Eur Radiol. 2005;15:16711685.

68. Azoulay R, Fallet-Bianco C, Garel C, Grabar S, Kalifa G,Adamsbaum C. MRI of the olfactory bulbs and sulci in hu-man fetuses. Pediatr Radiol. 2006;36:97107.

69. Mueller A, Rodewald A, Reden J, Gerber J, von KummerR, Hummel T. Reduced olfactory bulb volume in post-trau-matic and post-infectious olfactory dysfunction. Neurore-

port. 2005;16:475478.

70. Mueller A, Abolmaali ND, Hakimi AR, et al. Olfactorybulb volumes in patients with idiopathic Parkinsons diseasea pilot study. J Neural Transm. 2005;112:13631370.

71. Buschhuter D, Smitka M, Puschmann S, et al. Correlationbetween olfactory bulb volume and olfactory function. Neu-roimage. 2008;42:498502.

72. Rombaux P, Mouraux A, Bertrand B, Nicolas G, Duprez T,Hummel T. Retronasal and orthonasal olfactory function inrelation to olfactory bulb volume in patients with posttrau-matic loss of smell. Laryngoscope. 2006;116:901905.

73. Rombaux P, Mouraux A, Bertrand B, Nicolas G, Duprez T,Hummel T. Olfactory function and olfactory bulb volume inpatients with postinfectious olfactory loss. Laryngoscope.2006;116:436439.

74. Rombaux P, Duprez T, Hummel T. Olfactory bulb volumein the clinical assessment of olfactory dysfunction. Rhinol-ogy. 2009;47:39.

75. Turetsky BI, Moberg PJ, Yousem D, Arnold SE, Doty RL,Gur RE. Olfactory bulb volume is reduced in patients withschizophrenia. Am J Psychiatry. 2000;157:828830.

76. Turetsky BI, Moberg PJ, Arnold SA, Doty RL, Gur RE.Low olfactory bulb volume in 1st-degree relatives of patientswith schizophrenia. Am J Psychiatry. 2003;160:703708.

77. Doty RL, Bromley SM, Moberg PJ, Hummel T. Lateralityin human nasal chemoreception. In: Christman S, ed. Cere-

bral Asymmetries in Sensory and Perceptual Processing.Amsterdam, The Netherlands: North Holland Publishing;1997:497542.

78. Heine O, Galaburda AM. Olfactory asymmetry in the ratbrain. Exp Neurol. 1986;91:392398.

79. Prasada Rao PD, Finger TE. Asymmetry of the olfactorysystem in the brain of the winter flounder, Pseudopleuro-nectes americanus. J Comp Neurol. 1984;225:492510.

80. Scherfler C, Schocke MF, Seppi K, et al. Voxel-wise anal-ysis of diffusion weighted imaging reveals disruption ofthe olfactory tract in Parkinsons disease. Brain. 2006;129:538542.

81. Chi JG, Dooling EC, Gilles FH. Gyral development of thehuman brain. Ann Neurol. 1977;1:8693.

82. Vogl TJ, Stemmler J, Heye B, et al. Kallman syndrome ver-sus idiopathic hypogonadotropic hypogonadism at MR im-aging. Radiology. 1994;191:5357.

83. Abolmaali ND, Hietschold V, Vogl TJ, Huttenbrink KB,Hummel T. MR evaluation in patients with isolated anosmiasince birth or early childhood. AJNR AM J Neuroradiol.2002;23:157163.

84. Turetsky BI, Crutchley P, Walker J, Gur RE, Moberg PJ.Depth of the olfactory sulcus: A marker of early embryonicdisruption in schizophrenia? Schizophr Res. 2009; In press.

85. Gimenez M, Junque C, Vendrell P, et al. Abnormal orbito-frontal development due to prematurity. Neurology.2006;67:18181822.

86. Moberg PJ, Roalf DR, Gur RE, Turetsky BI. Smaller nasalvolumes as stigmata of aberrant neurodevelopment inschizophrenia. Am J Psychiatry. 2004;161:23142316.

87. Turetsky BI, Glass CA, Abbazia J, Kohler CG, Gur RE,Moberg PJ. Reduced posterior nasal cavity volume: a gen-der-specific neurodevelopmental abnormality in schizophre-nia. Schizophr Res. 2007;93:237244.

88. Larsen WJ. Human Embryology. 3rd ed. New York, NY:Churchill Livingstone; 2001.

89. Cantor-Graae E, McNeil TF, Torrey EF, et al. Link be-tween pregnancy complications and minor physical anoma-lies in monozygotic twins discordant for schizophrenia. AmJ Psychiatry. 1994;151:11881193.

90. Gallagher BJ, McFalls JA, Jones BJ, Pisa AM. Prenatal ill-ness and subtypes of schizophrenia: the winter pregnancyphenomenon. J Clinical Psychol. 1999;55:915922.

91. Hulshoff Pol HE, Hoek HW, Susser E, et al. Prenatal expo-sure to famine and brain morphology in schizophrenia. AmJ Psychiatry. 2000;157:11701172.

92. Shtasel DL, Gur RE, Gallacher F, Heimberg C, Gur RC.Gender differences in the clinical expression of schizophre-nia. Schizophr Res. 1992;7:225231.

93. Kobal G. Electrophysiological measurement of olfactoryfunction. In: Doty R, ed. Handbook of Olfaction and Gusta-tion. 2nd ed. New York, NY: Informa Health Care;2003:382416.

94. Evans WJ, Cui L, Starr A. Olfactory event-related potentialsin normal human subjects: effects of age and gender. Elec-troencephalogr Clin Neurophysiol. 1995;95:293301.

95. Turetsky BI, Moberg PJ, Owzar K, Johnson SA, Doty RL,Gur RE. Physiological impairment of olfactory stimulusprocessing in schizophrenia. Biol Psychiatry. 2003;53:403411.

96. Kettenmann B, Hummel C, Stefan H, Kobal G. Multiple ol-factory activity in the human neocortex identified by mag-netic source imaging. Chem Senses. 1997;22:493502.

1130



15/15

97. Turetsky BI, Kohler CG, Gur RE, Moberg PJ. Olfactoryphysiological impairment in first-degree relatives of schizo-phrenia patients. Schizophr Res. 2008;102:220229.

98. Knecht M, Hummel T. Recording of the human electro-olfactogram. Physiol Behav. 2004;83:1319.

99. Turetsky BI, Hahn CG, Arnold SE, Moberg PJ. Olfactoryreceptor neuron dysfunction in schizophrenia. Neuropsycho-

pharmacology. 2009;34:767774.

100. Arnold SE, Han LY, Moberg PJ, et al. Dysregulation of ol-factory receptor neuron lineage in schizophrenia. Arch GenPsychiatry. 2001;58:829835.

101. Feron F, Perry C, Hirning MH, McGrath J, Mackay-Sim A.Altered adhesion, proliferation and death in neural culturesfrom adults with schizophrenia. Schizophr Res. 1999;40:211218.

102. McCurdy RD, Feron F, Perry C, et al. Cell cycle alterationsin biopsied olfactory neuroepithelium in schizophrenia andbipolar I disorder using cell culture and gene expressionanalyses. Schizophr Res. 2006;82:163173.

103. Ronnett GV, Moon C. G proteins and olfactory signaltransduction. Annu Rev Physiol. 2002;64:189222.

104. Rawson NE, Gomez G, Cowart B, Restrepo D. The use ofolfactory receptor neurons (ORNs) from biopsies to studychanges in aging and neurodegenerative diseases. Ann N YAcad Sci. 1998;855:701707.

105. Gesteland RC, Yancey RA, Farbman AI. Development ofolfactory receptor neuron selectivity in the rat fetus. Neuro-science. 1982;7:31273136.

106. Lowe G, Nakamura T, Gold GH. Adenylate cyclase medi-ates olfactory transduction for a wide variety of odorants.Proc Natl Acad Sci U S A . 1989;86:56415645.

107. Natsukari N, Kulaga H, Baker I, Wyatt RJ, Masserano JM.Increased cyclic AMP response to forskolin in Epstein-Barrvirus-transformed human B-lymphocytes derived fromschizophrenics. Psychopharmacology (Berl). 1997;130:235241.

108. Millar JK, Pickard BS, Mackie S, et al. DISC1 and PDE4Bare interacting genetic factors in schizophrenia that regulatecAMP signaling. Science. 2005;310:11871191.

109. Minoretti P, Politi P, Coen E, et al. The T393C polymor-phism of the GNAS1 gene is associated with deficit schizo-phrenia in an Italian population sample. Neurosci Lett.2006;397:159163.

110. Chetkovich DM, Sweatt JD. NMDA receptor activationincreases cyclic AMP in area CA1 of the hippocampus viacalcium/calmodulin stimulation of adenylyl cyclase. J Neuro-chem. 1993;61:19331942.

111. Neves SR, Ram PT, Iyengar R. G protein pathways. Sci-ence. 2002;296:16361639.

112. Turetsky BI, Moberg PJ. An odor-specific detection thresh-

old sensitivity deficit implicates abnormal intracellular cyclicAMP signaling in schizophrenia. Am J Psychiatry.2009;166:226233.

113. Sklar PB, Anholt RRH, Snyder SH. The odorant-sensitiveadenylate cyclase of olfactory receptor cells. J Biol Chem.1986;261:1553815543.

114. Hahn CG, Han LY, Rawson NE, et al. In vivo and in vitroneurogenesis in human olfactory epithelium. J Comp Neurol.2005;483:154163.

115. Gomez G, Rawson NE, Hahn CG, Michaels R, Restrepo D.Characteristics of odorant elicited calcium changes in cul-tured human olfactory neurons. J Neurosci Res.2000;62:737749.

116. Borgmann-Winter KE, Rawson NE, Wang HY, et al. Humanolfactory epithelial cells generated in vitro express diverseneuronal characteristics. Neuroscience. 2009;158:642653.

117. Hahn CG, Gomez G, Restrepo D, et al. Aberrant intracellu-

lar calcium signaling in olfactory neurons from patients withbipolar disorder. Am J Psychiatry. 2005;162:616618.

118. Gourion D, Goldberger C, Bourdel MC, Jean BayleF, Loo H,Krebs MO. Minor physical anomalies in patients with schizo-phrenia and their parents: prevalence and pattern of craniofa-cial abnormalities. Psychiatry Res. 2004;125:2128.

119. Ismail B, Cantor-Graae E, McNeil TF. Minor physicalanomalies in schizophrenic patients and their siblings. AmJ Psychiatry. 1998;155:16951702.

120. Kelly BD, Cotter D, Denihan C, et al. Neurological softsigns and dermatoglyphic anomalies in twins with schizo-phrenia. Eur Psychiatry. 2004;19:159163.

121. Griffiths TD, Sigmundsson T, Takei N, et al. Minor physicalanomalies in familial and sporadic schizophrenia; the

Maudsley family study. J Neurol Neurosurg Psychiatry.1998;64:5660.

122. Compton MT, Bollini AM, McKenzie Mack L, et al. Neu-rological soft signs and minor physical anomalies in patientswith schizophrenia and related disorders, their first-degreerelatives, and non-psychiatric controls. Schizophr Res.2007;94:6473.

123. Maynard TM, Sikich L, Lieberman JA, LaMantia AS. Neu-ral development, cell-cell signaling, and the two hit hy-pothesis of schizophrenia. Schizophr Bull. 2001;457476.

124. LaMantia AS, Bhasin N, Rhodes K, Heemskerk J. Mesen-chymal/epithelial induction mediates olfactory pathway for-mation. Neuron. 2000;411425.

125. Goodman AB. Microarray results suggest altered transport

and lowered synthesis of retinoic acid in schizophrenia.Mol Psychiatry. 2005;10:620621.

126. Rioux L, Arnold SE. The expression of retinoic acid recep-tor alpha is increased in the granule cells of the dentate gyrusin schizophrenia. Psychiatry Res. 2005;133:1321.

127. Brown AS,Susser ES.Prenatal nutritional deficiency and riskof adult schizophrenia. Schizophr Bull. 2008;34:10541063.

128. Guo AY, Riley BP, Thiselton DL, Kendler KS, Zhao Z. Thedystrobrevin-binding protein 1 gene: features and networks.Mol Psychiatry. 2009;14:1829.

129. Goodman AB. Three independent lines of evidence suggestretinoids as causal to schizophrenia. Proc Natl Acad SciU S A. 1998;95:72407244.

130. Kurie JM, Allopenna J, Dmitrovsky E. Retinoic acid stimu-

lates protein kinase A-associated G proteins during humanteratocarcinoma differentiation. Biochim Biophys Acta.1994;1222:8894.

131. Rawson NE, LaMantia A-S. A speculative essay on retinoicacid regulation of neural stem cells in the developing and ag-ing olfactory system. Exp Gerontol. 2007;42:4653.

132. Roth TL, Lubin FD, Sodhi M, Kleinman JE. Epigeneticmechanisms in schizophrenia. Biochim Biophys Acta.2009;1790:869877.

1131


scents and nosense

Documents