OL

Bth

Mdtw

Raw

Cta

Ks

ArssdiwsTapsmo

aIfifhTii

bost

F

A

R

0d

lfaction and Taste Processing in Autismoisa Bennetto, Emily S. Kuschner, and Susan L. Hyman

ackground: Autism is often associated with sensory symptoms, but few studies have examined chemosensory functions in this popula-ion. We examined olfactory and taste functioning in individuals with autism to characterize chemosensory processing and test competingypotheses about underlying brainstem versus cortical abnormalities.

ethods: Twenty-one participants (10 –18 years) with autism were compared with 27 well-matched control participants with typicalevelopment. Taste identification was tested via sucrose, NaCl, citric acid, and quinine solutions applied to standard locations on the anterior

ongue. Taste detection thresholds were established in the same regions with electrogustometry, and olfactory identification was evaluatedith “Sniffin’ Sticks.”

esults: Participants with autism were significantly less accurate than control participants in identifying sour tastes and marginally lessccurate for bitter tastes, but they were not different in identifying sweet and salty stimuli. Taste detection thresholds via electrogustometryere equivalent. Olfactory identification was significantly worse among participants with autism.

onclusions: True differences exist in taste and olfactory identification in autism. Impairment in taste identification with normal detectionhresholds suggests cortical, rather than brainstem dysfunction. Further research is needed to determine the neurologic bases of olfactory

nd taste impairments, as well as the relationship of chemosensory dysfunction to other characteristics of autism.

ey Words: Autism, electrogustometry, olfaction, psychophysics,ensory processing, taste

utism is a neurodevelopmental disorder characterized bydeficits in socialization, communication, and range ofinterests. Children with autism often present with unusual

esponses to sensory stimuli. This is confirmed by parent reporttudies showing that children with autism experience increasedensory symptoms when compared with children with typicalevelopment or with general delays (1–3); however, individualsn other clinical groups, such as Fragile X syndrome, also presentith abnormal sensory responsiveness (4), suggesting that sen-

ory dysfunction, broadly defined, may not be specific to autism.he majority of laboratory studies have tested theories of hypo-nd hyperarousal as explanations for sensory dysfunction in thisopulation. As a whole, these studies do not provide strongupport for a global impairment in arousal in autism (5). Further-ore, hypo- or hyperarousal models are generally not specific tone sensory modality.

A different approach to understanding sensory dysfunction inutism is to examine the integrity of specific sensory systems.nconclusive results across previous studies may be clarified byocusing on response patterns within and across distinct modal-ties. Because the peripheral and central circuitries of sensoryunctions are well mapped in humans, this approach can alsoelp to advance our knowledge of the neurobiology of autism.his type of modality-specific investigation has been successful

n identifying atypical cortical activation in recent studies exam-ning auditory processing in autism (6 – 8).

Another promising direction for establishing links betweenehavioral responses and the neurobiology of autism is the studyf chemosensory processing. Considerable clinical evidenceuggests that individuals with autism have atypical responses toastes and odors. For example, a recent study examining the

rom the Departments of Clinical and Social Sciences in Psychology (LB, ESK)and Pediatrics (SLH), University of Rochester, Rochester, New York.

ddress reprint requests to Loisa Bennetto, Ph.D., University of Rochester,Department of Clinical and Social Sciences in Psychology, Box 270266,Rochester, NY 14627; e-mail: bennetto@psych.rochester.edu.

eceived November 1, 2006; revised April 13, 2007; accepted April 16, 2007.

006-3223/07/$32.00oi:10.1016/j.biopsych.2007.04.019

specificity of parent-reported sensory symptoms found thatabnormal response to taste and smell was the only factor thatdifferentiated children with autism from those with Fragile Xsyndrome, heterogeneous developmental disabilities, and typicaldevelopment (2). Other parent report studies similarly docu-mented increased abnormalities in autism relative to controlsubjects in the sense of smell (9). One study objectively testedolfactory functioning in 12 adults with Asperger syndrome andfound they were significantly impaired in identifying commonodors compared with matched, typical control subjects (10).

Taste and smell are both critical for ingestive behaviors, andthere is a growing literature documenting high rates of restrictedand atypical eating in autism (9,11–13). Feeding difficulties areestimated to occur in as many as 70%–90% of children withautism (11,14), yet no empirical studies have examined possibleneurobiological mechanisms involved in these difficulties.

Although the ability to identify and detect tastes has not beenexamined in autism, neurobiological studies provide indirectsupport for the possibility of taste dysfunction. There is evidenceof brainstem dysfunction in autism (15), including hypoplasia ofthe facial nerve (CN VII) nucleus (16). CN VII carries gustatoryinformation from the anterior two-thirds of the tongue via thechorda tympani, and damage to this nucleus or pathway affectstaste detection. Identification of tastants and the perception offlavor is mediated centrally by a complex network involvingregions of the thalamus, insula/operculum, orbitofrontal cortex(OFC), and amygdala (17). Several of these regions have beenimplicated in autism, most notably the OFC and amygdala (for areview, see reference 18).

In this study, we build on previous findings of parent-reportedsmell and taste abnormalities in autism (2,9) by characterizingchemosensory processing using objective, laboratory-based mea-sures. We also extend Suzuki and colleagues’ (10) study of adultswith Asperger syndrome by testing odor identification in a sampleof children and adolescents with high-functioning autism comparedwith well-matched, typically developing control participants. Fi-nally, by measuring both taste identification and detection, we testcompeting hypotheses about underlying brainstem versus corticalabnormalities. We hypothesized that participants with autism wouldbe less accurate than control participants in both odor and taste

identification. We did not have a strong prediction about taste

BIOL PSYCHIATRY 2007;62:1015–1021© 2007 Society of Biological Psychiatry

dsit

dnal(s

M

P

fppf

wwOsssttgd

epBht

SItPpdpSg

R

T

nAFPSHG

S

1016 BIOL PSYCHIATRY 2007;62:1015–1021 L. Bennetto et al.

w

etection thresholds: impaired performance would suggest brain-tem or peripheral involvement, whereas intact taste detection andmpaired identification would implicate regions above the level ofhe chorda tympani and facial nerve nucleus.

Studies of olfaction in individuals with schizophrenia haveemonstrated that odor identification deficits are related toegative symptoms in the disorder, such as social impairment,ffective flattening, and avolition (19 –22). Because of the simi-arities between these symptoms in schizophrenia and autism23–25), we were interested in whether olfaction was related toocial impairment in autism as well.

ethods and Materials

articipantsParticipants were 21 children and adolescents with high-

unctioning autism and 27 typically developing control partici-ants. Ages in both groups ranged from 10 to 18 years. Partici-ants were recruited from the community or from a database ofamilies who participated in previous studies.

Diagnoses of Autistic Disorder (based on DSM-IV-TR, 26)ere established with the Autism Diagnostic Interview—Revisedith the caregiver (ADI-R) (27) and the Autism Diagnosticbservation Schedule with the participant (ADOS) (28). These

tandardized measures yield diagnostic information as well ascores within core symptom domains (e.g., communication,ocialization). Only participants who met diagnostic criteria onhe ADI-R and ADOS, as well as clinician judgment, were invitedo participate. Participants with autism had no diagnoses ofenetic syndromes or definable postnatal etiologies for theirevelopmental difficulties (e.g., head injury, tumor).

Typically developing control participants had no history orvidence of autism on the ADI-R or ADOS, no behavioral orsychiatric disorder as assessed by parent ratings on the Childehavior Checklist (29), no learning disabilities, and no history ofead trauma. There were also no concerns about autism spec-rum disorders in their first- or second-degree relatives.

Cognitive ability was measured with the Wechsler Intelligencecale for Children, 4th edition (30) or the Wechsler Adultntelligence Scale, 3rd edition (31). Because our identificationasks had a receptive language component, we administered theeabody Picture Vocabulary Test, 3rd edition (PPVT-III) (32). Allarticipants had cognitive ability and receptive language stan-ard scores greater than 85. Participants with autism and controlarticipants were matched by group on chronological age, Fullcale IQ, PPVT-III Standard Score, socioeconomic status (33),ender, and handedness (see Table 1).

This research was approved by the University of Rochester’sesearch Subjects Review Board. Before testing, written in-

able 1. Descriptive Characteristics of the Autism and Control Groups

Autism M (SD) Control M (SD) F or �2 p

21 27ge 14.35 (2.46) 14.48 (2.16) .04 .85ull Scale IQ 105.62 (11.37) 109.73 (7.88) 1.91 .17PVT-III 113.76 (11.28) 118.26 (11.14) 1.45 .24ocioeconomic Status 52.12 (10.45) 54.18 (8.63) .39 .53andedness (R:L) 16:5 23:4 .63 .43ender (M:F) 17:4 20:7 .32 .57

PPVT-III, Peabody Picture Vocabulary Test, 3rd Ed. (standard scores).

ocioeconomic status was measured with Hollingshead’s (33) Index.

ww.sobp.org/journal

formed consent was obtained from parents and from 18-year-oldparticipants. Younger participants also gave written assent.

MaterialsTaste Identification. We measured basic taste identification

with a regional chemosensory exam. Four tastants were used:sweet (sucrose; 30%), salty (NaCl; 10%), sour (citric acid mono-hydrate; 10%), and bitter (quinine sulfate dihydrate; .25%).Concentrations were based on previous research (34,35) andpiloting with children and young adults. Tastants were sus-pended in a 2% carboxymethylcellulose solution to minimizespread of the stimulus across the tongue; carboxymethylcellulosealone was used as a control. Solutions were prepared in theUniversity of Rochester’s Strong Memorial Hospital Pharmacyunder sterile conditions and stored at 4°C. Solutions werebrought to room temperature before use. The tastants werepresented in one of two quasi-random orders, counterbalancedacross groups and side of initial presentation. The orders in-cluded multiple presentations of each stimulus to prevent spec-ulation about remaining stimuli. Quinine was always presentedlast because it can leave an aftertaste in the mouth that couldaffect subsequent trials.

Tastant solutions were applied to the right or left anterior twothirds of the tongue via a sterile cotton swab. Participants rinsedwith water and expectorated between trials. To reduce migrationof the solutions to other areas of the tongue and soft palate,participants kept their mouths open and tongues slightly ex-tended until they had responded by pointing to one of fourchoices. This allowed us to evaluate function only within the areainnervated by one of the chorda tympani to facilitate comparisonwith the electrogustometry thresholds described later. Responsechoices were presented visually as printed words (which werealso read aloud by the examiner) and paired with representativepictures (e.g., saltshaker) to reduce language and workingmemory demands. Accuracy was measured for each tastant andside of the tongue separately.

Electrogustometry Detection Thresholds. To examinewhether taste identification deficits could be secondary to dys-function earlier in the taste pathway (e.g., chorda tympani), weused electrogustometry to establish taste detection thresholds(TR-06 Rion Electrogustometer, Sensonics, Haddon Heights, NewJersey). Thresholds were measured in the same anterior regionevaluated in the Taste Identification test. Weak anodal stimuli (�400 �A) were presented via an electrode placed on the tongue.Liberation of protons at the site activates ionic taste receptors,producing a sour or metallic taste or sensation (36). We mea-sured detection thresholds rather than sour taste identificationbecause the higher currents needed to elicit reliable, accuratelabeling may also stimulate the trigeminal nerve (37).

Electrical stimuli were delivered for a duration of 1-sec via flat,circular electrodes (5-mm diameter) attached to a probe held bythe examiner. We used a dual electrode method, in which stimuliwere presented randomly to the right or left side of the tongue(1.5 cm from anterior midline and 1.5 cm from front). Participantsindicated the side on which the taste/sensation was detectedwith a hand raise.

Thresholds for the right and left sides were established concur-rently, using a two-alternative forced-choice adaptive staircaseprocedure as described in Loucks and Doty (38). Initial stimuluspresentation was at 10 dB, which is in the middle of the rangemeasured by the instrument (–6 to 34 dB, corresponding to 4 to 400�A). Stimulus intensities were increased in 2-dB steps following

incorrect responses, or repeated at the same intensity following

cflrosietml

sT(tawOapcotlpwtiAoomrsp

P

1rrttNiiwsadmmosombwtar

L. Bennetto et al. BIOL PSYCHIATRY 2007;62:1015–1021 1017

orrect responses, until participants reached an initial criterion ofive consecutive correct responses. After this basal was met, stimu-us intensities were decreased or increased (i.e., staircase waseversed) in 2-dB steps as follows: after two correct responses onne side at a stimulus level the intensity of next presentation on thatide was decreased, and after one incorrect response the stimulusntensity was increased. This procedure yields efficient and reliablestimates of psychophysiologic thresholds (39). The side of presen-ation was randomized by computer for each trial. Performance waseasured as detection thresholds, which were the average of the

ast four of seven staircase reversal points.Olfactory Identification. Olfactory identification was as-

essed with the ”Sniffin’ Sticks” Odor Identification Screeningest, a commercially available, standardized test of olfactionBurghart Medical Technology, Wedel, Germany) (40,41). Thisest evaluates receptive identification of 12 common odors. It isppropriate for children and adults (41) and has been usedidely to evaluate olfactory dysfunction in patient groups.dorants are presented in felt-tip pens; instead of ink, thebsorbent material in the pen is saturated with an odorant. Theens were uncapped by the examiner for 3 sec, then placed 1–2m in front of the participant’s nostrils. Participants indicated thedorant among a field of four choices. In the standard adminis-ration, the choices are presented as written words. To decreaseanguage demands, we adapted the response format: participantsointed to color photographs of the choices and foils. The choiceords were also printed below each picture and read aloud by

he examiner. Our pilot studies indicated that this adaptation wasmportant for reducing verbal demands for children with autism.

similar adaptation found that photographs did not improvedor identification performance in healthy volunteers (42), sour adaptation was not likely to significantly increase perfor-ance in the control group. We also presented this task in two

andom orders, which were counterbalanced across groups. As istandard in other studies, performance was measured by averageercent accuracy across the 12 trials.

roceduresParticipants did not eat or drink anything except water at leasthour before testing. We rescheduled testing if participants

eported or showed evidence of nasal congestion or otherespiratory illness. None of the participants were taking prescrip-ion or over-the-counter medication for upper respiratory infec-ions, allergies, or other medical illnesses at the time of testing.one of the control participants were taking psychotropic med-

cations for psychiatric diagnoses; however, it was not feasible todentify a sufficient number of potential volunteers with autismho were not prescribed psychotropic medications. Although

ome psychotropic medications have been shown to affect tastend saliva production, they are less commonly associated withecreased olfaction (43). Because stimulant medications (e.g.,ethylphenidate) are short acting, any participants taking theseedications stopped taking them 24 hours before testing. Ninef the participants with autism were taking either a selectiveerotonin reuptake inhibitor (e.g., fluoxetine, citalopram; n � 7)r risperidone (n � 2). Because we could not withhold theseedications without disrupting treatment, we repeated all theetween-group analyses, comparing those patients with andithout medications. We found no significant differences be-

ween the groups (in fact, mean performance levels were equiv-lent or even slightly better in the medicated group). Our null

esults for medications are consistent with research on schizo-

phrenia, in which medication status does not attenuate perfor-mance differences on a range of olfaction tests (44).

Data AnalysisBefore inferential statistics, we examined performance based

on presentation order for the two identification tasks. Perfor-mance did not differ based on order, so results were collapsedfor further analyses. Group differences on all tasks were evalu-ated with analysis of variance (ANOVA). Effect sizes werecalculated with partial eta squared (�2

partial). Values between .01and .06 are generally considered a small effect, between .06 and.14 a medium effect, and those above .14 are regarded as a largeeffect. Finally, we used Pearson correlations to examine therelationship between taste detection threshold and taste identi-fication in both groups and between olfactory identification andsocial impairment in the group with autism.

Results

Taste IdentificationWe found no significant effects of side of presentation, so

results were collapsed across right and left sides. Group perfor-mance was evaluated separately for each tastant by ANOVA(Figure 1). Participants with autism were significantly worse thancontrol participants at identifying citric acid, F (1,46) � 5.14, p �.03, �2

partial � .11, and marginally worse at identifying quinine,F (1,46) � 3.41, p � .07, �2

partial � .08. The groups were notdifferent in accuracy for the other tastes: sucrose, F (1,46) � .04,p � .84, �2

partial�.01; salt, F (1,46) � 1.43, p � .24, �2partial � .03.

The average accuracy scores for these tastants suggest that thesenull findings are not attributable to ceiling effects.

Electrogustometry Detection ThresholdsWe found no significant effects of side of presentation on this

task, so results were collapsed across sides. An ANOVA showedno significant difference between participants with autism andcontrol participants in taste detection thresholds, F (1,46) � .53,p � .47, �2

partial � .02 (Figure 2).We also examined the relationship between electrogustom-

etry thresholds and localized sour taste identification becauseanodal electrogustometry activates sour taste receptors. Becauseparticipants with autism were significantly worse than controlparticipants in sour taste identification, this analysis was con-ducted separately for each group. As expected, there was asignificant negative correlation between detection threshold andsour taste identification in the control group, r (25) � –.48, p �

Figure 1. Taste identification accuracy. Group means for percent accuracyon individual tastants, collapsed across side of presentation. Error bars rep-

resent standard error of the mean. * p �.05, † p �.10.

www.sobp.org/journal

.tcactbpt

O

it

crsascoissnrvwvrrogr

Fg(rabi

1018 BIOL PSYCHIATRY 2007;62:1015–1021 L. Bennetto et al.

w

01, indicating that control participants with lower (better)hresholds were more accurate in sour taste identification. Inontrast, these measures were unrelated in the group withutism, r (19) � .09, p � .71. The difference between theseorrelations was significant when converted with Fisher’s r to z=ransformation (45), Z � 1.97, p � .05. The lack of a relationshipetween detection and identification in the autism group sup-orts the idea that autism-specific impairment in taste identifica-ion is not attributable to impaired detection.

lfactory IdentificationAn ANOVA showed that participants with autism were signif-

cantly less accurate than control participants on olfactory iden-ification, F (1, 46) � 7.97, p � .007, �2

partial � .15 (see Figure 3).Previous research has found links between olfactory identifi-

ation and negative symptoms in schizophrenia (19,20,22). Aecent study that examined this relationship in schizophreniahowed that the overall link between smell identification deficitsnd negative symptoms was driven primarily by diminishedocial drive and particularly by lack of spontaneity and flow ofonversation and impaired volition (46). We performed a sec-ndary analysis to examine the relationship between olfactorydentification and comparable scores taken from the ADI-R, thetandardized parent interview we used for autism diagnosis. Thecores on the ADI-R that most closely approximate the keyegative symptoms identified above involved participants’ cur-ent social interchanges and initiation and maintenance of con-ersations. In participants with autism, olfactory identificationas marginally related to their ability to engage in socialerbalization or chatting, r (19) � –.44, p � .05, and significantlyelated to their skill at maintaining a reciprocal conversation,(19) � –.56, p � .01, where children with worse performancen the olfactory identification test were more likely to havereater social impairment. As a contrast, we also tested the

igure 2. Electrogustometry detection thresholds. Boxplots show eachroup’s full range of threshold detection points for the anterior tongue

chorda tympani region), collapsed across side of presentation. Boxes rep-esent the interquartile ranges, whiskers are the 10th and 90th percentiles,nd open circles are scores beyond these points. Group means are indicatedy a dashed line, and medians by a solid line. Output current for thresholds

s reported in decibels (possible range was – 6 to 34 dB).

elationship of olfaction to blunted affect, the negative symptom

ww.sobp.org/journal

that showed the smallest (and nonsignificant) relationship toolfactory identification in Malaspina and Coleman’s study. Simi-larly, in our study, the ADI-R score for range of facial expressionswas not significantly related to olfactory identification in partic-ipants with autism, r (19) � –.17, p � .45.

Discussion

This study provides empirical support for clinical and care-giver observations of atypical chemosensory processing in au-tism. We found that children and adolescents with high-function-ing autism were significantly less accurate than matched controlparticipants in identifying basic tastes and odors. Matching onreceptive language and Full Scale IQ, as well as the nonverbalresponse format of our tasks, suggests that these performancedifferences were not the result of cognitive limitations. Theseresults also help to clarify the inconsistencies across previousreports of sensory dysfunction in autism. Our participants withautism were not impaired on all tasks measured; even within thedomain of taste identification, we found a pattern of impairedand intact ability. Participants with autism were significantlyworse than control subjects at identifying citric acid and margin-ally worse at identifying quinine, but the groups did not differ intheir accuracy for sucrose or salt.

Another goal of this study was to evaluate whether tasteprocessing patterns in autism were consistent with damage at thebrainstem level. We found no differences between our groups ona psychophysiologic measure of taste detection. Because wemeasured electrogustometry thresholds for detection rather thanidentification, it is unlikely that participants’ performances wereaffected by trigeminal stimulation. Electrogustometry is effectivein detecting chorda tympani nerve damage (47); thus the lack ofgroup differences on this measure suggests that our finding ofimpaired taste identification in autism is not secondary to dys-function at the level of the chorda tympani or facial nucleus.Although electrogustometry is generally considered effective intesting the integrity of taste pathways (48), anodal stimulationonly activates sour taste receptors. Thus we cannot make as-sumptions about the function of other classes of taste receptors.Despite these limitations, our clear pattern of impaired sour taste

Figure 3. Olfactory identification. Group means for percent accuracy on“Sniffin’ Sticks” Odor Identification Test. Error bars represent standard error

of the mean. ** p � .01.

icecgtt

oiccsicamtodwdbea

oi(kDiurmhfoowdIiioa

aeiBswrOicaraat

L. Bennetto et al. BIOL PSYCHIATRY 2007;62:1015–1021 1019

dentification with intact electrogustometry detection implicatesortical dysfunction for individuals with autism. Furthermore,lectrogustometry was related to sour taste identification in theontrol participants, but these abilities were not associated in theroup with autism, further suggesting that dysfunction abovehe level of the brainstem is driving performance decrements inhis group.

Our data also provide strong support for the presence oflfactory deficits in autism. Participants with autism were signif-cantly less accurate than control participants in identifyingommon odors. This finding is consistent with Suzuki andolleagues’ (10) report of odor identification deficits in Aspergeryndrome, as well as parent reports of atypical smell processingn questionnaire studies (2,9). Our data do not allow us to drawonclusions about the level at which odor identification deficitsre likely to arise in the nervous system because we did noteasure olfactory detection thresholds. Previous research shows

hat adults with Asperger syndrome, although impaired onlfactory identification relative to matched control subjects,emonstrated intact olfactory detection (10); however, that studyas based on a relatively small sample (n � 12 per group), andetection thresholds were established with 1-butanol, which cane a trigeminal stimulant (49). Thus further studies are needed tovaluate the role of detection in olfactory identification deficits inutism.

There has been considerable recent interest in the role oflfactory dysfunction in other neurobehavioral disorders, includ-ng schizophrenia (50,51) and obsessive– compulsive disorder52,53), as well as neurodegenerative disorders, including Par-inson’s disease (54), Alzheimer’s disease (55), and adulthoodown syndrome (56). Because the neural circuitry of this system

s well characterized, olfactory functioning is increasingly beingsed as a behavioral probe for the functional integrity of brainegions in these disorders. In addition, there is evidence foroderate heritability of olfactory identification in a study ofealthy twins (57). Studies of schizophrenia found that unaf-ected family members, including monozygotic twins (58) andther first- or second-degree relatives (59), performed worse onlfactory identification than healthy control subjects, but some-hat better than their affected relatives, suggesting that olfactoryysfunction could be related to a predisposition for psychosis.ndividuals with familial risk for Alzheimer’s disease also showmpairments in olfactory functions (60,61). Together these stud-es suggest a genetic vulnerability to olfactory dysfunction inther disorders, so further investigation may be warranted inutism.

The degree of olfactory identification dysfunction in ourutism sample (Cohen’s d � .86) approached the strength of theffect size reported in a meta-analysis of 18 studies of olfactorydentification in schizophrenia (mean weighted d � .94; 44).ecause of the link between olfaction and social drive inchizophrenia, and the similarities between some of the socialithdrawal symptoms in the two disorders, we examined this

elationship between olfaction and social drive in our sample.ur results suggest a similar relationship between olfactory

dentification and current ratings of initiation and maintenance ofonversation and social interchange in autism. These correlationsre notable, considering the small sample size and relativelyestricted range on the social variables. Although these findingsre preliminary, they do suggest that future studies of olfaction inutism should include careful measurement of social functioning

o investigate this issue further.

Our findings of impaired taste and odor identification withintact performance on electrogustometry suggest that chemosen-sory processing problems in autism occur at the cortical ratherthan brainstem level. Several regions may be plausible candi-dates for further consideration. For example, the OFC containssecondary taste cortex (62) and olfactory cortex (63), and it playsa key role in flavor perception through the integration of tasteand olfactory information (64,65), although other brain areas arealso involved (66). The OFC is also involved in stimulus-reinforcement association learning, including the association ofolfactory stimuli and the primary reinforcement value of taste(67). Several groups have proposed dysfunction in OFC orOFC–amygdala circuitry in autism (18,68,69), and recent neuro-imaging studies reported evidence of developmental abnormal-ities in OFC volume (70,71).

Although this study found clear differences in chemosensoryprocessing compared with typically developing control partici-pants, individuals with other developmental disabilities may alsoshow impairments in these specific functions, as they do withmore general sensory symptoms (4). Future studies shouldinclude control groups of individuals with other developmentaldisabilities such as Fragile X syndrome and Down syndrome toevaluate the specificity of these deficits. Future investigationsshould also extend these findings to younger children withautism and those with more significant neurocognitive impair-ments. Sensory symptoms are often more clinically problematicin these groups, so evaluation of chemosensory abilities as wellas other symptoms (e.g., repetitive behaviors) will help todetermine which factors relate most to sensory impairments inautism.

Difficulty in identifying basic tastes and smells may contributeto high rates of food refusal and selectivity reported in childrenwith autism. The development of food preferences begins inearly toddlerhood, and depends on a complex interaction be-tween biological predispositions (e.g., taste or olfactory process-ing), tendencies toward food neophobia (i.e., rejection of novelfoods), the ability to learn associations between foods andcontexts, and the eating environment itself (for a review, seereference 72).

Future study of chemosensory processing in autism mayreveal important links between brain function, clinically relevantbehavior, and treatment. Furthermore, recent advances in thegenetics of both taste and olfaction, as well as the relationshipbetween olfactory impairments and neuropsychological andsocial dysfunction in other disorders, raise the possibility thatchemosensory dysfunction could serve as a biobehavioralmarker in autism.

This research was supported by an NIMH Center for Studies toAdvance Autism Research and Treatment (Grant No. U54MH066397), the National Alliance for Autism Research, and anNIH General Clinical Research Center Grant (5 M01 RR00044).We thank the children and families who participated in thisstudy.

None of the authors report any biomedical financial interestsor potential conflicts of interest.

1. Baranek GT, David FJ, Poe MD, Stone WL, Watson LR (2006): SensoryExperiences Questionnaire: Discriminating sensory features in youngchildren with autism, developmental delays, and typical development.J Child Psychol Psychiatry 47:591– 601.

2. Rogers SJ, Hepburn S, Wehner E (2003): Parent reports of sensory symp-toms in toddlers with autism and those with other developmental dis-

orders. J Autism Dev Disord 33:631– 642.

www.sobp.org/journal

1

1

1

1

11

1

1

1

1

2

2

2

2

2

2

1020 BIOL PSYCHIATRY 2007;62:1015–1021 L. Bennetto et al.

w

3. Kientz MA, Dunn W (1997): A comparison of the performance of childrenwith and without autism on the sensory profile. Am J Occup Ther 51:530 –537.

4. Miller L J, Reisman J, McIntosh DN, Simon J (2001): The ecological modelof sensory modulation: Performance of children with fragile X syn-drome, autism, ADHD, and SMD. In: Roley S, Schaaf RC, Blanche E (eds).Sensory Integration and Developmental Disabilities. San Antonio, TX:Therapy Skill Builders.

5. Rogers SJ, Ozonoff S (2005): Annotation: What do we know about sen-sory dysfunction in autism? A critical review of the empirical evidence.J Child Psychol Psychiatry 46:1255–1268.

6. Tecchio F, Benassi F, Zappasodi F, Gialloreti LE, Palermo M, Seri S, RossiniPM (2003): Auditory sensory processing in autism: A magnetoencepha-lographic study. Biol Psychiatry 54:647– 654.

7. Boddaert N, Belin P, Chabane N, Poline JB, Barthelemy C, Mouren-Simeoni MC, et al. (2003): Perception of complex sounds: Abnormalpattern of cortical activation in autism. Am J Psychiatry 160:2057–2060.

8. Boddaert N, Chabane N, Belin P, Bourgeois M, Royer V, Barthelemy C,et al. (2004): Perception of complex sounds in autism: Abnormal audi-tory cortical processing in children. Am J Psychiatry 161:2117–2120.

9. Nieminen-von Wendt T, Paavonen JE, Ylisaukko-Oja T, Sarenius S, Käll-man T, Järvelä I, von Wendt L (2005): Subjective face recognition diffi-culties, aberrant sensibility, sleeping disturbances and aberrant eatinghabits in families with Asperger syndrome. BMC Psychiatry 5:20.

0. Suzuki Y, Critchley HD, Rowe A, Howlin P, Murphy DGM (2003): Impairedolfactory identification in Asperger’s syndrome. J Neuropsychiatry ClinNeurosci 15:105–107.

1. Schreck KA, Williams K (2006): Food preferences and factors influencingfood selectivity for children with autism spectrum disorders. Res DevDisabil 27:353–363.

2. Schreck KA, Williams K, Smith AF (2004): A comparison of eating behav-iors between children with and without autism. J Autism Dev Disord34:433– 438.

3. Ahearn WH, Castine T, Nault K, Green G (2001): An assessment of foodacceptance in children with autism or pervasive developmental disor-der—not otherwise specified. J Autism Dev Disord 31:505–511.

4. DeMeyer MK (1979): Parents and Children in Autism. New York: Wiley.5. Rodier PM (2002): Converging evidence for brain stem injury in autism.

Dev Psychopathol 14:537–557.6. Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J (1996): Embryolog-

ical origin for autism: Developmental anomalies of the cranial nervemotor nuclei. J Comp Neurol 370:247–261.

7. Rolls ET, Scott TR (2003): Central taste anatomy and neurophysiology. In:Doty RL (ed). Handbook of Olfaction and Gustation, 2nd ed. New York:Marcel Dekker, 679 –705.

8. Bachevalier J, Loveland KA (2006): The orbitofrontal–amygdala circuitand self-regulation of social– emotional behavior in autism. NeurosciBiobehav Rev 30:97–117.

9. Corcoran C, Whitaker A, Coleman E, Fried J, Feldman J, Goudsmit N,Malaspina D (2005): Olfactory deficits, cognition and negative symp-toms in early onset psychosis. Schizophr Res 80:283–293.

0. Goudsmit N, Coleman E, Seckinger RA, Wolitzky R, Stanford AD, Corco-ran C, et al. (2003): A brief smell identification test discriminates be-tween deficit and non-deficit schizophrenia. Psychiatry Res 120:155–164.

1. Seckinger RA, Goudsmit N, Coleman E, Harkavy-Friedman J, Yale S,Rosenfield PJ, Malaspina D (2004): Olfactory identification and WAIS–Rperformance in deficit and nondeficit schizophrenia. Schizophr Res 69:55– 65.

2. Brewer WJ, Edwards J, Anderson V, Robinson T, Pantelis C (1996): Neu-ropsychological, olfactory, and hygiene deficits in men with negativesymptom schizophrenia. Biol Psychiatry 40:1021–1031.

3. Konstantareas MM, Hewitt T (2001): Autistic disorder and schizophrenia:Diagnostic overlaps. J Autism Dev Disord 31:19 –28.

4. Sporn AL, Addington AM, Gogtay N, Ordonez AE, Gornick M, Clasen L,et al. (2004): Pervasive developmental disorder and childhood-onsetschizophrenia: Comorbid disorder or a phenotypic variant of a veryearly onset illness? Biol Psychiatry 55:989 –994.

5. Brune M, Brune-Cohrs U (2006): Theory of mind— evolution, ontogeny,brain mechanisms and psychopathology. Neurosci Biobehav Rev 30:

437– 455.

ww.sobp.org/journal

26. American Psychiatric Association (2000): Diagnostic and Statistical Man-ual of Mental Disorders, 4th ed. (Text Revision). Arlington, VA: AmericanPsychiatric Publishing.

27. Rutter M, LeCouteur A, Lord C (2003): Autism Diagnostic Interview, Re-vised. Los Angeles, CA: Western Psychological Services.

28. Lord C, Rutter M, DiLavore PC, Risi S (1999): Autism Diagnostic Observa-tion Schedule. Los Angeles, CA: Western Psychological Services.

29. Achenbach TM, Rescorla LA, McConaughey SH, Pecora PJ, WetherbeeKM, Ruffle TM (2001): Child Behavior Checklist for Ages 6 –18. Burlington,VT: Achenbach System of Empirically Based Assessment.

30. Wechsler D (2003): Wechsler Intelligence Scale for Children— 4th ed. SanAntonio, TX: Harcourt Assessment.

31. Wechsler D (1997): Wechsler Adult Intelligence Scale—3rd ed. San Anto-nio, TX: Psychological Corporation.

32. Dunn LM, Dunn LM (1997): Peabody Picture Vocabulary Test, 3rd ed. CirclePines, MN: American Guidance Services.

33. Hollingshead AB (1975): Four-Factor Index of Social Status. New Haven,CT: Yale University Department of Sociology.

34. Frank ME, Hettinger TP, Barry MA, Gent JF, Doty RL (2003): Contempo-rary measurement of human gustatory function. In: Doty RL (ed). Hand-book of olfaction and gustation, 2nd ed. New York: Marcel Dekker, 783–804.

35. James CE, Laing DG, Oram N (1997): A comparison of the ability of8 –9-year-old children and adults to detect taste stimuli. Physiol Behav62:193–197.

36. DeSimone JA, Lyall V, Heck GL, Feldman GM (2001): Acid detection bytaste receptor cells. Resp Physiol 129:231–245.

37. Grant R, Ferguson MM, Strang R, Turner JW, Bone I (1987): Evoked tastethresholds in a normal population and the application of electrogus-tometry to trigeminal nerve disease. J Neurol Neurosurg Psychiatry 50:12–21.

38. Loucks CA, Doty RL (2004): Effects of stimulation duration on electro-gustometric thresholds. Physiol Behav 81:1– 4.

39. Levitt H (1971): Transformed up– down methods in psychoacoustics.J Acoust Soc Am 49:467– 477.

40. Kobal G, Hummel T, Sekinger B, Barz S, Roscher S, Wolf S (1996): “Sniffin’sticks”: Screening of olfactory performance. Rhinology 34:222–226.

41. Kobal G, Klimek L, Wolfensberger M, Gudziol H, Temmel A, Owen CM,et al. (2000): Multicenter investigation of 1,036 subjects using a stan-dardized method for the assessment of olfactory function combiningtests of odor identification, odor discrimination, and olfactory thresh-olds. Eur Arch Otorhinolaryngol 257:205–211.

42. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G (1997): “Sniffin’ Sticks”:Olfactory performance assessed by the combined testing of odor iden-tification, odor discrimination and olfactory threshold. Chem Senses 22:39 –52.

43. Murphy C, Doty RL, Duncan HJ (2003): Clinical disorders of olfaction. In:Doty RL (ed). Handbook of Olfaction and Gustation, 2nd ed. New York:Marcel Dekker, 461– 478.

44. Moberg PJ, Agrin R, Gur RE, Gur RC, Turetsky BI, Doty RL (1999): Olfactorydysfunction in schizophrenia: A qualitative and quantitative review.Neuropsychopharmacol 21:325–340.

45. Cohen J, Cohen J (2003): Applied Multiple Regression/Correlation Analysisfor the Behavioral Sciences, 3rd ed. Mahwah, NJ: Lawrence Erlbaum Asso-ciates.

46. Malaspina D, Coleman E (2003): Olfaction and social drive in schizophre-nia. Arch Gen Psychiatry 60:578 –584.

47. Grant R, Miller S, Simpson D, Lamey PJ, Bone I (1989): The effect ofchorda tympani section on ipsilateral and contralateral salivary secre-tion and taste in man. J Neurol Neurosurg Psychiatry 52:1058 –1062.

48. Stillman JA, Morton RP, Hay KD, Ahmad Z, Goldsmith D (2003): Electro-gustometry: Strengths, weaknesses, and clinical evidence of stimulusboundaries. Clin Otolaryngol 28:406 – 410.

49. Doty RL, McKeown DA, Lee WW, Shaman P (1995): A study of the test–retest reliability of ten olfactory tests. Chem Senses 20:645– 656.

50. Minor KL, Wright BD, Park S (2004): The Smell Identification Test as ameasure of olfactory identification ability in schizophrenia and healthypopulations: A Rasch psychometric study. J Abnorm Psychol 113:207–216.

51. Kopala LC, Good KP, Honer WG (1994): Olfactory hallucinations andolfactory identification ability in patients with schizophrenia and other

psychiatric disorders. Schizophr Res 12:205–211.

5

5

5

5

5

5

5

5

6

6

L. Bennetto et al. BIOL PSYCHIATRY 2007;62:1015–1021 1021

2. Barnett R, Maruff P, Purcell R, Wainwright K, Kyrios M, Brewer W, PantelisC (1999): Impairment of olfactory identification in obsessive– compul-sive disorder. Psychol Med 29:1227–1233.

3. Hermesh H, Zohar J, Weizman A, Voet H, Gross-Isseroff R (1999): Orbito-frontal cortex dysfunction in obsessive– compulsive disorder? II. Olfac-tory quality discrimination in obsessive– compulsive disorder. Eur Neu-ropsychopharmacol 9:415– 420.

4. Hentschel K, Baba Y, Williams LN, Doty RL, Uitti RJ, Wszolek ZK (2005):Olfaction in familial Parkinsonism (FP). Movement Disord 20:S52-S52.

5. Moberg PJ, Doty RL, Mahr RN, Mesholam RI, Arnold SE, Turetsky BI, GurRE (1997): Olfactory identification in elderly schizophrenia and Alzhei-mer’s disease. Neurobiol Aging 18:163–167.

6. McKeown DA, Doty RL, Perl DP, Frye RE, Simms I, Mester A (1996):Olfactory function in young adolescents with Down’s syndrome. J Neu-rol Neurosurg Psychiatry 61:412– 414.

7. Finkel D, Pedersen NL, Larsson M (2001): Olfactory functioning andcognitive abilities: A twin study. J Gerontol B Psychol Sci Soc Sci 56:P226 –233.

8. Kopala LC, Good KP, Torrey EF, Honer WG (1998): Olfactory function inmonozygotic twins discordant for schizophrenia. Am J Psychiatry 155:134 –136.

9. Kopala LC, Good KP, Morrison K, Bassett AS, Alda M, Honer WG (2001):Impaired olfactory identification in relatives of patients with familialschizophrenia. Am J Psychiatry 158:1286 –1290.

0. Handley OJ, Morrison CM, Miles C, Bayer AJ (2006): ApoE gene andfamilial risk of Alzheimer’s disease as predictors of odour identificationin older adults. Neurobiol Aging 27:1425–1430.

1. Schiffman SS, Graham BG, Sattely-Miller EA, Zervakis J, Welsh-Bohmer K

(2002): Taste, smell and neuropsychological performance of individualsat familial risk for Alzheimer’s disease. Neurobiol Aging 23:397– 404.

62. Rolls ET (2004): The functions of the orbitofrontal cortex. Brain Cogn55:11–29.

63. Sobel N, Johnson BN, Mainland J, Yousem DM (2003): Functional neuro-imaging of human olfaction. In: Doty RL (ed). Handbook of Olfaction andGustation, 2nd ed. New York: Marcel Dekker, 251–274.

64. Critchley HD, Rolls ET (1996): Olfactory neuronal responses in the pri-mate orbitofrontal cortex: Analysis in an olfactory discrimination task.J Neurophysiol 75:1659 –1672.

65. Rolls ET, Baylis LL (1994): Gustatory, olfactory, and visual convergencewithin the primate orbitofrontal cortex. J Neurosci 14:5437–5452.

66. Verhagen JV, Engelen L (2006): The neurocognitive bases of humanmultimodal food perception: Sensory integration. Neurosci BiobehavRev 30:613– 650.

67. Rolls ET, Critchley HD, Wakeman EA, Mason R (1996): Responses ofneurons in the primate taste cortex to the glutamate ion and to inosine5=-monophosphate. Physiol Behav 59:991–1000.

68. Dawson G, Munson J, Estes A, Osterling J, McPartland J, Toth K, et al.(2002): Neurocognitive function and joint attention ability in youngchildren with autism spectrum disorder versus developmental delay.Child Dev 73:345–358.

69. Sabbagh MA (2004): Understanding orbitofrontal contributions to the-ory-of-mind reasoning: Implications for autism. Brain Cogn 55:209 –219.

70. Girgis RR, Minshew NJ, Melhem NM, Nutche JJ, Keshavan MS, Hardan AY(2007): Volumetric alterations of the orbitofrontal cortex in autism. ProgNeuropsychopharmacol Biol Psychiatry 31:41– 45.

71. Hardan AY, Girgis RR, Lacerda ALT, Yorbik O, Kilpatrick M, Keshavan MS,Minshew NJ (2006): Magnetic resonance imaging study of the orbito-frontal cortex in autism. J Child Neurol 21:866 – 871.

72. Birch LL (1999): Development of food preferences. Annual Review ofNutrition 19:41– 62.

www.sobp.org/journal