Abnormal Peripheral Auditory Asymmetry in Schizophrenia

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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.1.88 on 1 January 2001. Downloaded from 88 J Neurol Neurosurg Psychiatry 2001;70:88–94 Abnormal peripheral auditory asymmetry in schizophrenia

E Veuillet, N GeorgieV, B Philibert, J Dalery, M Marie-Cardine, L Collet

Abstract sponse,23 the greatest diVerence with normal Objective—Auditory processing diYcul- controls occurring at left temporal electrode ties have been reported in schizophrenia. sites.45 Another electrophysiological abnor- This study explores peripheral auditory mality is that the P50 component is less function in patients with schizophrenia in reduced in response to repeated stimulation, whom certain early disturbances of audi- suggesting a deficit in the control of sensitivity tory message filtering have been found to auditory stimuli.6–8 Abnormal mismatch and may be associated with certain abnor- negativity generation has also been reported in malities which are particularly localised schizophrenic patients,9–11 particularly in the in the left temporal lobe. left hemisphere.12 This is consistent with a Methods—Otoacoustic emissions, includ- deficit in early cortical mechanisms of auditory ing click evoked and spontaneous emis- sensory analysis. Finally, the auditory brain- sions and measurements of functioning of stem responses occurring within 10 ms of the medial olivocochlear eVerent system stimulation can also be aVected in schizophre- were obtained from 12 chronic schizo- nia, with missing peaks or prolonged laten- phrenic patients and compared with nor- cies.13 All in all, it seems that the early stages of mative data recorded from 12 normal auditory processing and perception are not controls. intact in schizophrenic patients and that the Results—Otoacoustic emission ampli- underlying dysfunction may be an inability to tudes and medial olivocochlear function- properly filter the inflow of information from ing were similar between the normal the environment.14 15 This could lead to a controls and schizophrenic patients; the decrease in ability to focus on external sensory schizophrenic patients did, however, diVer stimuli and to the hyperawareness of back- UMR CNRS 5020, from the normal controls in otoacoustic ground noise described in schizophrenic pa- Neurosciences et emission intensity and in medial olivoco- tients.16 Although electrophysiological studies Systèmes Sensoriels, chlear asymmetry. A tendency to a higher tend to point to a disruption of initial encoding Hôpital Edouard number of spontaneous peaks, and a due to defective inhibitory mechanisms, the Herriot, Pavillon U, 3 significantly higher click evoked otoacous- existence of abnormally reduced neuronal sen- Place d’Arsonval, tic emission response amplitude were 69437 Lyon Cedex 03, sitivity leading to abnormal thresholds for France found in the right ear compared with the novel stimuli can also be proposed. Few studies E Veuillet left ear of schizophrenic patients. For the have looked for deficits in auditory perform- http://jnnp.bmj.com/ B Philibert medial olivocochlear system, whereas ance in schizophrenia. Experiments using tonal L Collet normal controls showed greater attenua- audiometric procedures have shown that these tion in the right than in the left ear, Institut des Sciences abnormalities in auditory function appear in a Cognitives, 8 Avenue schizophrenic patients lacked such an context of normal auditory acuity, except that Rockefeller, 69373 Lyon asymmetry. schizophrenic patients do not consistently Cedex O8, France Conclusion—In the absence of any atten- show the usual auditory threshold asymmetry N GeorgieV tion task, the findings show disturbed in favour of the right ear.17 In a more recent

peripheral lateralisation in schizophrenia study, Mathew et al found a degradation in on September 28, 2021 by guest. Protected copyright. CHS Le Vinatier, 95 bd of mechanisms involved in auditory infor- Pinel, 69500 Bron, hearing thresholds in schizophrenic patients, France mation filtering. Such a lack of right ear with better right ear acuity only in the J Dalery advantage in medial olivocochlear func- non-hallucinating patients.18 These data point tioning may thus be a peripheral reflec- to a loss of threshold asymmetry in one (hallu- JE 1882, Université tion of central lateralisation anomalies. cinating) subgroup of schizophrenic patients. Claude Bernard, Lyon, (J Neurol Neurosurg Psychiatry 2001;70:88–94) France There is thus evidence from many sources that auditory input integration and perception J Dalery Keywords: schizophrenia; auditory processing; asymme- M Marie-Cardine try; medial olivocochlear eVerent system; otoacoustic are disturbed in schizophrenia. In auditory emissions; lateralisation information processing, the signal undergoes CHS Le Vinatier, 95 bd encoding and initial filtering as early as the Pinel, 69500 Bron, cochlea. In 1992, Dallos showed that the outer France M Marie-Cardine Schizophrenia is a clinical syndrome highly hair cells of the organ of Corti have a characterised by cognitive dysfunctions. But primordial role in encoding the signal which is Correspondence to: severe auditory perception deficiencies consist- to be received and processed by the inner hair Dr E Veuillet ent with hypersensitivity to external stimuli are cells and then transmitted by auditory nerve [email protected] also reported.1 Deficient auditory processing aVerent neurons.19 These outer hair cells, in Received 26 April 2000 and has been widely reported in schizophrenia and turn, are the target of medial olivocochlear in revised form such defects clearly appeared in auditory neurons,20 originating in the superior olivary 19 September 2000 21 22 Accepted 28 September evoked responses. Schizophrenic patients show complex. It has been shown in animals that 2000 attenuation of the scalp recorded P300 re- electrical or acoustic stimulation of medial

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olivocochlear fibres alters the nervous message processing is suspected, as is also the case in released in the aVerent auditory fibre (see schizophrenia. Moreover, anatomical animal Guinan23 for a review). There is increasing evi- studies have shown neurophysiological connec- dence that the eVerent fibres of the olivococh- tions between certain cortical areas and the lear bundle, by innervating the outer hair cells, superior olivary complex,44 which raise the can aVect sensory processing at the periphery. possibility of central control of this modulatory In humans, this medial olivocochlear system olivocochlear feedback. Recent studies have can be easily explored by means of otoacoustic shown that the medial olivocochlear system emissions, which are sounds of cochlear shows a pattern of functional asymmetry which origin.24 It is now generally accepted that the is influenced by handedness,45 46 and so could origin of otoacoustic emissions lies in the outer be the reflection of a central laterality. hair cells, which undergo active mechanical These peripheral auditory mechanisms and displacement through the action of the con- their regulation by the CNS have never been tractile elements, myosin and actin, contained studied in schizophrenia. The aim of the in their infrastructure.25 26 In response to sound present study was therefore to compare coch- input, the outer hair cells change length, which lear mechanics and their central eVerent causes cochlear vibration and which may in suppression between schizophrenic patients turn generate sound. A small fraction of this and normal control subjects, with objective and biological energy is retransmitted backwards in non-invasive methods. As auditory abnormali- the form of a pressure wave to the tympanum ties are reported to be more consistent in via the oval window and ossicular chain. The hallucinating than in non- hallucinating schizo- consequent vibration of the tympanum gener- phrenic patients, we included only patients ates a low level acoustic signal which can be who reported auditory hallucinations. detected with a sensitive microphone in the outer auditory canal.27 There are diVerent Methods types of otoacoustic emission: the first major SUBJECTS class consists of continuous narrow band Twenty four subjects were recruited for the signals around one or more frequencies which study. All gave written consent. Exclusion can be found in the absence of any deliberate criteria included history of medical or neuro- acoustic stimulation. They are known as logical illness or trauma. Twelve were schizo- “spontaneous otoacoustic emissions”. Otoa- phrenic patients (four outpatients and eight coustic emissions can also occur as a broad inpatients) who met DSM-IV diagnostic crite- band acoustic signal in response to an evoking ria47 for chronic schizophrenia (duration of ill- click, and are then called “click evoked ness>2 years) with a mean illness duration of otoacoustic emissions.28 In humans, otoacous- 11.7 (SE 3.5) years (range 2–37 years) and a tic emissions are a unique tool for examining mean average age at symptom onset of 20.2 the cochlea, allowing direct non-invasive com- (SE 0.6) years (range 17–25 years). The clini- munication with the sensory cells. They are cal severity of the patients’ illness was assessed particularly sensitive in detecting hearing loss by the brief psychiatric rating scale (BPRS),48 and the fact that they are absent in patients the scale for assessment of negative symptoms with hearing loss exceeding 25–30 dB HL (see (SANS),49 and the scale for assessment of posi- 28 50 Probst et al for a review) shows that otoacous- tive symptoms (SAPS). There were five para- http://jnnp.bmj.com/ tic emission generation is related to optimal noid, two disorganised, and five undiVerenti- functioning of the ear. Kemp29 hypothesised ated schizophrenic patients, all reporting that discontinuities in outer hair cell distribu- auditory hallucinations (score 4.0 (SE 0.4); tion modified the sound energy produced by range 2–6 years). At the time of testing, 10 otoacoustic emissions. Moreover, click evoked patients were taking neuroleptic medication otoacoustic emissions have been found to (mean daily medication dose in decrease in amplitude when a noise is applied chlorpromazine-equivalents: 624 (SE 62.2) 30 31 in the contralateral ear. Such an eVect, in mg; range 380–950). Two patients had been on September 28, 2021 by guest. Protected copyright. which an eVerent pathway is able to aVect free of any treatment for at least 4 weeks. Seven cochlear mechanics, was initially described in patients were also receiving antiparkinsonism animal experiments.32 33 Evidence for eVerent treatment (tropatepine) with a mean dose of involvement comes not only from animal,34 35 14.3 mg (SE 2.0); range 10–20). All patients but also from human studies, in which it has were clinically stable at the time of evaluation been reported that this contralateral suppres- and testing. The 12 other subjects were normal sion of click evoked otoacoustic emission is controls with no history of psychiatric illness or absent or greatly reduced in patients with ves- neurological disorder. The mean ages of the tibular neurectomy.36–38 As this section con- two groups were statistically similar (31.9 (SE cerns the eVerent fibres, these findings provide 3.6) (range 21–58 years) for the schizophrenic one of the main arguments for medial olivoco- patients, and 29.5 (SE 3.3) (range 18–57 years) chlear system involvement in the contralateral for the normal controls (Mann-Whitney U test suppression eVect. The medial olivocochlear t=125.5, p=0.712)). Eight men and four system is part of the regulatory complex which women were included in each group. On the modulates or regulates cochlear activity and Edinburgh handedness scale,51 all subjects were auditory aVerent inputs, improving the detec- right handed with scores above 70. Mean tion of multitone complexes in noise.39–41 scores were statistically comparable between Abnormally reduced functioning of this system groups (92.5% (SE 3.3); range 70–100) for the has been found in hyperacusia,42 and autism,43 normal controls and 90.8% (SE 2.8); range two diseases in which impaired auditory 80–100) for the schizophrenic patients.

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HEARING TESTS if the signal to noise ratio exceeded 4 dB. The The battery of four tests was typically adminis- number of peaks/ear was also noted. For tered in the following order: medial olivocochlear exploration, the procedure allowed the equivalent attenuation to be Pure tone audiogram calculated. The equivalent attenuation allows Thresholds at 250, 500, 1000, 2000, 4000, and the quantification of medial olivocochlear 8000 Hz were measured in a soundproof room functioning, and it is defined as the decrease in using a Madsen DAIII audiometer. All the the ipsilateral stimulus (dB) which causes the subjects included in this study had auditory same reduction in click evoked otoacoustic threshold losses of less than 25 dB HL at all emission amplitude as does a 30 dB SL frequencies. contralateral acoustic stimulation.42 53 This cal- culation is made from the “echo” level Tympanogram presented at five intensities with and without Standard admittance screening was conducted contralateral acoustic stimulation (see above). using a manual tympanometer (Amplaid 702) The lateralisation of this contralateral suppres- to check the functional integrity of the middle sion eVect was quantified with an asymmetry ear. The threshold of the acoustic reflex to index corresponding to the relative diVerence contralateral broadband noise was also between equivalent attenuation for the right ear measured. All the subjects included in the and equivalent attenuation for the left ear. A present study (normal controls and schizo- positive value indicates a better functioning of phrenic patients) had a stapedial reflex with the medial olivocochlear system in the right ear threshold never below 80 dB SPL or above 100 and a negative value indicates a better function- dB SPL. The mean values obtained in the right ing in the left ear. and left ears did not diVer significantly between the two groups. STATISTICAL ANALYSIS Analysis was performed with SigmaStat® soft- Otoacoustic emission recordings and medial ware (Jandel Scientific). All data are expressed olivocochlear exploration as mean (SE). The group eVect, the ear eVect, All the measures were made in a sound- and the interaction of group and ear on total attenuated chamber, using the ILO92 equip- click evoked otoacoustic emission amplitude ment (Otodynamics® software, version 3.94 L), and equivalent attenuation were analyzed with described in detail elsewhere.52 The right ear two way repeated measures analysis of variance and left ear were investigated in random order. (RM ANOVA) on one factor. When the RM The subjects were instructed to relax, lie ANOVA was found to be significant at p<0.05 quietly, and remain awake. A probe was sealed (for either the two factors or the interaction), a with a perforated foam tip in the outer ear multiple comparison procedure was performed canal. Click evoked otoacoustic emissions were (Tukey test) to test diVerences between groups. obtained in response to a non-filtered click of A t test was used to compare the asymmetry 80 µs duration, presented at a repetition rate of index between the two groups. Z Tests were 50/s. Three hundred responses were averaged used to compare proportions. with a band pass of 500–6000 Hz. A first

recording used the non-linear diVerential mode Results http://jnnp.bmj.com/ to obtain click evoked otoacoustic emission at a OTOACOUSTIC EMISSIONS high stimulus intensity of around 83 (SE 3) dB Figure 1 A plots the mean values of click SPL (sound pressure level) for a time window evoked otoacoustic emission response level (by of between 2.6 and 20 ms. Spontaneous otoa- group and ear). The two way RM ANOVA on coustic emissions were then looked for. Finally, click evoked otoacoustic emission total ampli- the medial olivocochlear system was explored tude disclosed no eVect of group but an ear

by recording click evoked otoacoustic emis- eVect (F1, 22=9.85; p=0.005). Post hoc analyses

sions with and without contralateral acoustic by Tukey test indicated that the click evoked on September 28, 2021 by guest. Protected copyright. stimulation, following a protocol described otoacoustic emission amplitudes were signifi- elsewhere.42 Click evoked otoacoustic emission cantly larger in the right ear than in the left ear recording conditions were the same as above, (p<0.005). The interaction eVect between × except that five stimulus intensities, ranging (group ear) was significant (F1,22=5.63; between 60 and 72 dB SPL in 3 dB steps, were p=0.027). The post hoc Tukey test indicated applied in random order using the linear mode. that the diVerence between right ear and left For each intensity, one recording with and one ear reached significance only within the schizo- recording without contralateral acoustic stimu- phrenic patient group (p<0.001). lation were successively made, in random For spontaneous otoacoustic emissions in order. Each response was windowed, blanking the normal control group, the percentage of out the first 3.20 ms. The contralateral acous- subjects with right ear spontaneous otoacoustic tic stimulation was a 30 dB SPL continuous emissions was comparable with that for left ear broad band noise (band width 50–8000 Hz). spontaneous otoacoustic emissions (50%). These percentages were not significantly diVer- DATA PROCESSING ent from those obtained for the schizophrenic For each click evoked otoacoustic emission, a patient group (58% in the right ear and 33% in measure of total level (“echo”) was given in dB the left ear). On the other hand, schizophrenic SPL. In spontaneous otoacoustic emission patients tended to present multiple spontane- recordings, the presence or absence of a ous otoacoustic emissions more often than did spectrum peak was noted. A peak was retained normal controls (fig 1 B). Although spontane-

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15 RE A A 1.0

10 0.0 Asymmetry index 5 –1.0

CEOAE amplitude (dB) LE

Normal controls Schizophrenic patients 0 B RE LE RE LE 0.4

Normal controls 0.3 Schizophrenic patients 0.2 7 B 0.1 6 0 5 –0.1 Asymmetry index

4 –0.2

3 –0.3 Figure 3 (A) Individual and (B) mean (SE) equivalent 2 attenuation asymmetry index plotted according to group: normal controls and schizophrenic patients. A positive value indicates a right ear advantage and a negative value a left 1 ear advantage. **p<0.01. Number of spontaneous responses

0 RE LE RE LE MOC MEASUREMENTS Figure 1 (A) Mean (SE) amplitude of click evoked Functioning otoacoustic emissions and (B) peak number of spontaneous Figure 2 shows the mean absolute equivalent otoacoustic emissions for the normal control subjects and attenuation values for each group and ear. The schizophrenic patients. *p<0.05. contralateral suppressive eVect was statistically comparable between groups, with a non- ous otoacoustic emission peaks predominated significant eVect of group disclosed by two way http://jnnp.bmj.com/ in the right ear in both groups, the schizo- RM ANOVA. There was, however, a significant phrenic patients’ right ear values tended to be eVect of ear (F1, 22=4.23, p=0.05) and a signifi- higher. However, none of these diVerences cant interaction between group and ear (F1, reached significance. 22=10.13, p=0.004). Post hoc Tukey tests indicated that the normal controls showed a significantly greater contralateral suppressive RE LE RE LE eVect in the right than the left ear (p<0.001), 0 and such asymmetry was not found in the on September 28, 2021 by guest. Protected copyright. schizophrenic patient group.

–1 Laterality This absence of systematic lateral diVerence in schizophrenic patients, unlike normal controls, –2 is illustrated in fig 3. When the individual data are considered (fig 3 A), it is seen that 10 out of 12 normal controls (83%) presented signifi- –3 cantly greater right ear suppression—that is, a right ear advantage—whereas of schizophrenic patients only three (25%) showed such right Equivalent attenuation (dB) –4 ear advantage, eight presenting greater left ear Normal controls suppression and one showing no laterality. Schizophrenic patients Mean asymmetry index values are plotted –5 for both groups in fig 3 A. They were Figure 2 Mean (SE) equivalent attenuation obtained in significantly diVerent between the two groups normal control subjects and schizophrenic patients for the (t test: t=3.32; p<0.003) but only the mean right and left ears. *p<0.05. The more negative the equivalent attenuation, the greater the contralateral value of the normal control group diVered from suppression of click evoked otoacoustic emissions. 0(t=3.93; p<0.001).

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Discussion system—and is probably involved in the early This study is the first direct objective compari- auditory processing.59 There is strong evidence son between normal controls and schizo- that schizophrenic patients, particularly those phrenic patients of functional peripheral audi- with auditory hallucinations, have reduced cer- tory processing thought to be involved in the ebral asymmetry in the region of the planum filtering of acoustic input. As expected, schizo- temporale.(see Ross and Pearlson60 for a phrenic patients diVered from normal controls, review61) Thus, the absence of functional but the distinction was found only in compari- medial olivocochlear asymmetry found in sons related to laterality: in all other cases, no schizophrenic patients may be attributed to an significant diVerence appeared between impairment of the central modulation influenc- groups. ing the auditory eVerent pathways, and so Schizophrenic patients had otoacoustic reflects the reduced central auditory asymme- emission amplitudes comparable with those of try in these cortical areas. Based on this the normal controls, with however, particularly hypothesis, the present study could support the high click evoked intensity and spontaneous notion that schizophrenia involves certain otoacoustic emission number in the right ear. abnormalities in cerebral laterality.62–64 How- The literature mentions fluctuating but signifi- ever, no significant diVerence in suppression cant rises in hearing threshold, particularly in was found between normal controls and hallucinating schizophrenic patients, in whom schizophrenic patients and it was not possible the asymmetry in favour of the right ear is here to determine on which side (right or left) absent.18 As otoacoustic emissions test inner the medial olivocochlear system was more ear functional integrity, and degrade rapidly impaired and on which it was more activated. when hearing thresholds rise, there would seem Atypical lateralisation of auditory function in to be a mismatch between our data, obtained schizophrenic patients compared with normal with an objective test, and the findings of controls has also been reported for other func- Mathew et al,18 obtained with a subjective test tional measures such as right ear advantage in of hearing perception levels. There is, however, dichotic listening tests,65 66 or P300,67 which, another possible interpretation. The presence being subjective procedures requiring active of otoacoustic emissions is a reliable indicator participation from subjects, are thought to of outer hair cell structural integrity. It can be involve attention processes which are greatly hypothesised that higher click evoked otoa- impaired in schizophrenia.68 The strength of coustic emission amplitude and spontaneous the present study is that all the procedures were otoacoustic emissions having multiple spectral objective, and subjects had no response to pro- peaks reflect an increase in cochlear amplifica- vide nor any cognitive task to perform. Our tion. Such a modification could aVect nervous findings thus cannot be attributed to any activity generated in the aVerent, as found in alteration of attention processes, but rather animals,54 disrupting the processing of infor- identify, in a significant fraction of schizo- mation, and which could perhaps explain the phrenic patients, disturbances indicating degradation of hearing threshold described.18 processing anomalies of auditory message per- Medial olivocochlear functioning was quantita- ception as of peripheral level, which could in tively similar between normal controls and turn be related to anomalies in central laterali-

schizophrenic patients, suggesting that the sation. http://jnnp.bmj.com/ auditory dysfunction found in such patients is It is important to acknowledge several diVerent from the impairment described in limitations of the present study. Firstly, there is autistic children, in whom the medial olivoco- the possible influence of the antipsychotic chlear system was found to be significantly less medication taken by most of the schizophrenic functional than in controls.43 In fact, the main patients in this study. However, the primary finding of the present study is that schizo- eVect of antipsychotic medication is an im- phrenic patients show an absence of normal provement in cognitive functions such as 69 functional medial olivocochlear asymmetry. attention (see Green and King for a review. on September 28, 2021 by guest. Protected copyright. Whereas mean medial olivocochlear function- This eVect has been seen to be lateralised, ing was better in the right ear of normal advantaging left hemisphere attentional proc- controls, confirming previous investiga- esses (seeGruzelier70 for a review). The present tions,45 46 right handed schizophrenic patients study, however, used a methodology which showed the kind of non-lateralised medial does not rely on subjects’ conscious processing, olivocochlear functioning seen in left handed thus limiting the influence of cognitive process- normal controls.46 This absence of medial ing and of the attention component in particu- olivocochlear function asymmetry cannot be lar. Moreover, our findings with patients under linked to the increased click evoked otoacoustic neuroleptic drugs tend to show an absence of emission intensity in the right ear.55 56 It is now lateralisation, which seems to further confirm well established that the auditory pathways are the fact that this procedure does not involve crossed, so that acoustic signals perceived in such attentional processes. Hence, there is no the right ear are integrated by auditory areas particular evidence that the absence of right ear located in the left temporal cortex. Moreover, advantage in medial olivocochlear functioning the planum temporale, thought to play an could be attributable to any such medication important part in language, is larger in this left eVect. On the other hand, this persistent loss of hemisphere for normal right handed sub- asymmetry even under medication might con- jects,57 58 receives direct auditory projections stitute a state independent vulnerability from the medial geniculate body—the subcor- marker, as it seems to be the case for the P300 tical relay nucleus for the auditory aVerent abnormalities found in the auditory mode.

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This is also an important argument against any 12 Hirayasu Y, Potts GF, O’Donnel BF, et al. Auditory mismatch negativity in schizophrenia: evaluation with high significant impact of the second possible density recording voltage. Am J Psychiatry 1998;155:1281– limitation of the present work, the existence of 4. 13 Igata M, Ohta M, Hayashida Y, et al. Normalization of audi- auditory hallucinations at test time, this factor tory brainstem responses resulting from improved clinical being always diYcult to quantify. For technical symptoms in schizophrenia. Schizophr Res 1995;16:81–2. 14 Venables P. Input dysfunction in schizophrenia. In: Maher reasons, it must be underlined that the patients BA, ed. Progress in experimental personality research. Orlando, were always tested outside hallucinating peri- FL: Academic Press, 1964:1–47. ods. 15 Gruzelier J. The cardiac response of schizophrenics to orienting signal and non-signal tones. Biol Psychiatry 1975; Lastly, our study concerned peripheral audi- 3:143–55. tory mechanisms only in schizophrenic pa- 16 McGhie A, Chapman J. Disorders of attention and perception in early schizophrenia. Br J Med Psychol 1961;34:103– tients who reported several times auditory hal- 16. lucinations as compared with normal controls, 17 Gruzelier J, Hammond NV. Gain, losses, and lateral diVerences in the hearing of unmedicated schizophrenic and so does not provide data as to whether the patients. Br J Psychol 1979;70:319–30. abnormal peripheral auditory asymmetry in 18 Mathew VM, Gruzelier J, Liddle PF. Lateral asymmetries in auditory acuity distinguish hallucinating from non- schizophrenia concerns psychosis in general, or hallucinating schizophrenic patients. Psychiatry Res 1992; is specific to schizophrenia itself, or indeed to 46:127–138. 19 Dallos P. The active cochlea. J Neurosci 1992;12:4575–85. auditory hallucinations. Further studies com- 20 Rasmussen GL. EVerent fibers of the cochlear nerve and paring subjects with psychotic depression, cochlear nucleus. In: Rasmussen GL, Windle WL, eds. Neural mechanisms of auditory and vestibular systems. non-psychotic depression, and schizophrenia Springfield: Charles C Thomas, 1960:105–15. with and without auditory hallucinations seem 21 Warr WB, Guinan JJJr, White JS. Organization of the eVer- ent fibers: the lateral and medial olivocochlear systems. In: to be warranted. Altshuler R, Bobbin RP, HoVman D, eds. Neurobiology of To summarise the present study is, to our hearing: the cochlea. New York: Raven Press, 1986:333–48. 22 Warr WB. Organization of olivocochlear eVerent system in knowledge, the first to explore objectively, in mammals. In: Webster DB, Popper AN, Fay RR, eds. schizophrenia, certain functional auditory Mammalian auditory pathway: neuroanatomy. New York: mechanisms thought to be under cerebral con- Springer Verlag, 1992:420–48. 23 Guinan JJJr. Physiology of olivocochlear eVerents. In: Fay trol, and provides a promising approach for the RR, Popper AN, eds. The cochlea. New York: Springer Ver- objective study of alterations in auditory lag, 1996:435–502. 24 Kemp DT. Stimulated acoustic emissions from within the perception in schizophrenia. This medial olivo- human auditory system. J Acoust Soc Am 1978;64:1386–1. cochlear system lateralisation, which could be 25 Brownell WE, Bader CR, Bertrand D, et al. Evoked mechanical responses of isolated cochlear outer hair cells. of importance in peripheral auditory filtering, Science 1985;277:194–6. could be an interesting “trait-like” cognitive 26 Zenner HP. Motile responses in outer hair cells. Hear Res 1986;22:83–90. marker in schizophrenia and its measurement 27 Kemp DT. Otoacoustic emissions, travelling waves and might be usefully integrated in the functional cochlear mechanisms. Hear Res 1986;22, 95–104. 28 Probst R, Lonsbury-Martin BL, Martin GK. A review of exploration test battery, so as better to otoacoustic emissions. J Acoust Soc Am 1991;89:2027–67. understand the auditory abnormalities which 29 Kemp DT. Evidence of mechanical nonlinearity and characterise some mental diseases such as frequency selective wave amplification in the cochlea. Archives of Otology Rhinology and Laryngology 1979;224:37– schizophrenia. The present data suggest that 45. additional studies on a larger sample are 30 Collet L, Kemp DT, Veuillet E, et al.EVect of contralateral auditory stimuli on active cochlear micro-mechanical needed not only to improve the statistical properties in human subjects. Hear Res 1990;43:251–62. power regarding non-significant findings but 31 Veuillet E, Duclaux R, Collet L. EVect of contralateral acoustic stimulation on active cochlear micromechanical also to compare between subtypes. properties in human subjects: dependence on stimulus

variables. J Neurophysiol 65:724–35. http://jnnp.bmj.com/ 32 Mountain DC. Changes in endolymphatic potential and crossed olivocochlear bundle stimulation alter cochlear We thank Drs Berthaud, Burgat, Dubuis, and Parriaud, Hôpital mechanics. Science 1980;210:71–2. du Vinatier, Lyon, France, for facilitating patient recruitment. 33 Siegel JH, Kim DO. EVerent neural control of cochlear mechanics? Olivocochlear bundle stimulation aVects cochlear biomechanical nonlinearity. Hear Res 1982;6:171–82. 1 Hetrick WP, Youssef MM, Jin Y, et al. A structured clinical 34 Puel JL, Rebillard G. EVects of contralateral sound stimula- assessment of external sensory gating deﬁcit in schizophre- tion on the distortion product 2F1-F2: evidence that the nia. Schizophr Res 1995;15:177–8. medial eVerent system is involved. J Acoust Soc Am 2 Pritchard WS. Cognitive event-related potential correlates 1990;87:1630–5. of schizophrenia. Psychol Bull 1986;100:43–66. 35 Warren EH, Liberman MC. EVects of contralateral sound

3 Hill H, Weisbrod M. The relation between asymmetry and on auditory nerve responses: I. Contributions of cochlear on September 28, 2021 by guest. Protected copyright. amplitude of the P300 field in schizophrenia. Clin eVerents. Hear Res 1989;37:89–104. Neurophysiol 1999;110:1611–17. 36 Williams EA, Brookes GB, Prasher DK. EVects of 4 Faux SF, Torello MW, McCarley RW, et al. P300 in contralateral acoustic stimulation on acoustic emissions schizophrenia: confirmation and statistical validation of following vestibular neurectomy. Scandinavian Audiology temporal region deficit in P300 topography. Biol Psychiatry 1993;22:197–203. 1988;23:776–90. 37 Williams EA, Brookes GB, Prasher DK. EVects of olivoco- 5 McCarley RW, Faux SF, Shenton ME, et al. Event-related chlear bundle section on otoacoustic emissions in humans: potentials in schizophrenia: their biological and clinical eVerent eVects in comparison with control subjects. Acta correlates and a new model of schizophrenic pathophysiol- Otolaryngol 1994;114:121–9. ogy. Schizophr Res 1991;4:209–31. 38 Giraud AL, Collet L, Chéry-Croze S, et al. Evidence of a 6 Adler LE, Patchman E, Franks R, et al. Neurophysiological medial olivocochlear involvement in contralateral suppres- evidence for a defect in neuronal mechanisms involved in sion of otoacoustic emissions in humans. Brain Res sensory gating in schizophrenia. Biol Psychiatry 1982;17: 1995;705:15–23. 639–54. 39 Micheyl C, Morlet T, Giraud AL, et al. Contralateral 7 Boutros NN, Zouridakis G, Overall J. Replication and suppression of evoked otoacoustic emissions and detection extension of P50 findings in schizophrenia. Clin Electroen- of a multi-tone complex noise. Acta Otolaryngol 1995;115: cephalogr 1991;22:40–5. 178–82. 8 Ward P, HoVer LD, Liebert BJ, et al. Replication of P50 40 Micheyl C, Collet L. Involvement of medial olivocochlear auditory gating deficit in Australian patients with schizo- system in the detection of tones in noise. J Acoust Soc Am phrenia. Psychiatry Res 1996;64:121–35. 1996;99:1604–10. 9 Shelley AM, Ward PB, Catts SV, et al. Mismatch negativity: 41 Micheyl C, Perrot X, Collet L. Relationship between an index of preattentive processing deficit in schizophrenia. auditory intensity discrimination in noise and olivocochlear Biol Psychiatry 1991;30:1059–62. eVerent system activity in humans. Behav Neurosci 10 Javitt DC, Doneshka P, Grochowski S, et al. Impaired 1997;111:801–7. mismatch negativity generation reflects widespread dys- 42 Collet L, Veuillet E, Bene J, et al.EVects of contralateral function of working memory in schizophrenia. Arch Gen white noise on click-evoked emissions in normal and Psychiatry 1995;52:550–8. sensorineural ears: towards an exploration of the medial 11 Alain C, Hargrave R, Woods DL. Processing of auditory olivocochlear system. Audiology 1992;31:1–7. stimuli during visual attention in patients with schizophre- 43 Collet L, Roge B, Descouens D, et al. An objective auditory nia. Biol Psychiatry 1998;44:1151–9. dysfunction in infantile autism. Lancet 1993;342:923–4.

www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.70.1.88 on 1 January 2001. Downloaded from 94 Veuillet,GeorgieV, Philibert, et al

44 HuVman RF, Henson OWJr. The descending auditory 58 Steinmetz H. Structure, function and cerebral asymmetry: pathway and acousticomotor systems: connections with the In vivo morphometry of the planum temporale. Neurosci inferior colliculus. Brain Res Brain Res Rev 1990;15:295– Biobehav Rev 1996;20:587–91. 323. 59 Binder JR, Frost JA, Hammeke TA, et al. Function of the left 45 Khalfa S, Collet L. Functional asymmetry of medial planum temporale in auditory and linguistic processing. olivocochlear system in humans: towards a peripheral audi- Brain 1996;119:1239–47. tory lateralization. Neuroreport 1996;7:993–6. 46 Khalfa S, Veuillet E, Collet L. Inﬂuence of handedness on 60 Ross CA, Pearlson GD. Schizophrenia, the heteromodal peripheral auditory asymmetry. Eur J Neurosci 1998b;10: association neocortex and development: potential for a 2731–7. neurogenic approach. TINS 1996;19:171–6. 47 American Psychiatric Association. Diagnostic and statistical 61 Crow TJ. Schizophrenia as a failure of hemispheric manual of mental disorders. 4th ed. Washington, DC: Ameri- dominance for language. Trends Neurosci 1997;20:339–43. can Psychiatric Press, 1994. 62 Flor-Henry P. Psychosis in temporal lobe epilepsy. Epilepsia 48 Overall JR, Gorham DR. The brief psychiatric rating scale. 1969;10:363–95. Journal of Operational Psychiatry 1980;11:48–64. 63 Crow TJ. Temporal lobe asymmetries as the key to the etiol- 49 Andreasen NC. The scale for the assessment of negative ogy of schizophrenia. Schizophr Bull 1990;16:433–43. symptoms (SANS). Iowa City, IA: The University of Iowa, 64 Crow TJ, Ball J. Schizophrenia as an anomaly of 1983. development of cerebral asymmetry. A postmortem study 50 Andreasen NC. The scale for the assessment of positive and a proposal concerning the genetic basis of the disease. symptoms (SAPS). Iowa City, IA: The University of Iowa, 1984. Arch Gen Psychiatry 1989;46:1145–50. 51 Oldﬁeld RC. The assessment and analysis of handedness. 65 Wexler BE, Giller ELJr, Southwick S. Cerebral laterality, Neuropsychologia 1971;9:97–111. symptoms and diagnosis in psychotic patients. Biol Psychia- 52 Kemp DT, Ryan S, Bray P. A guide to the eVective use of try 1991;29:103–16. otoacoustic emissions. Ear Hear 1990;11:93–105. 66 Bruder GE, Rabinowicz E, Towey J, et al. Smaller right ear 53 Veuillet E, Bazin F, Collet L. Objective evidence of periph- (left hemisphere) advantage for dichotic fused words in eral auditory disorders in learning-impaired children. Jour- patients with schizophrenia. Am J Psychiatry 1985;152: nal of Audiological Medicine 1999;8:18–29. 932–5. 54 Powers NL, Salvi RJ, Wang J, et al. Elevation of auditory 67 McCarley RW, Shenton M, O’Donnell BF et al. Auditory thresholds by spontaneous cochlear oscillations. Nature P300 abnormalities and left posterior superior temporal 1995;375:585–7. gyrus volume reduction in schizophrenia. Arch Gen 55 Veuillet E, Duverdy-Bertholon F, Collet L. EVect of Psychiatry 1993;50:190–7. contralateral acoustic stimulation on the growth of 68 BraV DL. Information processing and attention dysfunc- click-evoked otoacoustic emissions in humans. Hear Res 1996;96:128–35. tions in schizophrenia. Schizophr Bull 1992;19:233–59. 56 Khalfa S, Micheyl C, Veuillet E, et al. L. Peripheral auditory 69 Green JF, King DJ. Cognitive functioning in schizophrenia. assessment using TEOAEs. Hear Res 1998;121:29–34. CNS Drugs 1996;6:382–98. 57 Geschwind N, Levitsky W. Human brain: left-right asym- 70 Gruzelier JH. Functional neuropsychophysiological asymmetries in temporal speech region. Science 1968;161:186– metry in schizophrenia: a review and reorientation. Schizo- 7. phr Bull 1999;25:91–120. http://jnnp.bmj.com/ on September 28, 2021 by guest. Protected copyright.