Evidence of Normal Hearing Laterality in Familial Schizophrenic Patients and Their Relatives Timothea Toulopoulou,1,2 Siew E

American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:73–76 (2008)

Evidence of Normal Hearing Laterality in Familial Schizophrenic Patients and Their Relatives Timothea Toulopoulou,1,2 Siew E. Chua,1,3* Isabel Lam,3 Vinci Cheung,3 Robin M. Murray,1 and Anthony S. David1 1Department of Psychological Medicine, Institute of Psychiatry, King’s College London, London, UK 2Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 3Department of Psychiatry, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Dichotic listening (DL) has been used as a tool to Sakuma et al. [1996] reviewed all studies from 1975 to 1995 and investigate possible left cerebral dysfunction in found that 22 of 24 studies reported reduction in REA in schizophrenia. However, the wide range of DL schizophrenia. However, the proposed functional asymmetry tests (e.g., words, emotions, sentences) as well as may be a function of poorer cognitive performance among patient groups (‘‘heterogeneity’’) has introduc- patients with schizophrenia [Sakuma et al., 1996], or related to ed several confounders. Assessing relatives of illness duration [Loberg et al., 2002] and clinical state [Wexler patients with schizophrenia may overcome some et al., 1991a; Green et al., 1994; Sakuma et al., 1996; Loberg of these problems, and may be more useful in et al., 2006], that normalizes on recovery [Wexler et al., 1991a; determining if loss of functional cerebral later- Sakuma et al., 1996; Loberg et al., 2002]. Nonetheless, if DL is ality in schizophrenia is a state or a trait phenom- proved to demonstrate the loss of functional cerebral laterality enon. The fused consonant-vowel DL test was in schizophrenia, it might serve as a useful marker for detec- administered to 114 subjects: 20 individuals with tion and monitoring of the disorder. One way of investigating familial schizophrenia, 42 of their healthy rela- whether the abnormal cerebral functional laterality is a state tives, and 52 healthy volunteers. We did this to or trait characteristic of schizophrenia is by looking for the investigate whether the normal language proces- impairment not only in the patients, but also in their non- sing asymmetry—a right ear advantage (REA)—is psychotic relatives. If the healthy relatives turn out to show a present, and whether it could serve as a marker similar deficit in language processing asymmetry with that of for genetic liability. General performance accu- their ill relatives, then this would suggest that abnormalities racy level was lower in schizophrenia patients of functional cerebral laterality is an indicator of genetic risk and their relatives but the expected REA was for schizophrenia. present in all groups. Adjusting for age, accuracy, In this study, we used the fused consonant-vowel DL task to and obligate status made no difference. In conclu- examine whether there is any disturbance in functional sion, familial schizophrenic patients and their language lateralization in familial schizophrenia. A second relatives have normal REA and hearing laterality objective was to determine whether it can serve as a trait on the fused DL test. ß 2007 Wiley-Liss, Inc. marker by assessing not only the patients, but also their non- psychotic relatives. The advantage of using a sample of KEY WORDS: endophenotype; cerebral lateral- relatives is that they do not experience psychotic symptoms, ity; dichotic listening and have not been exposed to medication, whose effects may confound the performance of patients. We expected to find a Please cite this article as follows: Toulopoulou T, Chua REA reduction in both the patients with schizophrenia and SE, Lam I, Cheung V, Murray RM, David AS. 2008. their relatives. Evidence of Normal Hearing Laterality in Familial Schizophrenic Patients and Their Relatives. Am J Med MATERIALS AND METHODS Genet Part B 147B:73–76. Recruitment of the Sample One hundred fourteen subjects participated in the study, INTRODUCTION including 20 subjects with DSM-IV schizophrenia and 42 of their healthy relatives. These subjects came from fifteen Dichotic listening (DL) performance using phonological families with two or more schizophrenic members and where stimuli usually produces a significant right ear advantage there was evidence of unilineal transmission (disease trans- (REA). The REA is greater after callosotomy [Sugishita et al., mitted through one parent only). The families were referred 1995] since left ear input cannot reach the language dominant from clinics and voluntary care organizations in the United left hemisphere, and decreases have been reported after left- Kingdom. This project was part of a wider study of the relatives hemisphere lesions [Hugdahl and Wester, 1992], and in of psychotic patients (Maudsley Family Study) and full details dyslexia [Hugdahl et al., 1995] anxiety, depression [Bruder of the screening criteria and clinical assessments are stated et al., 1989, 1999] as well as psychosis [Lishman et al., 1978]. elsewhere [Frangou et al., 1997; Toulopoulou et al., 2003a,b, 2004, 2006]. Briefly, the patients were all chronic, mostly in remission and receiving antipsychotic medication. Exclusion criteria for all subjects were as follows: history of head trauma resulting in loss of consciousness for 1 hr or more, neurological *Correspondence to: Siew E. Chua, Department of Psychiatry, illness, headaches requiring medical consultation, substance The University of Hong Kong, Queen Mary Hospital, Pokfulam abuse in the past 12 months. In addition, subjects had no Road, Hong Kong, China. E-mail: [email protected] history of hearing difficulties nor ear, nose and throat referral. Received 23 January 2007; Accepted 15 June 2007 52 unrelated normal healthy volunteers were recruited by DOI 10.1002/ajmg.b.30587 announcements in local newspapers (see Table I for sample

ß 2007 Wiley-Liss, Inc. 74 Toulopoulou et al.

TABLE I. Demographic and Clinical Characteristics of the Sample (n ¼ 114)

Schizophrenics Relatives Healthy volunteers Characteristics (n ¼ 20) (n ¼ 42) (n ¼ 52) Age in years—mean (SD) 34 (8.6)a 46 (14.9)a 35 (12.6)a Sex (% of males) 52 38 56 Handedness (% Rt-handers) 86 90 92 NART IQ—mean (SD) 102 (12) 105 (13) 109 (10) Years of education—mean (SD) 13 (2) 13 (3) 12 (4) Best premorbid social class 90 93 80 (%classes I–III/classes IV–VI) Age at ﬁrst diagnosis—mean (SD) 23.5 (3.9) n/a n/a Illness duration in years—mean (SD) 13.4 (9.1) n/a n/a

aKey: Significant difference in age between groups (ANOVA) with relatives being significantly older than both schizophrenics (t tests of independent samples, two tailed P ¼ 0.009) as well as controls (t tests of independent samples, two tailed P ¼ 0.0008). description). Healthy volunteers were broadly comparable as a Laterality index: calculated from the non-identical 30 pairs group to schizophrenic subjects on age, gender, socio-economic of CV syllables as follows: status, and ethnicity, fulfilled entry criteria, and were free of any personal or family history of major psychiatric disorders. All subjects gave informed consent to participate in the project. Laterality Indexð%Þ Clinical Assessments ðRight Ear Left EarÞ correct responses ¼ 100 All interviews were carried out blind to diagnostic and family ðRight Ear þ Left EarÞ correct responses status. DSM-IV [American Psychiatric Association, 1994] diagnoses were made using the Schedule for Affective Dis- orders and Schizophrenia—Lifetime version [Spitzer and Statistical Analysis Endicott, 1978] on all subjects in a face-to-face interview with the same interviewer. Additional information regarding psycho- pathology was obtained from family members and hospital (1) The schizophrenia patients, relatives and controls were records. An extensive family history was taken using a compared on socio-demographic variables using ANOVA modified interview based on the Family History Research for continuous variables (age, years of education, premor- Diagnostic Criteria [Endicott et al., 1975]. A semi-structured bid IQ, accuracy) and Chi-square test for dichotomous interview collected demographic and other data. Best premor- variables (sex, handedness, social class). Subjects whose bid social class was based upon best premorbid occupation and screening performance accuracy was poor (accuracy 3/6), related to categories of the Office of Population Censuses and as a result of inability to reliably distinguish the syllables Surveys [1991]. Unemployed or retired subjects were coded by were excluded from the analysis. their last occupation. (2) Laterality index was compared between schizophrenics, relatives and controls, and potentially confounding varia- The Dichotic Listening (DL) Test bles (age, premorbid IQ, accuracy level) were entered into Any subject incidentally detected to be hard of hearing was the analysis as covariates. The analysis was repeated to excluded. As a further precaution against any inequalities in compare patients with schizophrenia, their relatives the sound delivery system, earphones were reversed halfway (including separate analyses for presumed obligate car- through the DL test. riers and non-presumed obligate carriers) and controls. We chose to use the fused consonant-vowel test, which unlike Presumed obligate carriers were defined as non-psychotic other types of DL tests employs only syllables. Thus it is individuals who had a parent or a sibling as well as an free from bias for semantic content, or emotional arousal, or offspring with psychosis [Toulopoulou et al., 2005]. sequencing of words or sentences. Basically, it involves the simultaneous presentation of one syllable to each ear, after which the subject has to report which syllable was heard more RESULTS clearly. For example, the subject may hear ‘‘da’’ to the left ear and ‘‘ka’’ to right ear. There are six syllables altogether (‘‘da,’’ Table I shows the sample characteristics. There was no ‘‘ba,’’ ‘‘pa,’’ ‘‘ta,’’ ‘‘ga,’’ ‘‘ka’’) and the subject hears one pair every significant difference between the groups on sex, handed- 3 sec from a cassette-recorder connected to earphones worn by ness, years of education, best premorbid social class, and the subject. In total, there are 36 pairs, consisting of 30 pairs premorbid IQ. Age differed between the groups (F ¼ 10.6, where the two syllables are different (e.g., ‘‘da’’ to left ear, ‘‘ka’’ P < 0.0001), with relatives being older than both the schizo- to right ear) and 6 pairs where they are identical (e.g., ‘‘da’’ to phrenic group (P ¼ 0.009) and healthy volunteer group both ears). Responses are recorded for all 36 pairs. Subjects (P ¼ 0.0008). were told that there were six response options. In addition they The difference in general performance accuracy level were shown a card with the six options available to point to. between the three groups was significant (F ¼ 4.96, P ¼ 0.01) Test-retest reliabilities using this consonant-vowel test is and persisted after covarying for age. The sample had a mean around 0.80. accuracy score of 5.2 (SD 0.9). The schizophrenic group The following scores were calculated: obtained the lowest score (4.75, SD 0.9), and the healthy General performance accuracy screen: calculated from the volunteers the best (5.59, SD 0.7), with the relatives scoring in identical 6 pairs of CV syllables, total 6/6. between (5.0, SD 0.9). Laterality in Familial Schizophrenia 75

Accordingly, age and accuracy were entered into the analysis [1999] study, schizophrenic patients asked to direct their as covariates. attention either to the right ear or the left one were sur- prisingly unsuccessful. The presumption is that the internal Comparison of Schizophrenics, Relatives, and Healthy auditory hallucinations they were experiencing had the effect Volunteers for Ear Advantage/Laterality Index of saturating their auditory processing system. This could account for the failure to process external auditory stimuli to The majority of subjects had a clear REA. There was no the preferred right ear, and account for the reduced REA under significant difference in laterality index between the groups conditions of directed attention. Similarly, Oleary et al. [1996] (F ¼ 0.541, P ¼ .584; patients: mean ¼ 15.9, SD ¼ 38.3; rela- scanned actively psychotic patients off all antipsychotics and tives: mean ¼ 23.6, SD ¼ 30.8; controls: mean ¼ 19.7, SD ¼ observed that these patients were unable to shift auditory 21.9). The results remained non-significant after entering age attention. and accuracy level as covariates in the analyses (total sample: This study should be seen in the context of the following F ¼ 0.532, P ¼ 0.661; patients versus controls: F ¼ 0.284, limitations. Even though we excluded any participant that was P ¼ 0.60; relatives versus controls: F ¼ 0.520, P ¼ 0.473). There incidentally detected to be hard of hearing we did not formally was no difference in laterality between males and females, and assess their hearing or compared hearing acuity in right versus the results did not differ when left-handers were excluded. left ear. It is possible a left hearing impairment to have Finally, when the groups were classified by obligate carrier produced these results in the patient and relatives; though this status (n ¼ 7) there was no difference either. in itself would have been of interest. Second, some studies that reported laterality differences used word, instead of conso- DISCUSSION nant-vowel, stimuli. Our results might have been different if we used a word DL paradigm. The patients and their relatives performed the initial Taking all these findings into account, our data from the ‘screening’ binaural listening task less accurately than healthy fused consonant-vowel DL test do not support abnormal controls. In the case of the relatives, it is possible that this is hearing laterality as a genetically determined trait marker because they are significantly older than the other two groups. for schizophrenia. The most likely explanation is that this reflects a general non-specific performance impairment which will introduce statistical noise to the estimate of REA. The possibility that the ACKNOWLEDGMENTS finding may be a function of the genetic liability for schizophrenia cannot be excluded, but we would need an epidemio- We are grateful to Dr. Pak Sham for statistical advice and logical sample to explore this effect. to Dr. Thor Sigmundssun for his assistance in the clinical Familial schizophrenic patients and their relatives had a assessments. We would also like to thank Dr. Tonmoy Sharma normal REA. Our patients were mostly in remission and living and Ms Heather King. in the community. The results of the present study concur with evidence from familial schizophrenia studies of smaller samples [Ragland et al., 1992; Malaspina et al., 1998]. It is also in keeping with our previous findings in the same sample, which REFERENCES showed no differences between the groups in the volume of the American Psychiatric Association. 1994. Diagnostic and statistical manual corpus callosum, the major conduit for inter-hemispheric trans- of mental disorders (DSM-IV). Washington, DC: APA. mission of auditory information [Chua et al., 2000]. Bruder G, Rabinowicz E, Towey J, Brown A, Kaufmann CA, Amador X, It is arguable that abnormal laterality reported on the DL Malaspina D, Gorman JM. 1995. Smaller right ear (left-hemisphere) test may be related to hallucinations rather than the disorder advantage for dichotic fused words in patients with schizophrenia. Am J per se [Loberg et al., 2004]. For example, normal laterality has Psychiatry 152:932–935. been shown in early-onset schizophrenic patients [Oie et al., Bruder GE. 1983. Cerebral laterality and psycho-pathology—A Review of 1998] as well as schizophrenic patients in clinical remission Dichotic-Listening Studies. Schizophr Bull 9:134–151. [Bruder, 1983]. Auditory hallucinations [Green et al., 1994; Bruder GE, Quitkin FM, Stewart JW, Martin C, Voglmaier MM, Harrison Levitan et al., 1999] or positive symptoms [Bruder et al., 1995] WM. 1989. Cerebral laterality and depression: Differences in perceptual asymmetry among diagnostic subtypes 22. J Abnorm Psychol 98:177– have been shown to be associated with a reduced REA. Carr 186. and Wale [1988] showed acutely psychotic medicated patients Bruder GE, Wexler BE, Stewart JW, Price LH, Quitkin FM. 1999. were less accurate on the DL task but no difference in hearing Perceptual asymmetry differences between major depression with or asymmetry compared with normal controls. However, a study without a comorbid anxiety disorder: A dichotic listening study. comparing psychotic patients with a history of frequent J Abnorm Psychol 108:233–239. hallucinations (though not necessarily hallucinating at the Carr V, Wale J. 1988. The Effects of antipsychotic-drugs and symptomatol- time) against those with very few or minimal hallucinations ogy on perceptual asymmetry in schizophrenia. J Neurol Neurosurg showed no differences on a similar DL task [Rossell et al., Psychiatry 51:1531–1537. 2001]. Furthermore DL parameters were unrelated to meas- Chua SE, Sharma T, Takei N, Murray RM, Woodruff PWR. 2000. A magnetic ures of corpus callosum morphology. Nevertheless, DL and resonance imaging study of corpus callosum size in familial schizo- specifically the REA deserves scrutiny as a possible ‘‘state phrenic subjects, their relatives, and normal controls. Schizophr Res 41:397–403. marker’’ of auditory hallucinations. The symptom should also be considered as a potential confound of DL task performance Endicott J, Andreasen NC, Spitzer RL. 1975. Family history research diagnostic criteria. USA, New York: New York State Institute. [Loberg et al., 2006]. Ragland et al. [1992] compared 18 pairs of monozygotic Frangou S, Sharma T, Sigmudsson T, Barta P, Pearlson G, Murray RM. 1997. The Maudsley Family Study .4. Normal planum temporale twins discordant for schizophrenia with 7 pairs concordant for asymmetry in familiar schizophrenia—a volumetric MRI study. Br J schizophrenia with 7 pairs of healthy twins. They found that all Psychiatry 170:328–333. had REA, the affected twins to a lesser degree than the healthy Green MF, Hugdahl K, Mitchell S. 1994. Dichotic-listening during auditory twins. hallucinations in patients with schizophrenia. Am J Psychiatry Turning to treatment-resistant schizophrenia patients with 151:357–362. persistent psychotic symptoms, a number of studies have Hugdahl K, Helland T, Faerevaag MK, Lyssand ET, Asbjornsen A. 1995. reported reduced REA [Loberg et al., 1999]. In Loberg et al. Absence of ear advantage on the consonant-vowel dichotic listening test 76 Toulopoulou et al.

in adolescent and adult dyslexics: Specific auditory-phonetic dysfunc- Ragland JD, Goldberg TE, Wexler BE, Gold JM, Torrey EF, Weinberger DR. tion. J Clin Exp Neuropsychol 17:833–840. 1992. Dichotic-listening in monozygotic twins discordant and concord- Hugdahl K, Wester K. 1992. Dichotic listening studies of hemispheric ant for schizophrenia. Schizophr Res 7:177–183. asymmetry in brain damaged patients. Int J Neurosci 63:17–29. Rossell SL, Shapleske J, Fukuda R, Woodruff PWR, Simmons A, David AS. Levitan C, Ward PB, Catts SV. 1999. Superior temporal gyral volumes and 2001. Corpus callosum area and functioning in schizophrenic patients laterality correlates of auditory hallucinations in schizophrenia. Biol with auditory-verbal hallucinations. Schizophr Res 50:9–17. Psychiatry 46:955–962. Sakuma M, Hoff AL, DeLisi LE. 1996. Functional asymmetries in Lishman WA, Toone BK, Colbourn CJ, McMeekan ER, Mance RM. 1978. schizophrenia and their relationship to cognitive performance. Psychia- Dichotic listening in psychotic patients. Br J Psychiatry 132:333–341. try Res 65:1–13. Loberg EM, Hugdahl K, Green MF. 1999. Hemispheric asymmetry in Spitzer RL, Endicott J. 1978. Schedule for affective disorders and schizophrenia: A ‘‘dual deficits’’ model. Biol Psychiatry 45:76–81. schizophrenia—Lifetime version. New York, USA: New York State Loberg EM, Jorgensen HA, Green MF, Rund BR, Lund A, Diseth A, Oie M, Psychiatric Institute. Hugdahl K. 2006. Positive symptoms and duration of illness predict Sugishita M, Otomo K, Yamazaki K, Shimizu H, Yoshioka M, Shinohara A. functional laterality and attention modulation in schizophrenia. Acta 1995. Dichotic-listening in patients with partial section of the corpus- Psychiatr Scand 113:322–331. callosum. Brain 118:417–427. Loberg EM, Jorgensen HA, Hugdahl K. 2002. Functional brain asymmetry Toulopoulou T, Mapua-Filbey F, Quraishi S, Kravariti E, Morris RG, and attentional modulation in young and stabilised schizophrenic McDonald C, Walshie M, Bramon E, Murray RM. 2005. Cognitive patients: A dichotic listening study. Psychiatry Res 109:281–287. performance in presumed obligate carriers for psychosis. Br J Psychiatry Loberg EM, Jorgensen HA, Hugdahl K. 2004. Dichotic listening in 187:284–285. schizophrenic patients: Effects of previous vs. ongoing auditory Toulopoulou T, Grech A, Morris RG, Schulze K, McDonald C, Chapple B, hallucinations. Psychiatry Res 128:167–174. Rabe-Hesketh S, Murray RM. 2004. The relationship between volumet- Malaspina D, Friedman JH, Kaufmann C, Bruder G, Amador X, Strauss D, ric brain changes and cognitive function: A family study on schizophre- Clark S, Yale S, Lukens E, Thorning H, Goetz R, Gorman J. 1998. nia. Biol Psychiatry 56:447–453. Psychobiological heterogeneity of familial and sporadic schizophrenia. Toulopoulou T, Morris RG, Rabe-Hesketh S, Murray RM. 2003. Selectivity of Biol Psychiatry 43:489–496. verbal memory deficit in schizophrenic patients and their relatives. Am J Office of Population Censuses and Surveys. 1991. Classification of Med Genet Part B 116B:1–7. occupations. Standard occupational classification (SOC). London: Her Toulopoulou T, Quraishi S, McDonald C, Murray RM. 2006. The Maudsley Majesty’s Stationery Office. Family Study: Premorbid and current general intellectual function Oie M, Rund BR, Sundet K, Bryhn G. 1998. Auditory laterality and selective levels in familial bipolar I disorder and schizophrenia. J Clin Exp attention: Normal performance in patients with early-onset schizophre- Neuropsychol 28:243–259. nia. Schizophr Bull 24:643–652. Toulopoulou T, Rabe-Hesketh S, King H, Murray RM, Morris RG. 2003. Oleary DS, Andreasen NC, Hurtig RR, Kesler ML, Rogers M, Arndt S, Episodic memory in schizophrenic patients and their relatives. Schiz- Cizadlo T, Watkins GL, Ponto LLB, Kirchner PT, Hichwa RD. 1996. ophr Res 63:261–271. Auditory attentional deficits in patients with schizophrenia—a positron Wexler BE, Giller EL Jr, Southwick S. 1991. Cerebral laterality, symptoms, emission tomography study. Arch Gen Psychiatry 53:633–641. and diagnosis in psychotic patients. Biol Psychiatry 29:103–116.