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Hemispheric asymmetry in schizophrenia: a “dual deficits” model
Hemispheric Asymmetry in Schizophrenia: A “Dual Deficits” Model Else-Marie Løberg, Kenneth Hugdahl, and Michael F. Green Background: The aim was 1) to investigate left hemisphere functional integrity for auditory language processing in schizophrenic patients; and 2) to investigate the interaction between brain laterality and attentional processing by having subjects shift attention to the left or right ear. Methods: The subjects were 33 schizophrenic inpatients, and 33 healthy comparison subjects with the same age, handedness, and gender distribution as the patient subjects. All subjects were tested with dichotic listening (DL) to consonant–vowel syllables, which is a measure of lateralized temporal lobe language processing. The subjects were tested under three different attentional conditions: a non–forced attention condition, attention focused to the right ear stimulus, and attention focused to the left ear stimulus. Results: The main findings were 1) an absence of the expected right ear advantage in the schizophrenic group during the non–forced attention condition; and 2) a failure to modify DL performance through shifting of attention to either the right or left ear. The comparison group showed a right ear advantage during the non-forced and forcedright attention conditions (increased right ear advantage during the forced-right condition), and a left ear advantage during the forced-left attention condition. There were no significant effects of handedness. Conclusions: This pattern of results may indicate a “dual deficit” involving both automatic and controlled processing deficits in schizophrenia. Biol Psychiatry 1999;45: 76 – 81 © 1999 Society of Biological Psychiatry Key Words: Schizophrenia, laterality, dichotic listening, attention, dual deficit processing
Introduction
I
n a previous study, we found that schizophrenic patients were impaired on a dichotic listening (DL) test with verbal stimuli (Green et al 1994; see also Green 1998).
From the Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway (E-ML, KH); Department of Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, California (MFG); and West Los Angeles, VA Medical Center, Los Angeles, California (MFG). Address reprint requests to Kenneth Hugdahl, University of Bergen, Department of Biological and Medical Psychology, Årstadveien 21, N-5009 Bergen, Norway. Received March 3, 1998; revised June 5, 1998; accepted June 12, 1998.
© 1999 Society of Biological Psychiatry
Specifically, patients who were experiencing auditory hallucinations failed to show an expected right ear advantage on the DL test. Thus, schizophrenic patients seemed to lack aspects of the normal left hemisphere language lateralization, particularly in a hallucinatory state (cf. Bruder et al 1995; Crow 1997; Wexler and Heninger 1979; Woodruff et al 1997). The DL test of verbal stimuli is a measure of hemispheric asymmetry, especially left temporal lobe functional integrity (Bryden 1988; Hugdahl 1995). In the dichotic listening task of the present study, two different verbal stimuli (consonant–vowel syllables) were presented simultaneously, one in each ear. The typical finding in normal healthy subjects is a right ear advantage (REA) to verbal stimuli. The REA results from a predominance of contralateral auditory pathways from the right ear to the left, speech dominant, hemisphere, as well as an inhibition of the ipsilateral pathways by input from the contralateral ear (Kimura 1961). Most individuals can, however, increase or decrease the ear advantage through shifting of attention to either the right or left ear (Bryden et al 1983; Hugdahl 1995; Hugdahl and Andersson 1984). This probably reflects the influence of attentional and perceptual factors on brain laterality dominance patterns, resulting in a dynamic interaction between structural and cognitive laterality (see Hugdahl 1995 for further discussion). Thus, DL is a relatively uncomplicated behavioral test for studying both automatic (stimulus-driven) and controlled (instructiondriven) performance. In the previous study (Green et al 1994), we noted that patients were unable to modify their DL performance when specifically instructed to focus their attention to either the right or left ear, whether they hallucinated or not. Although this aspect of performance was not a primary focus of that study, it was a potentially important observation. In essence, schizophrenic patients seemed to be impaired both with regard to a left hemisphere superiority for processing of dichotically presented stimuli, and with regard to the ability to modify the ear advantage through shifting of attention. In other words, schizophrenia may involve “dual deficits” with regard to both 0006-3223/99/$19.00 PII S0006-3223(98)00219-4
Laterality and Attention in Schizophrenia
automatic and controlled processing (cf. O’Leary et al 1996). Our previous study had two methodological limitations. First, the schizophrenic patients were on a wide variety of medications at a large range of doses. This variability in medications may have obscured some performance patterns. Second, there was no control or comparison group. Thus the performance of the schizophrenic patients could not directly be compared to healthy comparison subjects. The main purpose of the present study was to more carefully test the possibility of “dual deficits” in schizophrenia. For this study, we assessed treatment-resistant patients who were participating in a clinical trial protocol and who were receiving a relatively narrow dose of the same antipsychotic medication. As part of the treatmentresistant criteria, all of the patients were experiencing active psychotic symptoms. Hence, they were relatively homogenous on this aspect of illness as well. Furthermore, a clear majority (26 out of 33) of the patients in the present sample scored in the clinical Brief Psychiatric Rating Scale (BPRS) range for hallucinations. We compared the performance of these patients to nonpsychotic healthy individuals, drawn from the dichotic listening database gathered by Hugdahl (1995). In a more general sense, the purpose of the present study was to: 1) investigate left hemisphere functional integrity for auditory language processing in schizophrenic patients; and 2) investigate the interaction between brain laterality and attentional processing by having subjects shift attention to the left or right auditory space. We hypothesize that schizophrenic patients will show abnormalities in both these performance areas.
Methods and Materials Subjects The subjects included 33 patients with treatment-resistant schizophrenia (23 men and 10 women) drawn from the UCLA Clinical Research Unit at the Camarillo State Hospital, California, USA. Subjects were participating in a larger clinical trials study and were assessed in the baseline phase prior to assignment to study medication (Green et al 1997). Patients were excluded if they had: 1) clinically significant neurological disease (including seizure disorder); 2) a history of head injury; 3) physical, cognitive, or language impairment that could adversely affect the validity of clinical ratings; and 4) a history of substance abuse, as defined by DSM-III-R (American Psychiatric Association 1987) within the past 6 months. Further, subjects were not tested on the dichotic listening test if they had any known hearing difficulties. Treatment resistance was defined according to the criteria of Kane et al (1988). A complete list of selection criteria is included in Green et al (1997). Written consent was obtained from every patient, and tangible reinforcers were given. The patients were compared with 33 healthy subjects drawn from the dichotic
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listening data bank of Hugdahl (1995), with the same age, handedness, and sex distribution as the patients. The normal comparison subjects were selected from the data bank on the basis of random number assignments within the respective age, gender, and handedness segments. Six schizophrenic subjects were left-handed (and consequently there were 6 left-handed comparison subjects). For the schizophrenic subjects, handedness was assessed with a manual preference test involving eight items, such as “drawing,” “drinking from a glass,” and “throwing a ball.” The eight items were administered three times. Patients with scores 14 –24 were considered right-handers, and 0 –7 were considered left-handers. For the comparison subjects, handedness was determined with the handedness questionnaire developed by Raczkowski et al (1974). This questionnaire has been validated against similar manual performance items as those used for the patient subjects. The comparison subjects had to identify 13 or more items (out of 15) as preferred with the right hand to be classified as a right-hander, and 13 or more items (out of 15) preferred with the left hand to be classified as a left-hander. All patients met the DSM-III-R criteria for schizophrenia as determined by the Structured Clinical Interview (SCID) (Spitzer et al 1990). The interviewers were trained by the Diagnosis and Psychopathology Unit of the UCLA Clinical Research Center for the Study of Schizophrenia, and the agreement for ratings of key psychotic and mood items was within acceptable limits (minimum kappa 5 .75). For symptom ratings, the expanded 24-item version of the BPRS was used (Ventura et al 1993). Raters for the BPRS were trained to a minimum interclass correlation coefficient of .80 by the Diagnosis and Psychopathology Unit. All of the patients were receiving haloperiodol at the time of testing; dosing for all except 2 of the patients was 20 mg per day (1 patient was receiving 25 mg and 1 receiving 30 mg). Patients could also receive lorazapam, propranolol, chloral hydrate, and benzotropine mesylate as needed. Testing did not occur within 10 hours of lorazapam administration. Mean age, education, and age of onset for the patients were 36.73 (SD 5 8.30) years, 11.67 (SD 5 2.38) years, and 17.91 (SD 5 4.25) years, respectively. Available demographic data and symptom scores are shown in Table 1.
Dichotic Listening Testing Procedure The dichotic listening test was administrated under three attention conditions: a non-forced (NF) attention condition in which no specific attentional instructions were given, a forced-right (FR) attention condition in which the subjects were instructed to attend to stimuli presented in the right ear, and a forced-left (FL) attention condition in which the subjects were instructed to attend to stimuli presented in the left ear. The non–forced attention condition was always -given first, and the order of the two forced-attention conditions was (pseudo) counterbalanced across subjects. The dichotic stimuli consisted of the six stop-consonants paired with the vowel /a/ to form six consonant–vowel (CV) syllables: /ba/, /da/, /ga/, /pa/, /ta/, and /ka/. The tape was computer designed so that the CVs were simultaneously presented to each ear. The syllables were paired with each other for all possible combinations, yielding
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Table 1. Demographic Data and Symptom Scores for the 33 (23 Men and 10 Women) Schizophrenic Subjects Item
Table 2. Mean Percentage of Correct Reports and Standard Deviations in the Three Attention Conditions for the Schizophrenic and Comparison Subjects
Minimum Maximum value value Mean SD
Age (years) 18 51 Education (years) 5 16 Medication (haloperidol) 20 mg/day 30 mg/day Age of onset (years) 9 27 BPRS scores Total 43 91 Hallucination item 1 7 Unusual thought item 4 7 Conceptual disorganization item 1 7 Negative symptoms (3 items) 3 15
36.73 8.30 11.67 2.38 — — 17.91 4.25 69.21 4.85 5.39 3.15 7.58
13.02 2.29 0.83 1.52 2.93
Age of onset 5 age at first institutionalization. Duration of illness 5 age at testing minus age of onset. BPRS 5 expanded version of the Brief Psychiatric Rating Scale. Negative symptoms 5 blunted affect, emotional withdrawal, and motor retardation items.
36 dichotic pairs (six trials in which the same consonant–vowel was presented to both ears 5 homonymic pairs). The tape consisted of three lists of 36 stimuli (one list for each attention condition). The dichotic tape was prepared on a PDP 11/45 computer with analogto-digital (A/D) and D/A converters, and with a D/A multiplexer. Each CV syllable was approximately 450 msec in duration, and the intertrial interval was approximately 4 sec. Temporal alignment between channels was set at the energy release in the consonant segment of the CV syllable. Maximum onset difference between the channels was 0.5 msec due to the D/A multiplexer resolution and the sampling frequency (min 10 kHz). The syllables were originally recorded from the computer onto a NAGRA IV reel-to-reel tape recorder; however, to more easily test the subjects in their respective environmental setting, the tape was copied onto a chrome dioxide cassette and played to the subject from a minicassette player through high-quality stereo headphones. All subjects were administrated five practice trials to ensure that they understood the nature of the task. The 30 trials of different consonant–vowel syllables were scored separately for the right and left ears. The subjects were instructed to give a single response after each presentation, either by saying the consonant–vowel aloud or by pointing to a sheet in front of them that listed all six possible responses vertically. The comparison subjects were instructed to say the syllable they heard on each trial, but were shown the same sheet as the patients before the test. All subjects were told that if they thought they heard more than one stimulus, they were to select the one they heard the best. During the forced-left and forced-right conditions, arrows were placed in front of the subjects to remind them which ear to attend to.
Statistical Analyses A two-way analysis of variance (ANOVA) was performed according to a 2 (Group: schizophrenic patients, comparison subjects) 3 2 (Ear: right, left) design, separately for the three attention conditions. Post hoc Tukey’s honest significant difference (HSD) tests were performed as follow-up tests for significant ANOVA effects involving more than two means. A separate four-way ANOVA was also performed with the factors Handedness and Attentional instruction
Nonforced Right ear Left ear Forced-right Right ear Left ear Forced-left Right ear Left ear
Schizophrenic subjects
Comparison subjects
Mean
(SD)
Mean
(SD)
32.42 32.32
(11.55) (12.00)
49.64 38.61
(7.73) (8.79)
34.94 31.92
(13.90) (11.64)
63.99 25.61
(12.39) (10.21)
33.43 34.24
(13.76) (10.28)
29.56 58.38
(13.59) (14.07)
included in the analysis to evaluate possible interaction effects with handedness and attention.
Results Table 2 shows the percentage of correctly reported syllables from each ear for the schizophrenic patients and comparison subjects in the three attention conditions. To test for interaction effects of handedness and attentional instructions, a four-way ANOVA was carried out on the design Ear 3 Group 3 Handedness 3 Attentional instruction. This analysis yielded a significant three-way interaction of Ear 3 Group 3 Attentional instruction, F(2,124) 5 36.36, p , .0001. The interaction was followed up with Tukey’s HSD test for multiple comparisons, which revealed that the schizophrenic subjects failed to modulate their ear scores for the FR and FL attentional conditions, whereas the comparison subjects significantly increased their REA in the FR attention condition, and switched to a left ear advantage (LEA) in the FL attention condition. There were no significant effects of handedness, neither main effect, nor any interactions. The same was true when the 2 patients who were on slightly higher medication dosages were excluded from the analysis. The F ratio for the significant three-way interaction of Group 3 Ear 3 Attentional instruction marginally increased from 36.36 to 38.96. To more closely follow up the significant three-way interaction, separate analyses for each of the three attentional conditions were carried out. In the NF attention condition, there was a significant main effect of Group, F(1,128) 5 43,97, p , .001; and of Ear, F(1,128) 5 9.87, p , .01. Overall, the schizophrenic patients reported fewer correct syllables than the comparison subjects, and there were more correctly reported items from the right ear. There was also a significant interaction between Group and Ear, F(1,128) 5 9.52, p , .01. Post hoc Tukey tests showed that the schizophrenic patients reported fewer correct syllables from the right ear compared to the
Laterality and Attention in Schizophrenia
Figure 1. Scatter-plot of individual performance for the schizophrenic and the comparison subjects in the non–forced attention condition. Squares and triangles below the diagonal 45° symmetry line indicate a right ear advantage (REA). Squares and triangles above the diagonal line indicate a left ear advantage (LEA).
comparison subjects, p , .001, with a similar trend for the left ear, p , .10. The comparison subjects showed a significant REA (p , .01), whereas the schizophrenic patients had roughly equivalent correct reports from the right and left ears and thus no ear advantage (EA). In the FR attention condition, there was a significant main effect of Group, F(1,128) 5 29.10, p , .001; and of Ear, F(1,128) 5 96.54, p , .001. Again, the schizophrenic patients overall reported fewer correct syllables than the comparison subjects, and there were overall more correctly reported syllables from the right ear. The two-way interaction between Group and Ear was also significant, F(1,128) 5 70.35, p , .001. Post hoc Tukey tests showed that the schizophrenic patients reported fewer correct syllables from the right ear than the comparison subjects, p , .001, and showed no EA. The comparison subjects, on the other hand, showed a highly significant REA (p , .001). Also in the FL attention condition there was a significant main effect of Group, F(1,128) 5 20.02, p , .001; and of Ear, F(1,128) 5 42.74, p , .001. Overall, the schizophrenic patients reported fewer correct syllables than the comparison subjects, and there were reported more correct syllables from the left ear. There was also a significant interaction between Group and Ear, F(1,128) 5 38.20, p , .001. Post hoc Tukey tests showed that the schizophrenic patients reported fewer correct syllables from the left ear than the comparison subjects, p , .001. They also failed to show an EA, whereas the comparison subjects showed a significant LEA (p , .01). Figures 1–3 show scatter-plots of the individual data for each of the three attention conditions that correspond to
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Figure 2. Scatter-plot of individual performance for the schizophrenic and comparison subjects in the forced-right attention condition. Squares and triangles below the diagonal 45° symmetry line indicate a right ear advantage (REA). Squares and triangles above the diagonal line indicate a left ear advantage (LEA).
the means and standard deviations presented in Table 2. Each dot in the scatter-plots represents 1 subject. Note the 45° symmetry line in the scatter-plots, which represent the dividing line between the REA (lower right) and LEA (upper left) response “space.” For the recall of the homonymic syllable pairs (5 the same syllable presented in both ears), the schizophrenic patients had a mean of 4.27 (out of 6 possible) reported items, whereas the corresponding mean for the comparison subjects was 5.45.
Figure 3. Scatter-plot of individual performance for the schizophrenic and comparison subjects in the forced-left attention condition. Squares and triangles below the diagonal 45° symmetry line indicate a right ear advantage (REA). Squares and triangles above the diagonal line indicate a left ear advantage (LEA).
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Discussion The schizophrenic group did not show a REA in the non–forced attention condition as compared to the normal comparison subjects who showed the typical REA. In fact, the schizophrenic subjects had a tendency toward reversed laterality (see Figure 1), with more patient subjects showing a LEA in the NF attention condition compared with the comparison subjects. Also, the schizophrenic group was not able to shift attention in the FR and FL conditions, again as opposed to the normal comparison subjects. Not surprisingly, the schizophrenic patients reported less correct syllables than the comparison subjects in all three attention conditions. There was furthermore a nonsignificant correlational tendency for the schizophrenic subjects with the lowest overall accuracy to also have the greatest problems in shifting attention. The lack of a REA in the schizophrenia group in the non–forced attention condition suggests a dysfunction in temporal lobe language processing. In this respect the present study replicates prior findings of reduced right ear advantage in schizophrenia (Bruder et al 1995; Wexler and Henninger 1979; Wexler 1986). The present data also fit with recent electrophysiological data based on recordings of event-related potentials (ERPs) (e.g., Salisbury et al 1998; Turetsky et al 1998). These authors showed reductions in the P3 ERP component over left temporal sites in schizophrenic patients. This may be thought of as a failure of laterality for “automatic” or “stimulus-driven” processing. The lack of left hemispheric dominance in the schizophrenic group is, moreover, congruent with the thinking of Crow (1997), who suggested that a left hemisphere language dominance failure, based on reduced asymmetry of the planum temporale, is a central aspect of schizophrenia. The planum temporale area in the posterior part of the superior temporal gyrus is also critically involved in auditory phonological processing (Ja¨ncke and Steinmetz 1993), and abnormal planum temporale asymmetry has been observed in language deficits (Larsen et al 1990). Moreover, Schall et al (1997) used brief (100–300 msec) sound clicks and found that schizophrenic patients had a left temporal lobe impairment. These authors also used ERPs recorded over the left hemispheres as dependent measures. The present group differences in the non–forced-attention condition were largely attributable to the fewer correctly reported syllables from the right ear in the schizophrenia group compared to the comparison group. This may indicate decreased activation of the left temporal lobe, which in turn may be related to previous findings regarding left hemisphere dysfunction in schizophrenia (cf. Crow 1997). If the lack of structural asymmetry gives rise to DL performance abnormalities in schizophrenia, it might also give rise to an enduring left hemisphere abnormality that is
E.M. Løberg et al
a risk factor in the development of hallucinations. Our previous study showed an association between auditory hallucinations and reduced REA. These finding are consistent with other studies that have examined DL performance and schizophrenia symptoms. Bruder et al (1995) found a negative correlation between hallucinations and REA for fused words. Similarly, Wexler and Heninger (1979) showed that right-handed patients had smaller REA for CV syllables when they were in a psychotic episode compared to when they were not. In the present study the schizophrenic group showed no EA in the non–forced attention condition, analogous to the hallucinating group in our previous study. This similarity to the hallucinating group may not be surprising given that the current sample was treatment resistant with active psychotic symptoms and that most of the patients had ratings of hallucinations that were in the clinical range. In addition to a lack of ear advantage in the non– forced attention condition, the lack of an ear advantage in the forced-attention conditions in the schizophrenic group may also indicate cognitive inflexibility. The ability to modify the ear advantage through shifting of attention to either side in auditory space is not present until the age of 8 –9 years (Andersson and Hugdahl 1987), possibly coinciding with the onset of literacy, a critical development in language function. This is also consistent with the recent findings by Oades et al (1997), who recorded ERPs to frequent and deviant tone pips in a standard oddball paradigm. The results showed that the schizophrenic patients did not show an increase in late positivity while focusing attention to the deviant stimulus, in comparison to the comparison subjects. Oades et al (1997) argues that automatic processing deficits are best seen in experimental situations that require the activation of controlled attentional processes. This is comparable to the present DL paradigm where both automatic and controlled processes may be investigated at the same time. Separate correlations moreover showed a tendency for that those patients who made more overall errors also were the ones who had the greatest difficulty in shifting attention, indicating an interaction between automatic and controlled processing. A limitation of the current study was that the patients and comparison subjects were tested in separate laboratories. Administration of the dichotic listening test was simplified slightly for the patients in that the headphones were not switched between conditions and subjects (which is typically done in dichotic listening studies). It was decided to forego this aspect of the procedure because of concerns about scoring and administration errors by the testing staff in a clinical trials project. This may, however, be a limiting factor in the present study.
Laterality and Attention in Schizophrenia
In conclusion, the schizophrenic subjects clearly failed to reveal an expected right ear advantage during the non–forced-attention condition. Moreover, attention to the right ear did not help in advancing the right ear reports, as is almost always found in healthy subjects (see Bryden 1988; Hugdahl 1995, for reviews). This may indicate a “double” laterality dysfunction involving both “automatic” and “controlled” processing deficits. Thus, the dichotic listening technique may be a relatively simple method of testing both automatic and controlled cognitive processing, including possible stable laterality effects and dynamic attentional modulation.
The project received support from the NIMH UCLA Clinical Research Center for the study of Schizophrenia (R. P. Liberman, P.I.), an investigator-initiated grant from the Janssen Research Foundation (M.F. Green and B.D. Marshall, Co-P.I.s), and from the school of Psychology, University of Bergen, Norway (to K. Hugdahl). The data were collected at the Camarillo State Hospital, Camarillo, California, while Else-Marie Løberg was a visiting student. The authors thank B.D. Marshall, Jr, MD, Robert Kern, PhD, Mary Jane Robertsen, MS, Jeffery L. Hayden, Kimmy S. Kee, PhD, Mark McGee, Dustin Salveson, Robert Mangano, Renee Galbavy, Katherine Narr, Maryam Etemadjam, Kristin Mangis, and Crystal Ray for their collective efforts in the data collection. In addition, we are grateful to the patients and staff of Camarillo State Hospital for their participation in the study and support of this project.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press. Andersson B, Hugdahl K (1987): Effects of sex, age, and forced attention on dichotic listening in children: A longitudinal study. Dev Neuropsychol 3:191–206. Bruder G, Rabinowicz E, Towey J, Brown A, Kaufmann CA, Amador X, et al (1995): Smaller right (left hemisphere) advantage for dichotic fused words in patients with schizophrenia. Am J Psychiatry 152:932–935. Bryden MP (1988): An overview of the dichotic listening procedure and its relation to cerebral organization. In: Hugdahl K, editor. Handbook of Dichotic Listening: Theory, Methods and Research. Chichester, UK: Wiley, pp 1– 45. Bryden MP, Munhall K, Allard F (1983): Attentional biases and the right-ear effect in dichotic listening. Brain Lang 18:236–248. Crow TJ (1997): Schizophrenia as a failure of the hemispheric dominance for language. Trends Neurosci 20:339 –343. Green MF (1998): Schizophrenia from a Neurocognitive Perspective: Probing the Impenetrable Darkness. Needham Heights, MA: Allyn & Bacon. Green MF, Marshall BD Jr, Wirshing WC, Ames D, Marder SR, McGurk S, et al (1997): Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 154:799 – 804. Green MF, Hugdahl K, Mitchell S (1994): Dichotic listenig
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during auditory hallucinations in schizophrenia. Am J Psychiatry 151:357–362. Hugdahl K (1995): Dichotic listening: Probing temporal lobe functional integrity. In: Davidson RJ, Hugdahl K, editors. Brain Asymmetry. Cambridge: MIT Press, pp 123–156. Hugdahl K, Andersson L (1984): A dichotic listening study of differences in cerebral organization in dextral and sinistral subjects. Cortex 20:135–141. Ja¨ncke L, Steinmetz H (1993): Auditory lateralization and planum temporale asymmetry. Neuroreport 5:169 –172. Kane J, Honigfield G, Singer J, Meltzer H, Group CCS (1988): Clozapine for the treatment-resistant schizophrenic: A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789 –796. Kimura D (1961): Cerebral dominance and the perception of verbal stimuli. Can J Psychol 15:166 –171. Larsen JL, Høien T, Lundberg I, Ødegaard H (1990): MRI evaluation of the size and symmetry of the planum temporale in adolescents with developmental dyslexia. Brain Lang 39:255– 288. Oades RD, Dittman-Balcar A, Zerbin D, Grzella I (1997): Impaired attention-dependent augmentation of MMN in nonparanoid vs paranoid schizophrenic patients: A comparison with obsessive-compulsive disorder and healthy subjects. Biol Psychiatry 41:1196 –1210. O’ Leary DS, Andreasen NC, Hurtig RR, Kesler ML, Rogers M, Arndt S, et al (1996): Auditory attentional deficits in patients with schizophrenia. A positron emission tomography study. Arch Gen Psychiatry 53:633– 641. Raczkowski D, Kalat JW, Nebes RD (1974): Reliability and validity of some handedness questionnaire items. Neuropsychologia 12:43– 47. Salisbury DF, Shenton ME, Sherwood AR, Fiscvher IA, Yurgelun-Todd DA, Tohen M, et al (1998): First-episode schizophrenic psychosis differs from first-episode affective psychosis and controls in P300 amplitude over the left temporal lobe. Arch Gen Psychiatry 55:173–180. Schall U, Sco¨n A, Zerbin D, Bender S, Eggers C, Oades RD (1997): A left temporal lobe impairment of auditory information processing in schizophrenia: An event-related potential study. Neurosci Lett 229:25–28. Spitzer RL, Williams JBW, Gibbon M, First MB (1990). Structured Clinical Interview for DSM-III-R Patient Edition (SCID-P, Version 1.0). Washington, D.C.: American Psychiatric Press. Turetsky B, Colbath EA, Gur RE (1998): P300 subcomponent abnormalities in schizophrenia: II. Longitudinal stability and relationship to symptom change. Biol Psychiatry 43:84 –96. Ventura J, Green MF, Shaner A, Liberman RP (1993): Training and quality assurance with the Brief Psychiatric Rating Scale: “The drift busters”. Int J Methods Psychiatr Res 3:221–244. Wexler BE (1986): Alteration in cerebral laterality during acute psychotic illness II. Br J Psychiatry 149:202–209. Wexler BE, Heninger GR (1979): Alterations in cerebral laterality during acute psychotic illness. Arch Gen Psychiatry 36:278 –284. Woodruff PWR, Wright IC, Bullmore ET, Brammer M., Howard RJ, Williams SCR, et al (1997): Auditory hallucinations and the temporal cortical response to speech in schizophrenia: A functional magnetic resonance imaging study. Am J Psychiatry 154:1676 –1682.
Introduction
I
n a previous study, we found that schizophrenic patients were impaired on a dichotic listening (DL) test with verbal stimuli (Green et al 1994; see also Green 1998).
From the Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway (E-ML, KH); Department of Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, California (MFG); and West Los Angeles, VA Medical Center, Los Angeles, California (MFG). Address reprint requests to Kenneth Hugdahl, University of Bergen, Department of Biological and Medical Psychology, Årstadveien 21, N-5009 Bergen, Norway. Received March 3, 1998; revised June 5, 1998; accepted June 12, 1998.
© 1999 Society of Biological Psychiatry
Specifically, patients who were experiencing auditory hallucinations failed to show an expected right ear advantage on the DL test. Thus, schizophrenic patients seemed to lack aspects of the normal left hemisphere language lateralization, particularly in a hallucinatory state (cf. Bruder et al 1995; Crow 1997; Wexler and Heninger 1979; Woodruff et al 1997). The DL test of verbal stimuli is a measure of hemispheric asymmetry, especially left temporal lobe functional integrity (Bryden 1988; Hugdahl 1995). In the dichotic listening task of the present study, two different verbal stimuli (consonant–vowel syllables) were presented simultaneously, one in each ear. The typical finding in normal healthy subjects is a right ear advantage (REA) to verbal stimuli. The REA results from a predominance of contralateral auditory pathways from the right ear to the left, speech dominant, hemisphere, as well as an inhibition of the ipsilateral pathways by input from the contralateral ear (Kimura 1961). Most individuals can, however, increase or decrease the ear advantage through shifting of attention to either the right or left ear (Bryden et al 1983; Hugdahl 1995; Hugdahl and Andersson 1984). This probably reflects the influence of attentional and perceptual factors on brain laterality dominance patterns, resulting in a dynamic interaction between structural and cognitive laterality (see Hugdahl 1995 for further discussion). Thus, DL is a relatively uncomplicated behavioral test for studying both automatic (stimulus-driven) and controlled (instructiondriven) performance. In the previous study (Green et al 1994), we noted that patients were unable to modify their DL performance when specifically instructed to focus their attention to either the right or left ear, whether they hallucinated or not. Although this aspect of performance was not a primary focus of that study, it was a potentially important observation. In essence, schizophrenic patients seemed to be impaired both with regard to a left hemisphere superiority for processing of dichotically presented stimuli, and with regard to the ability to modify the ear advantage through shifting of attention. In other words, schizophrenia may involve “dual deficits” with regard to both 0006-3223/99/$19.00 PII S0006-3223(98)00219-4
Laterality and Attention in Schizophrenia
automatic and controlled processing (cf. O’Leary et al 1996). Our previous study had two methodological limitations. First, the schizophrenic patients were on a wide variety of medications at a large range of doses. This variability in medications may have obscured some performance patterns. Second, there was no control or comparison group. Thus the performance of the schizophrenic patients could not directly be compared to healthy comparison subjects. The main purpose of the present study was to more carefully test the possibility of “dual deficits” in schizophrenia. For this study, we assessed treatment-resistant patients who were participating in a clinical trial protocol and who were receiving a relatively narrow dose of the same antipsychotic medication. As part of the treatmentresistant criteria, all of the patients were experiencing active psychotic symptoms. Hence, they were relatively homogenous on this aspect of illness as well. Furthermore, a clear majority (26 out of 33) of the patients in the present sample scored in the clinical Brief Psychiatric Rating Scale (BPRS) range for hallucinations. We compared the performance of these patients to nonpsychotic healthy individuals, drawn from the dichotic listening database gathered by Hugdahl (1995). In a more general sense, the purpose of the present study was to: 1) investigate left hemisphere functional integrity for auditory language processing in schizophrenic patients; and 2) investigate the interaction between brain laterality and attentional processing by having subjects shift attention to the left or right auditory space. We hypothesize that schizophrenic patients will show abnormalities in both these performance areas.
Methods and Materials Subjects The subjects included 33 patients with treatment-resistant schizophrenia (23 men and 10 women) drawn from the UCLA Clinical Research Unit at the Camarillo State Hospital, California, USA. Subjects were participating in a larger clinical trials study and were assessed in the baseline phase prior to assignment to study medication (Green et al 1997). Patients were excluded if they had: 1) clinically significant neurological disease (including seizure disorder); 2) a history of head injury; 3) physical, cognitive, or language impairment that could adversely affect the validity of clinical ratings; and 4) a history of substance abuse, as defined by DSM-III-R (American Psychiatric Association 1987) within the past 6 months. Further, subjects were not tested on the dichotic listening test if they had any known hearing difficulties. Treatment resistance was defined according to the criteria of Kane et al (1988). A complete list of selection criteria is included in Green et al (1997). Written consent was obtained from every patient, and tangible reinforcers were given. The patients were compared with 33 healthy subjects drawn from the dichotic
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listening data bank of Hugdahl (1995), with the same age, handedness, and sex distribution as the patients. The normal comparison subjects were selected from the data bank on the basis of random number assignments within the respective age, gender, and handedness segments. Six schizophrenic subjects were left-handed (and consequently there were 6 left-handed comparison subjects). For the schizophrenic subjects, handedness was assessed with a manual preference test involving eight items, such as “drawing,” “drinking from a glass,” and “throwing a ball.” The eight items were administered three times. Patients with scores 14 –24 were considered right-handers, and 0 –7 were considered left-handers. For the comparison subjects, handedness was determined with the handedness questionnaire developed by Raczkowski et al (1974). This questionnaire has been validated against similar manual performance items as those used for the patient subjects. The comparison subjects had to identify 13 or more items (out of 15) as preferred with the right hand to be classified as a right-hander, and 13 or more items (out of 15) preferred with the left hand to be classified as a left-hander. All patients met the DSM-III-R criteria for schizophrenia as determined by the Structured Clinical Interview (SCID) (Spitzer et al 1990). The interviewers were trained by the Diagnosis and Psychopathology Unit of the UCLA Clinical Research Center for the Study of Schizophrenia, and the agreement for ratings of key psychotic and mood items was within acceptable limits (minimum kappa 5 .75). For symptom ratings, the expanded 24-item version of the BPRS was used (Ventura et al 1993). Raters for the BPRS were trained to a minimum interclass correlation coefficient of .80 by the Diagnosis and Psychopathology Unit. All of the patients were receiving haloperiodol at the time of testing; dosing for all except 2 of the patients was 20 mg per day (1 patient was receiving 25 mg and 1 receiving 30 mg). Patients could also receive lorazapam, propranolol, chloral hydrate, and benzotropine mesylate as needed. Testing did not occur within 10 hours of lorazapam administration. Mean age, education, and age of onset for the patients were 36.73 (SD 5 8.30) years, 11.67 (SD 5 2.38) years, and 17.91 (SD 5 4.25) years, respectively. Available demographic data and symptom scores are shown in Table 1.
Dichotic Listening Testing Procedure The dichotic listening test was administrated under three attention conditions: a non-forced (NF) attention condition in which no specific attentional instructions were given, a forced-right (FR) attention condition in which the subjects were instructed to attend to stimuli presented in the right ear, and a forced-left (FL) attention condition in which the subjects were instructed to attend to stimuli presented in the left ear. The non–forced attention condition was always -given first, and the order of the two forced-attention conditions was (pseudo) counterbalanced across subjects. The dichotic stimuli consisted of the six stop-consonants paired with the vowel /a/ to form six consonant–vowel (CV) syllables: /ba/, /da/, /ga/, /pa/, /ta/, and /ka/. The tape was computer designed so that the CVs were simultaneously presented to each ear. The syllables were paired with each other for all possible combinations, yielding
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Table 1. Demographic Data and Symptom Scores for the 33 (23 Men and 10 Women) Schizophrenic Subjects Item
Table 2. Mean Percentage of Correct Reports and Standard Deviations in the Three Attention Conditions for the Schizophrenic and Comparison Subjects
Minimum Maximum value value Mean SD
Age (years) 18 51 Education (years) 5 16 Medication (haloperidol) 20 mg/day 30 mg/day Age of onset (years) 9 27 BPRS scores Total 43 91 Hallucination item 1 7 Unusual thought item 4 7 Conceptual disorganization item 1 7 Negative symptoms (3 items) 3 15
36.73 8.30 11.67 2.38 — — 17.91 4.25 69.21 4.85 5.39 3.15 7.58
13.02 2.29 0.83 1.52 2.93
Age of onset 5 age at first institutionalization. Duration of illness 5 age at testing minus age of onset. BPRS 5 expanded version of the Brief Psychiatric Rating Scale. Negative symptoms 5 blunted affect, emotional withdrawal, and motor retardation items.
36 dichotic pairs (six trials in which the same consonant–vowel was presented to both ears 5 homonymic pairs). The tape consisted of three lists of 36 stimuli (one list for each attention condition). The dichotic tape was prepared on a PDP 11/45 computer with analogto-digital (A/D) and D/A converters, and with a D/A multiplexer. Each CV syllable was approximately 450 msec in duration, and the intertrial interval was approximately 4 sec. Temporal alignment between channels was set at the energy release in the consonant segment of the CV syllable. Maximum onset difference between the channels was 0.5 msec due to the D/A multiplexer resolution and the sampling frequency (min 10 kHz). The syllables were originally recorded from the computer onto a NAGRA IV reel-to-reel tape recorder; however, to more easily test the subjects in their respective environmental setting, the tape was copied onto a chrome dioxide cassette and played to the subject from a minicassette player through high-quality stereo headphones. All subjects were administrated five practice trials to ensure that they understood the nature of the task. The 30 trials of different consonant–vowel syllables were scored separately for the right and left ears. The subjects were instructed to give a single response after each presentation, either by saying the consonant–vowel aloud or by pointing to a sheet in front of them that listed all six possible responses vertically. The comparison subjects were instructed to say the syllable they heard on each trial, but were shown the same sheet as the patients before the test. All subjects were told that if they thought they heard more than one stimulus, they were to select the one they heard the best. During the forced-left and forced-right conditions, arrows were placed in front of the subjects to remind them which ear to attend to.
Statistical Analyses A two-way analysis of variance (ANOVA) was performed according to a 2 (Group: schizophrenic patients, comparison subjects) 3 2 (Ear: right, left) design, separately for the three attention conditions. Post hoc Tukey’s honest significant difference (HSD) tests were performed as follow-up tests for significant ANOVA effects involving more than two means. A separate four-way ANOVA was also performed with the factors Handedness and Attentional instruction
Nonforced Right ear Left ear Forced-right Right ear Left ear Forced-left Right ear Left ear
Schizophrenic subjects
Comparison subjects
Mean
(SD)
Mean
(SD)
32.42 32.32
(11.55) (12.00)
49.64 38.61
(7.73) (8.79)
34.94 31.92
(13.90) (11.64)
63.99 25.61
(12.39) (10.21)
33.43 34.24
(13.76) (10.28)
29.56 58.38
(13.59) (14.07)
included in the analysis to evaluate possible interaction effects with handedness and attention.
Results Table 2 shows the percentage of correctly reported syllables from each ear for the schizophrenic patients and comparison subjects in the three attention conditions. To test for interaction effects of handedness and attentional instructions, a four-way ANOVA was carried out on the design Ear 3 Group 3 Handedness 3 Attentional instruction. This analysis yielded a significant three-way interaction of Ear 3 Group 3 Attentional instruction, F(2,124) 5 36.36, p , .0001. The interaction was followed up with Tukey’s HSD test for multiple comparisons, which revealed that the schizophrenic subjects failed to modulate their ear scores for the FR and FL attentional conditions, whereas the comparison subjects significantly increased their REA in the FR attention condition, and switched to a left ear advantage (LEA) in the FL attention condition. There were no significant effects of handedness, neither main effect, nor any interactions. The same was true when the 2 patients who were on slightly higher medication dosages were excluded from the analysis. The F ratio for the significant three-way interaction of Group 3 Ear 3 Attentional instruction marginally increased from 36.36 to 38.96. To more closely follow up the significant three-way interaction, separate analyses for each of the three attentional conditions were carried out. In the NF attention condition, there was a significant main effect of Group, F(1,128) 5 43,97, p , .001; and of Ear, F(1,128) 5 9.87, p , .01. Overall, the schizophrenic patients reported fewer correct syllables than the comparison subjects, and there were more correctly reported items from the right ear. There was also a significant interaction between Group and Ear, F(1,128) 5 9.52, p , .01. Post hoc Tukey tests showed that the schizophrenic patients reported fewer correct syllables from the right ear compared to the
Laterality and Attention in Schizophrenia
Figure 1. Scatter-plot of individual performance for the schizophrenic and the comparison subjects in the non–forced attention condition. Squares and triangles below the diagonal 45° symmetry line indicate a right ear advantage (REA). Squares and triangles above the diagonal line indicate a left ear advantage (LEA).
comparison subjects, p , .001, with a similar trend for the left ear, p , .10. The comparison subjects showed a significant REA (p , .01), whereas the schizophrenic patients had roughly equivalent correct reports from the right and left ears and thus no ear advantage (EA). In the FR attention condition, there was a significant main effect of Group, F(1,128) 5 29.10, p , .001; and of Ear, F(1,128) 5 96.54, p , .001. Again, the schizophrenic patients overall reported fewer correct syllables than the comparison subjects, and there were overall more correctly reported syllables from the right ear. The two-way interaction between Group and Ear was also significant, F(1,128) 5 70.35, p , .001. Post hoc Tukey tests showed that the schizophrenic patients reported fewer correct syllables from the right ear than the comparison subjects, p , .001, and showed no EA. The comparison subjects, on the other hand, showed a highly significant REA (p , .001). Also in the FL attention condition there was a significant main effect of Group, F(1,128) 5 20.02, p , .001; and of Ear, F(1,128) 5 42.74, p , .001. Overall, the schizophrenic patients reported fewer correct syllables than the comparison subjects, and there were reported more correct syllables from the left ear. There was also a significant interaction between Group and Ear, F(1,128) 5 38.20, p , .001. Post hoc Tukey tests showed that the schizophrenic patients reported fewer correct syllables from the left ear than the comparison subjects, p , .001. They also failed to show an EA, whereas the comparison subjects showed a significant LEA (p , .01). Figures 1–3 show scatter-plots of the individual data for each of the three attention conditions that correspond to
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Figure 2. Scatter-plot of individual performance for the schizophrenic and comparison subjects in the forced-right attention condition. Squares and triangles below the diagonal 45° symmetry line indicate a right ear advantage (REA). Squares and triangles above the diagonal line indicate a left ear advantage (LEA).
the means and standard deviations presented in Table 2. Each dot in the scatter-plots represents 1 subject. Note the 45° symmetry line in the scatter-plots, which represent the dividing line between the REA (lower right) and LEA (upper left) response “space.” For the recall of the homonymic syllable pairs (5 the same syllable presented in both ears), the schizophrenic patients had a mean of 4.27 (out of 6 possible) reported items, whereas the corresponding mean for the comparison subjects was 5.45.
Figure 3. Scatter-plot of individual performance for the schizophrenic and comparison subjects in the forced-left attention condition. Squares and triangles below the diagonal 45° symmetry line indicate a right ear advantage (REA). Squares and triangles above the diagonal line indicate a left ear advantage (LEA).
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Discussion The schizophrenic group did not show a REA in the non–forced attention condition as compared to the normal comparison subjects who showed the typical REA. In fact, the schizophrenic subjects had a tendency toward reversed laterality (see Figure 1), with more patient subjects showing a LEA in the NF attention condition compared with the comparison subjects. Also, the schizophrenic group was not able to shift attention in the FR and FL conditions, again as opposed to the normal comparison subjects. Not surprisingly, the schizophrenic patients reported less correct syllables than the comparison subjects in all three attention conditions. There was furthermore a nonsignificant correlational tendency for the schizophrenic subjects with the lowest overall accuracy to also have the greatest problems in shifting attention. The lack of a REA in the schizophrenia group in the non–forced attention condition suggests a dysfunction in temporal lobe language processing. In this respect the present study replicates prior findings of reduced right ear advantage in schizophrenia (Bruder et al 1995; Wexler and Henninger 1979; Wexler 1986). The present data also fit with recent electrophysiological data based on recordings of event-related potentials (ERPs) (e.g., Salisbury et al 1998; Turetsky et al 1998). These authors showed reductions in the P3 ERP component over left temporal sites in schizophrenic patients. This may be thought of as a failure of laterality for “automatic” or “stimulus-driven” processing. The lack of left hemispheric dominance in the schizophrenic group is, moreover, congruent with the thinking of Crow (1997), who suggested that a left hemisphere language dominance failure, based on reduced asymmetry of the planum temporale, is a central aspect of schizophrenia. The planum temporale area in the posterior part of the superior temporal gyrus is also critically involved in auditory phonological processing (Ja¨ncke and Steinmetz 1993), and abnormal planum temporale asymmetry has been observed in language deficits (Larsen et al 1990). Moreover, Schall et al (1997) used brief (100–300 msec) sound clicks and found that schizophrenic patients had a left temporal lobe impairment. These authors also used ERPs recorded over the left hemispheres as dependent measures. The present group differences in the non–forced-attention condition were largely attributable to the fewer correctly reported syllables from the right ear in the schizophrenia group compared to the comparison group. This may indicate decreased activation of the left temporal lobe, which in turn may be related to previous findings regarding left hemisphere dysfunction in schizophrenia (cf. Crow 1997). If the lack of structural asymmetry gives rise to DL performance abnormalities in schizophrenia, it might also give rise to an enduring left hemisphere abnormality that is
E.M. Løberg et al
a risk factor in the development of hallucinations. Our previous study showed an association between auditory hallucinations and reduced REA. These finding are consistent with other studies that have examined DL performance and schizophrenia symptoms. Bruder et al (1995) found a negative correlation between hallucinations and REA for fused words. Similarly, Wexler and Heninger (1979) showed that right-handed patients had smaller REA for CV syllables when they were in a psychotic episode compared to when they were not. In the present study the schizophrenic group showed no EA in the non–forced attention condition, analogous to the hallucinating group in our previous study. This similarity to the hallucinating group may not be surprising given that the current sample was treatment resistant with active psychotic symptoms and that most of the patients had ratings of hallucinations that were in the clinical range. In addition to a lack of ear advantage in the non– forced attention condition, the lack of an ear advantage in the forced-attention conditions in the schizophrenic group may also indicate cognitive inflexibility. The ability to modify the ear advantage through shifting of attention to either side in auditory space is not present until the age of 8 –9 years (Andersson and Hugdahl 1987), possibly coinciding with the onset of literacy, a critical development in language function. This is also consistent with the recent findings by Oades et al (1997), who recorded ERPs to frequent and deviant tone pips in a standard oddball paradigm. The results showed that the schizophrenic patients did not show an increase in late positivity while focusing attention to the deviant stimulus, in comparison to the comparison subjects. Oades et al (1997) argues that automatic processing deficits are best seen in experimental situations that require the activation of controlled attentional processes. This is comparable to the present DL paradigm where both automatic and controlled processes may be investigated at the same time. Separate correlations moreover showed a tendency for that those patients who made more overall errors also were the ones who had the greatest difficulty in shifting attention, indicating an interaction between automatic and controlled processing. A limitation of the current study was that the patients and comparison subjects were tested in separate laboratories. Administration of the dichotic listening test was simplified slightly for the patients in that the headphones were not switched between conditions and subjects (which is typically done in dichotic listening studies). It was decided to forego this aspect of the procedure because of concerns about scoring and administration errors by the testing staff in a clinical trials project. This may, however, be a limiting factor in the present study.
Laterality and Attention in Schizophrenia
In conclusion, the schizophrenic subjects clearly failed to reveal an expected right ear advantage during the non–forced-attention condition. Moreover, attention to the right ear did not help in advancing the right ear reports, as is almost always found in healthy subjects (see Bryden 1988; Hugdahl 1995, for reviews). This may indicate a “double” laterality dysfunction involving both “automatic” and “controlled” processing deficits. Thus, the dichotic listening technique may be a relatively simple method of testing both automatic and controlled cognitive processing, including possible stable laterality effects and dynamic attentional modulation.
The project received support from the NIMH UCLA Clinical Research Center for the study of Schizophrenia (R. P. Liberman, P.I.), an investigator-initiated grant from the Janssen Research Foundation (M.F. Green and B.D. Marshall, Co-P.I.s), and from the school of Psychology, University of Bergen, Norway (to K. Hugdahl). The data were collected at the Camarillo State Hospital, Camarillo, California, while Else-Marie Løberg was a visiting student. The authors thank B.D. Marshall, Jr, MD, Robert Kern, PhD, Mary Jane Robertsen, MS, Jeffery L. Hayden, Kimmy S. Kee, PhD, Mark McGee, Dustin Salveson, Robert Mangano, Renee Galbavy, Katherine Narr, Maryam Etemadjam, Kristin Mangis, and Crystal Ray for their collective efforts in the data collection. In addition, we are grateful to the patients and staff of Camarillo State Hospital for their participation in the study and support of this project.
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