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structural magnetic resonance imaging investigation
Journal of Psychiatric Research 38 (2004) 153–162 www.elsevier.com/locate/jpsychires
Superior temporal gyrus and P300 in schizophrenia: a combined ERP/structural magnetic resonance imaging investigation E.M. Meisenzahla,*, T. Frodla, D. Mu¨llera, G. Schmitta, J. Gallinata, T. Zetzschea, A. Marcusea, G. Juckela, G. Leinsingerb, K. Hahnb, H.J. Mo¨llera, U. Hegerla a
Department of Psychiatry, Psychiatrische Klinik der LMU Mu¨nchen, Nussbaumstr. 7, 80 336 Munich, Germany b Radiology, Ludwig-Maximilians-University, D-80336 Munich, Germany Received 10 January 2003; received in revised form 19 May 2003; accepted 23 May 2003
Abstract Decrement of the auditory P300 component of the event-related potentials (ERP) is a robust finding in schizophrenic patients and seems to be most pronounced in the left temporal region. Structural MRI studies support the hypothesis that regional structural brain differences in this patient group include reduced volume in temporal lobe structures. The aim of the presented study was to investigate the possible gray matter volume reductions in the left posterior superior temporal gyrus (STG) and the P300 reduction and left < right topographic asymmetry in schizophrenic patients. Therefore, in 50 male schizophrenic patients and 50 age- and educational level-matched male controls, auditory ERPs and structural MRI measurements of the gray matter volume of the STG were assessed. In the group of patients, the psychopathological symptom of thought disorder was correlated with the electrode site T3 and underlying gray matter of the left posterior superior temporal gyrus. The subgroup of patients with pronounced negative symptoms was analyzed with respect to ERP and structural MRI measurements. Our data revealed no evidence for a reduction of P300 amplitude or left STG gray matter volume in schizophrenic patients. However, the higher amount of thought disorders was related to a small T3 amplitude. No associations between the electrophysiological and structural measurements could be detected. There were also no significant reductions of ERP and MRI measurements within the subgroup of patients with pronounced negative symptoms. # 2003 Elsevier Ltd. All rights reserved. Keywords: P300; Schizophrenia; Temporal; Superior temporal gyrus; Magnetic resonance imaging
1. Introduction In the research on the neurobiology of schizophrenia, decrement of the auditory P300 component of the eventrelated potentials (ERP) is a robust finding and seems most pronounced in the left temporal region (Ford, 1999; Salisbury et al., 1999). Moreover, structural MRI studies in schizophrenia support the hypothesis that regional structural brain differences in patients include reduced volume in temporal lobe structures (Wright et al., 2000). Lesion data and neurophysiological studies have demonstrated that the superior temporal gyrus (STG), including the Heschl’s gyrus (HG), plays a vital role in * Corresponding author. Tel.: +49-89-5160-5772x5753. E-mail address: [email protected] (E.M. Meisenzahl). 0022-3956/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0022-3956(03)00078-5
auditory function and language processing (Galaburda & Sanides, 1980). The planum temporale (PT) is a neocortical area at the surface of the posterior superior temporal gyrus within the peri-Sylvian region. It contains auditory association cortex and is localized lateral and posterior to Heschl’s gyrus, as part of Wernicke’s speech area. Electrical stimulation of the STG elicits auditory hallucinations, and lesions including the PT lead to a number of speech comprehension deficits (Shapleske et al., 1999). Therefore, a neurodevelopmentally altered left temporal brain cortex, including the key region of the superior temporal gyrus has been suggested as one model of an underlying key process of schizophrenia (McCarley et al., 1993). The contribution of structural cortical abnormalities to P300 reduction in schizophrenia is still a matter of debate. In the research on the direct spatial relationship between P300 amplitude and the gray matter volumes
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underlying the recording electrode, one approach used to identify neuroanatomical substrates of P300 involves studying patients with focal brain pathology. There is support for the cortical contribution to the P300 from stroke studies, which have revealed that lesions of the superior temporal gyrus diminish auditory P300 amplitude (Woods et al., 1987). Whether the P300 amplitude reflects the integrity of the cortex underlying the recorded elecrodes, or rather reflects the dependancy on the integrity of cortical systems linked to the psychological processes responsible for P300, is not yet clear (Ford et al., 1994a and b). Up to now, only a few studies have combined auditory ERP and structural MRI with the aim to investigate the relationship of auditory P300 and STG volumes in schizophrenic patients (McCarley et al., 1993, 2002; Kawasaki et al., 1997; Havermans et al., 1999). The first and pioneering study on 15 male chronic schizophrenic patients showed a significant association between gray matter volume deficits in the left posterior STG and both temporal P300 amplitude reduction and left < right P300 topographic asymmetry (McCarley et al., 1993). This result was confirmed by a second study of first episode schizophrenic patients (McCarley et al., 2002). Two further investigations that used the combined imaging approach with auditory ERP and structural MRI failed to confirm the relationship between left posterior STG volumes and P300 amplitudes (Kawasaki et al., 1997; Havermans et al., 1999). This investigation therefore examines acoustic eventrelated potentials and structural MRI measurements of the gray matter volume of the anterior, posterior and total STG, as well as STG length in male schizophrenic patients compared to healthy male control subjects. The main aim of the study was to test first the hypothesis that schizophrenic patients show temporal P300 topographic asymmetries and amplitude reductions, as well as volume reductions of the left posterior STG. Furthermore, it was planned to test possible associations between these two measurements. Addi-
tionally, we wanted to investigate the hypothesis that the psychopathological symptom of thought disorder is correlated with the electrode site T3 or with the underlying gray matter volume of the left posterior superior temporal gyrus in schizophrenic male patients. Finally, we also investigated the subgroup of patients with pronounced negative symptoms with respect to possible reductions of ERP and structural MRI measurements.
2. Materials and methods 2.1. Subjects The study was approved by the local ethics committee and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. After complete oral and written description of the study to the patients and control subjects, written informed consent was obtained. Fifty male right-handed schizophrenic patients (age range 18–50 years) who fulfilled DSM-IV and ICD-10 criteria for schizophrenia were recruited over 2 years from the psychiatric hospital of the Ludwig-Maximilians University in Munich. Fifty right-handed male healthy control subjects without a personal history of psychiatric disorder or family history of psychosis were recruited from the local community. They were matched to the patients by age [widest age pairing disparity was 3 years (two pairs)] and educational achievement. Educational achievement was assessed by the number of years of secondary education. Sample characteristics of patients and controls are given in Table 1. Subjects were excluded if they had a current neurological disorder, a history of head injury resulting in loss of consciousness, previous alcohol or substance abuse, metallic objects in their body, or if they had taken cortisol, benzodiazepine or anticonvulsive medication during the three months prior entering in the study.
Table 1 Sociodemographic data of the 50 right-handed male schizophrenic patients and matched healthy controls
Age (years) Height (m) Weight (kg) BPRSa PANSSb PANSS positive subscale PANSS negative subscale Thought disorder index (BPRS) Age of onset (years) Illness duration (years) a b
Patients (n=50)
Healthy controls (n=50)
P-values
30.0 1.79 81.7 42.2 38.4 12.9 25.5 8.8 23.1 6.8
30.2 8.8 1.81 0.06 75.3 9.2 – –
0.92 0.24 0.013
8.4 0.07 15.2 11.3 10.1 4.9 7.5 3.79 6.1 6.9
BPRS, sum score on the Brief Psychiatric Rating Scale. PANSS, sum scores on the Positive and Negative Syndrome Scale.
– – –
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Patients were also excluded if they had any comorbid DSM-IV axis I disorder, or had previously undergone electroconvulsive therapy. 2.2. Assessment Diagnoses were made on the basis of interviews by two trained psychiatrists. The type of medication was recorded: 30 patients were being treated with atypical neuroleptics (clozapine 75–550 mg; risperidone 4–8 mg; olanzapine 5–30 mg) and 12 patients were treated with typical neuroleptics (haloperidol 2–20 mg, fluanxol 2–20 mg). Eight patients were being treated concomitantly with typical and atypical neuroleptics. Age at onset of schizophrenia was based on the age when patients first clearly manifested either delusions or hallucinations. Psychopathology was assessed with the Brief Psychiatric Rating Scale (BPRS) (Overall & Gorham, 1962) and Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). The thought disorder index of the BPRS was applied (Overall & Gorham, 1962). Handedness was determined by the Edinburgh Handedness Inventory (Oldfield, 1971). 2.3. MRI collection and processing MRI images were obtained (1.5 Tesla Magnetom Vision, Siemens) using a coronar T2- and protondensity-weighted Dual-Echo-Sequence (TR 3710 ms/ TE 22/90 ms; total aquisition time: 9 min, number of aquisitions: 1; FOV 230 mm; Matrix 256242, slice thickness 3 mm, voxel 0.90.93 mm) and a 3DMPRAGE sequence (TR/TE 11.6 ms/4.9 ms; total aquisition time: 8 min, number of acquisitions: 1; FOV 230 mm; Matrix 512512, Slice thickness 1.5 mm, voxel 0.450.451.5mm). The commercial software package Analyze was used (ANALYZE, Biomedical Imaging Resource, Mayo Foundation, Rochester, MN) to further process the images of all three sequences, with size reduction from 16 to 8 bit and transformation to a uniform matrix of 256256 on 126 slices of 1.5 mm slice thickness (voxel size 0.90.91.5). Every MRI dataset (consisting in a MPRAGE, T2 and pd-sequence) was segmented with the software program BRAINS (Brain Research: Analysis of Images, Networks, and Systems; developed by NC Andreasen and colleagues) (Andreasen et al., 1992, 1993; Harris et al., 1999). First, every dataset was realigned and resampled three-dimensionally according to the coordinates of Talairach. This was performed by resampling so that the anteroposterior axis of the brain was realigned parallel to the anteroposterior commissural line, and the interhemispheric fissure was aligned on the other two axes. The discriminant analysis technique used to achieve tissue classification required the a priori identification of tissue ‘‘training classes’’ from
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which a classification of all the pixels in the image data set can be generated. This was performed by manual tracing by an experienced technician (E.M.). The operator switched between sequences, and all three sequences were checked before a training class was accepted. The operator defined circular regions of interest in each hemisphere on 16 coronal slices selected to provide thorough spatial representation throughout the brain. Each region contained between five and 15 voxels. The total number of voxels selected for each tissue type was between 150 and 300 voxels. Subsequently, specific tissue volume measurements on every dataset (consisting in a MPRAGE, T2 and pd-sequence) were obtained for the predefined 17 talairachboxes, each with gray matter, white matter and CSF values in ml (Andreasen et al., 1992, 1993). The total brain volume was the sum of all predefined talairach boxes minus the two boxes of the brainstem. STG measurements were performed interactively. 2.4. Definition of the superior temporal gyrus (STG) Images were analyzed using BRAINS, an imaging analysis software program that allows simultaneous viewing of images in three mutually orthogonal planes. Tracings were performed after the entire sample had been collected. Images were mixed and identified only by number so that the investigators were blind to group affilation. Intrarater reliability estimates for the regions of the STG (left, right, anterior, posterior) were based on a random sample of 10 MRI datasets that were measured twice by the same investigator (E.M.) who performed all of the tracings. Estimates of interrater reliability between two raters (E.M.; A.M.) were based on a separate random sample of 10 MRI datasets. The intraclass correlations for the STG regions ranged from 0.89 to 0.93. The borders of the superior temporal gyrus were defined according to the criteria already established in the literature (Shenton et al., 1992) (Fig. 1). STG tracings included gray and white matter tissue. The STG was divided according to Shenton into the anterior and posterior portion. The anterior portion started at the temporal stem, and the posterior boundary of the anterior portion was defined by the first appearance of the mammillary bodies. The adjacent posterior portion was delimited posteriorly by the last appearence of the crux of the fornix (Shenton et al., 1992). The ROIs were determined by summation of the contiguous coronal slices of the defined ROI. The lengths of the anterior and posterior STG were measured by multiplying the number of slices within each ROI by the slice thickness. Asymmetry coefficients (AC) of the gray matter of the four ROIs of the STG measurements (left/right, anterior/posterior, total) were calculated according to Galaburda’s equation:
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AC ¼ ðright STGvolume-left STGvolumeÞ=ð0:5 ðright STGvolume þ left STGvolumeÞ ACs were classified into three groups (categorical lateralization) according to the following definition: leftward asymmetric (AC < 0.05), rightward asymmetric (AC > 0.05) and symmetric (0.054AC40.05) (Galaburda et al., 1987). 2.5. P300 recording P300 recording for all 100 subjects was obtained within 24 h of the MRI scanning. An auditory oddball paradigm was used in which tones (80 dB Sound Pres-
sure Level, 40 ms duration, 10 ms rise/fall time using a fixed 1.5 s interstimulus interval) were presented binaurally via eartips in pseudorandomized order. Twenty percent of these tones were targets (100 sinusoidal tones, 1000 Hz), and 80% were standards (400 sinusoidal tones, 500 Hz). Subjects were seated in a reclining chair with their eyes closed and were instructed to press a button with their dominant hand in response to target stimuli. The average number of correct reactions and mean reaction time was recorded for each subject. Event-related potentials were recorded with 30 channels (29 tin-electrodes of an electro cap and three additional tin-electrodes at the nasion and mastoids, referenced to Cz). The electrodes were positioned precisely according to the international 10–20 system. A coronal line of four electrodes was added between frontal
Fig. 1. Interactive measurement of the left and right superior temporal gyrus: (a) one representative slice of the region of the anterior part of the superior temporal gyrus, (b) one representative slice of the posterior part of the superior temporal gyrus.
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and central electrode locations, and another coronal line of four electrodes was added between central and parietal electrode locations, and one electrode was added at the inion. Electrode impedance was maintained at less than 5 kOhm. The EEG was amplified with bandpass filters of 0.16–70 Hz (sampling rate of 256 Hz). EOG was recorded with electrodes above and lateral to the eyes and at the nasion. To avoid artifacts all trials were excluded if their voltage exceeded 50 mV in any one of the 30 channels at any moment during the averaging epoch (from 200 ms prestimulus to 800 ms poststimulus). Amplitudes were measured with reference to a 200 ms prestimulus baseline. Subchannel analyses were performed in order to obtain data that could be compared with those of McCarley (1993). For the analysis of single channel P300 the data were calculated with reference to linked mastoids. The amplitudes and latencies of the P300 were defined as the most positive point in the P300 time interval (166 ms time window starting 40 ms after the P200 peak).
regarding STG length were also calculated by the ANCOVA design. Laterality was further explored by use of the Asymmetry coefficients (AC) by an independent t-test. For electrophysiological data repeated measurement ANOVA with one between-subject-factor (diagnosis) and two within-subject factors (laterality [mideline (Fz/ Cz/Pz), left (F3/C3/P3), far left (F7/T3/T5), right (F4/ C4/P4), far right (F8/T4/T6)]; topography [frontal (Fz,F3,F4,F7,F8), central (Cz,C3,C4,T3,T4) parietal (Pz,P3,P4,T5,T6)]) on P300 amplitudes were performed. Correlations between morphometric and electrophysiological data were performed by Pearson product moment correlation. Correlations between both the morphometric and the electrophysiological data and psychopathology were examined by Spearman correlation analysis. The subgroup of patients with pronounced negative symptoms was analyzed by median split of the PANSS subscale of negative symptoms.
2.6. Statistical analysis
3. Results
Statistics were performed using the SPSS 11.0 software (statistical package for social sciences, SPSS, Inc., Chicago, 2001). t-Tests were applied to test for differences in sociodemographic variables between healthy controls and patients. Morphometric data (only the segmentation of gray matter tissue was entered into the STG statistics) were analyzed for region and laterality effects by a mixed model analysis of covariance (ANCOVA) with one between-subject factor (diagnosis) and two within-subject factors [laterality, region (anterior vs. posterior STG)]. The covariate intracranial volume was added to the analysis. Group differences
No differences in age (t=0.08, P=0.93), height (t =1.18, P=0.24) or total brain volume (t=1.66, P=0.10) were detected between patients and controls. An overview of the morphometric and electrophysiological data is given in Table 2.
Table 2 Direct comparisons of uncorrected morphometric and electrophysiological data between 50 schizophrenic patients and 50 healthy controls SZ patients
Healthy controls
Total intracranial content (ml) 1347.7 95.6 1383.1 115.9 Left total STG (ml) 9.20 1.30 9.60 1.36 Right total STG (ml) 10.14 1.28 10.47 1.36 Left anterior STG (ml) 2.42 0.61 2.52 0.61 Right anterior STG (ml) 3.16 0.68 3.22 0.59 Left posterior STG (ml) 6.78 1.01 7.25 1.15 Right posterior STG (ml) 6.98 1.07 7.25 1.11 Length, left anterior STG (mm) 9.5 1.6 9.6 1.6 Length, right anterior STG (mm) 11.5 1.8 11.4 1.4 Length, left posterior STG (mm) 22.8 1.9 22.6 2.3 Length, right posterior STG (mm) 22.2 1.6 21.9 2.1 0.099 0.13 0.089 0.12 ACtotalSTG AC posterior STG 0.027 0.15 0.029 0.15 0.25 0.24 0.27 0.23 AC anterior STG P300-amplitude at T3 (m volt) 3.55 1.48 3.75 1.75 P300-amplitude at T4 (m volt) 3.48 1.57 3.13 1.39
3.1. I 3.1.1. STG measurements In the ANCOVA no significant main effect for group with respect to morphometric STG measurements (F=0.40; df=1/97; P=0.53) was detected. There was no significant two-way interaction of diagnosis and laterality (F=0.15; df=1/97; P=0.70) or diagnosis and region (F=0.06; df=1/97; P=0.82), and no significant three-way interaction of diagnosis, laterality, and region (F=0.004, df=1/97, P=0.95). Neither STG length (F=1.5; df=97; P=0.23). nor AC (total STG: t=0.42, P=0.67, anterior STG: t=0.38, P=0.70, posterior STG: t=0.08, P=0.93) differed between patients and healthy controls. Results did not change when ANOVAs were calculated without the covariate total brain volume. 3.1.2. Electrophysiological data of P300 amplitudes The ANOVA on P300 amplitudes did not reveal significant main effects on diagnosis [F (1/98)=0.21, P=0.65] (Fig. 2). The parietal distribution of P300 was significant (anterior–posterior topography [F (1.25/ 445.5)=43.5, P < 0.001] as was the laterality effect [F (1.76/445.5)=207.4, P< 0.001], reflecting larger P300 closer to the midline). The interactions of diagnosis with topography [F (1.25/445.5)=0.75, P=0.42] and laterality
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(F=0.009; df=1/75; P=0.92) was detected. There was no significant two-way interaction of diagnosis and laterality (F=0.19; df=1/75; P=0.65) or diagnosis and region (F=0.008; df=1/75; P=0.93), and no significant three-way interaction of diagnosis, laterality and region (F=0.01, df=1/75, P=0.92). AC did not differ between patients and healthy controls (total STG: t=0.17, P=0.86, anterior STG: t=0.10, P=0.91, posterior STG: t=0.37, P=0.71). No group differences regarding STG length for left anterior (t=0.09, P=0.92) left posterior (t=0.38, P=0.70), right anterior (t=0.32, P=0.74) and right posterior (t=0.38, P=0.70) STG were detected. Results did not change when ANOVAs were calculated without the covariate total brain volume. Fig. 2. Grand average curves of the scalp data measurements are depicted for the electrodes T3 and T4 with reference to linked mastoids for 50 schizophrenic patients and 50 healthy control subjects.
[F (1.76/445.5)=1.2, P=0.29] were not significant. Reaction time (t=0.1.2, P=0.22) and the task performance (t=0.7, P=0.48) did not differ between patients and controls. 3.1.3. Correlations between ERP and the gray matter of the left posterior STG The correlation between the P300 amplitude at T3 and gray matter of the left posterior STG revealed no association in patients (r=0.15; P=0.30) or in healthy controls (r=0.16; P=0.27). 3.2. II 3.2.1. Correlations of thought disorder, ERP (T3) and left posterior STG P300 amplitude at the T3 electrode site was significantly negatively correlated with the formal thought disorder subscore (r=0.47, P=0.001) of the BPRS whereas the left posterior STG (r=0.07, P=0.65) did not correlate. 3.3. III 3.3.1. Subgroup of patients with pronounced negative symptoms This subgroup of patients (N=28 of 50) had higher scores than the mean value of 25.5 on the PANSS subscore for negative symptoms. No differences in age (t=0.498, P=0.62), height (t=0.807, P=0.42) or total brain volume (t=1.73, P=0.08) between this subgroup and the healthy control group were detected. 3.3.2. STG measurements In the ANCOVA no significant main effect for group with respect to morphometric STG measurements
3.3.3. Electrophysiological data of P300 amplitudes The ANOVA on P300 amplitudes did not reveal significant main effects on diagnosis [F (1/76)=0.003, P=0.96]. The parietal distribution of P300 was significant (anterior–posterior topography [F (1.24/ 89.0)=27.1, P < 0.001] as was the laterality effect [F (1.95/140.5)=153.9, P < 0.001], reflecting larger P300 closer to the midline. The interactions of diagnosis with topography [F (1.24/89.0)=0.49, P=0.53] and laterality [F (1.95/140.5)=1.3, P=0.28] were not significant. Reaction time (t=1.3, P=0.21) and task performance time (t=0.75, P=0.45) did not differ between patients and controls. 3.3.4. Correlations between ERP (T3) and the gray matter of the left posterior STG The correlation between the P300 amplitude at T3 and gray matter of the left posterior STG revealed no association in patients (r=0.03; P=0.87) or in healthy controls (r=0.16; P=0.27). 3.3.5. Correlations of thought disorder, ERP (T3) and left posterior STG Again, P300 amplitude at the T3 electrode site was significantly negatively correlated with the formal thought disorder subscore (r=0.52, P=0.004) of the BPRS. Finally, the left posterior STG did not correlate with the formal thought disorder score (r=0.16, P=0.38) of the BPRS scale.
4. Discussion This study aimed to investigate the hypothesis that schizophrenic patients show temporal P300 topographic asymmetries and amplitude reductions as well as volume reductions of the left posterior STG. As our schizophrenic patients did not show either altered P300 amplitudes or asymmetries for electrode sites T3/T4 compared to healthy control subjects, the
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failure to replicate the reduced P300 amplitude component of the event-related potential and altered asymmetry deserves discussion. In the research on the neurobiology of schizophrenia, decrement of the auditory P300 is a robust finding and seems most pronounced in the left temporal region (Ford, 1999). However, some studies failed to demonstrate decreased auditory P300 amplitudes in comparison to controls (Umbricht et al., 1998; Fukuda et al., 1997; Shelley et al., 1996; Strik et al., 1993; Duncan-Johnson et al., 1982; Roth et al., 1981, 1979; Shagass et al., 1978). It must be taken into account that partial remediation of P300 amplitude reduction in schizophrenia was demonstrated with improvement of psychotic symptoms by antipsychotic medication in some studies (Matsubayashi, 1984; Duncan, 1988; Mintz et al., 1995; Gallinat et al., 2001) and by nonpharmacological interventions such as feedback training in others (Fukuda et al., 1989, 1997). Pallanti et al. (1999) found that after a 6-month period of treatment with clozapine, the P300 differences between 22 schizophrenic patients and healthy controls were no longer statistically significant. Furthermore, other studies reported a normalization of previously reduced P300 amplitudes after psychopharmacological treatment (Schall et al., 1998, Umbricht et al., 1998, Coburn et al., 1998). This is in line with our results since the patients participating in our study were medicated and stabilized and had fewer positive symptoms. Their stabilized state might explain why they showed normal P300. In contrast, the patients in McCarley et al.’s studies had been suffering from chronic schizophrenia with continuing productive symptomatology for years (McCarley et al., 1993) or were first episode patients (McCarley et al., 2002), although the patients in the latter study showed slightly less psychopathology on the BPRS scores than our patients. However, our subgroup of patients with pronounced negative symptomatology also failed to show significant reductions of either ERP or STG measurements. It still remains a matter of debate whether P300 amplitude reductions represent state or trait markers in the pathophysiology of the disease. Some data support the trait aspect of P300 deficits because P300 reductions are stable over time despite significant changes in symptomatology (Turetsky et al., 1998; Mathalon et al., 2000) Finally, as our data were not obtained in the study with a longitudinal design, they may not qualify to contribute to the trait/state problem of ERPs in schizophrenia. The STG volume and length measurements did not reveal a difference between schizophrenic patients and healthy control subjects. These were unexpected results in view of the large effect sizes reported by Shenton et al. (1992) when they compared the superior temporal gyrus gray matter volumes of schizophrenic patients with those of healthy controls. Shenton et al. subdivided according to defined anatomical guidelines STG
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measurements into an anterior and posterior portion, guided by the same subcortical landmarks (Shenton et al., 1992) that we applied, in order to replicate the prior findings. However, the use of subcortical landmarks represents a source of potential measurement errors and is a significant source of variability, which might explain in part our negative findings. Nevertheless, our lack of findings cannot not be explained by a general absence of morphometric abnormalities in this group of subjects because patients had significantly larger third ventricles (Meisenzahl et al., 2002b), and bilaterally reduced hippocampal volumes and a reduced anterior cingulate (Meisenzahl et al., submitted for publication). In order to further explore the possibility of reduced superior temporal gyrus laterality, the asymmetry coefficients of the groups were also compared. Although no group differences in AC coefficents were detected, the findings did reveal in all 100 subjects a significant rightward laterality for the anterior part of the gray matter STG, and a symmetric laterality for the posterior part. In line with our findings, Shenton and collegues also failed to detect a leftward asymmetry for the superior temporal gryus in healthy control subjects (Shenton et al., 1992). However, both results are somewhat surprising in view of the literature, which has reported a leftward lateralisation of the posterior superior temporal gyrus for macroscopic parameters of brain anatomy and, more specifically, language function. In this regard, it is of interest that recent investigations of our group on in vivo analysis of the planum temporale in healthy controls (Zetzsche et al., 2001) and schizophrenic patients (Meisenzahl et al., 2002a) by use of three different definitions of PT borders detected that results and the degree of asymmetry between left and right regions of interest were strongly dependent on the definition used for the ROI borders. Our observations leaded us to the conclusion that the influence of the definitions on the investigated ROIs may explain some of the discrepancies between studies. Therefore, the fact that morphometric evaluations of the superior temporal gyrus in patients with schizophrenia are inconsistent may therefore not be that astonishing after all. In the past, several studies have reported unilateral or bilateral left-sided volume deficits in the anterior, posterior or total STG in schizophrenic patients compared to healthy control subjects (Barta et al., 1990; Shenton et al., 1992; Marsh et al., 1997; Hirayasu et al., 1998; Levitan et al., 1999; Rajarethinam et al., 2000). However, a number of studies failed to replicate these findings (DeLisi et al., 1994; Kulynych et al., 1996; Woodruff et al., 1997). In contrast, investigations of patients with chronic, early-onset schizophrenia reported a lower bilateral volume of the STG in patients (Marsh et al., 1997), and a superior temporal gyrus enlargement in adolescents with childhood-onset schizo-
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phrenia (Jacobsen et al., 1996). In another study, adolescents with early-onset schizophrenia showed lower right superior temporal gyrus volumes compared to controls (Matsumoto et al., 2001). One of the two post-mortem studys on STG (Highley et al., 1999; Vogeley et al., 1998) reported an interesting methodological issue: Vogeley and colleagues demonstrated a bilateral volume and length decrease of the left STG in a sample of female schizophrenic patients. The authors pointed out that the detected volume decrease of the left STG in the schizophrenic group was caused by the significantly reduced length of the STG regions (Vogeley et al., 1998). In fact, we agree that additional measurements of the length of the STG compartment seem an often neglected aspect in volumetric studies of the STG. Volumetric reductions of the STG compartment may be caused simply by a reduction of the length of the STG part measured so that study results which do not consider this detail may give a distorted picture of regional brain changes of the STG region. However, in our sample no length differences in the STG compartments, which could have lead to false negative results, emerged. In the group of patients no reductions emerged for either electrophysiological or structural data. Therefore, it can be speculated if the failure to replicate significant associations between P300 amplitude at T3 and the gray matter of the left posterior STG might be explained by the normal amount of gray matter volume in schizophrenic patients. After all, our finding of no association between left temporal ERP amplitude and left gray matter volume of the STG in 50 healthy subjects is in line with recent studies (McCarley et al., 1993, 2002; Ford et al., 1994a) and supports the idea that the P300 in the CNS of healthy controls may not depend on the cortex directly underlying the electrode site (Ford et al. 1994a). Therefore, physiological structure–function relationships seems still difficult to establish, given the dynamic nature of P300 in comparison to the more static nature of brain structure (for review see Ford et al., 1994b; Ford, 1999). Finally, within the groups of patients there was a significant correlation between the psychopathological symptom of thought disorder and the electrode site T3. The hypothesis that a small T3 amplitude is related to a higher amount of thought disorders was confirmed in our sample of schizophrenic patients (Frodl et al., 2002; Hegerl et al., 1995). However, the volume of the left posterior superior STG was not related to a greater number of thought disorders. This is in contrast to prior findings which have indicated that thought disorder is explicitly linked to brain abnormalities in the STG as this area represents one key region of language functioning (Shenton et al., 1992). Therefore, the lack of an relationship between gray matter volume of the left posterior STG and the psychopathological item of
thought disorders may not support the idea of a primary pathology in the STG with regard to this key symptom. Our negative study results necessitate some comments about the patient group. As our study examined a large population of schizophrenic patients, we do not assume that our findings occurred by chance. Our patients comprised stabilized male schizophrenic inpatients who, although severely ill at the time of admission, were mostly showing a good remission of productive psychotic symptoms at the time of the study. Therefore, it cannot be excluded that differences in the clinical course of the disease may at least in part explain our negative findings compared to the two studies of McCarley’s group. This may be further supported by the finding that the the results of analysis of the subgroup of patients with pronounced negative symptoms were not different with respect to the hypotheses investigated in the presented paper. However, the present study suffers from the limitation that only male subjects were investigated and therefore our data cannot give contribute to the question of possible gender effects. In conclusion, our data revealed no evidence for left P300 amplitude and left gray matter volume reductions of the STG, in either male schizophrenic patients or male healthy controls. Our study results may point to the possibility that differences in the clinical course of the disease may at least in part explain the negative findings compared to the ealier two studies of McCarley’s group. Nevertheless, and given the fact that our here presented data support the hypothesis that a higher number of thought disorders is related to a small T3 amplitude but not to a reduced volume of the left posterior superior STG, these findings may demonstrate that the direct spatial relationship between functional and structural data is still a matter of debate and difficult to establish.
Acknowledgements This work was supported by the Deutsche Forschungsgemeinschaft No. 231/96. We would like to thank Prof. Nancy Andreasen and her staff, who provided generous support with the segmentation program BRAINS, and Dr. Strauß, Bernhard Burgermeister and Jacqueline Klesing for technical support.
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Turetsky B, Colbath EA, Gur RE. P300 subcomponent abnormalities in schizophrenia: II. Longitudinal stability and relationship to symptom change. Biological Psychiatry 1998;43:31–9. Umbricht D, Javitt D, Novak G, Bates J, Pollack S, Lieberman J, Kane J. Effects of clozapine on auditory event-related potentials in schizophrenia. Biological Psychiatry 1998;44:716–25. Vogeley K, Hobson T, Schneider-Axmann T, Honer WG, Bogerts B, Falkai P. Compartmental volumetry of the superior temporal gyrus reveals sex differences in schizophrenia—a post-mortem study. Schizophrenia Research 1998;31:83–7. Woodruff PW, Wright IC, Shuriquie N, Russouw H, Rushe T, Howard RJ, et al. Structural brain abnormalities in male schizophrenics reflect fronto- temporal dissociation. Psychological Medicine 1997;27:1257–66. Woods DL, Clayworth CC, Knight RT, Simpson GV, Naeser MA. Generators of middle- and long-latency auditory evoked potentials: implications from studies of patients with bitemporal lesions. Electroencephalography and Clinical Neurophysiology 1987;68: 132–48. Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET. Meta-analysis of regional brain volumes in schizophrenia. The American Journal of Psychiatry 2000;157:16– 25. Zetzsche T, Meisenzahl EM, Preuss UW, Holder JJ, Kathmann N, Leinsinger G, et al. In-vivo analysis of the human planum temporale (PT): does the definition of PT borders influence the results with regard to cerebral asymmetry and correlation with handedness? Psychiatry Research 2001;107:99–115.
Superior temporal gyrus and P300 in schizophrenia: a combined ERP/structural magnetic resonance imaging investigation E.M. Meisenzahla,*, T. Frodla, D. Mu¨llera, G. Schmitta, J. Gallinata, T. Zetzschea, A. Marcusea, G. Juckela, G. Leinsingerb, K. Hahnb, H.J. Mo¨llera, U. Hegerla a
Department of Psychiatry, Psychiatrische Klinik der LMU Mu¨nchen, Nussbaumstr. 7, 80 336 Munich, Germany b Radiology, Ludwig-Maximilians-University, D-80336 Munich, Germany Received 10 January 2003; received in revised form 19 May 2003; accepted 23 May 2003
Abstract Decrement of the auditory P300 component of the event-related potentials (ERP) is a robust finding in schizophrenic patients and seems to be most pronounced in the left temporal region. Structural MRI studies support the hypothesis that regional structural brain differences in this patient group include reduced volume in temporal lobe structures. The aim of the presented study was to investigate the possible gray matter volume reductions in the left posterior superior temporal gyrus (STG) and the P300 reduction and left < right topographic asymmetry in schizophrenic patients. Therefore, in 50 male schizophrenic patients and 50 age- and educational level-matched male controls, auditory ERPs and structural MRI measurements of the gray matter volume of the STG were assessed. In the group of patients, the psychopathological symptom of thought disorder was correlated with the electrode site T3 and underlying gray matter of the left posterior superior temporal gyrus. The subgroup of patients with pronounced negative symptoms was analyzed with respect to ERP and structural MRI measurements. Our data revealed no evidence for a reduction of P300 amplitude or left STG gray matter volume in schizophrenic patients. However, the higher amount of thought disorders was related to a small T3 amplitude. No associations between the electrophysiological and structural measurements could be detected. There were also no significant reductions of ERP and MRI measurements within the subgroup of patients with pronounced negative symptoms. # 2003 Elsevier Ltd. All rights reserved. Keywords: P300; Schizophrenia; Temporal; Superior temporal gyrus; Magnetic resonance imaging
1. Introduction In the research on the neurobiology of schizophrenia, decrement of the auditory P300 component of the eventrelated potentials (ERP) is a robust finding and seems most pronounced in the left temporal region (Ford, 1999; Salisbury et al., 1999). Moreover, structural MRI studies in schizophrenia support the hypothesis that regional structural brain differences in patients include reduced volume in temporal lobe structures (Wright et al., 2000). Lesion data and neurophysiological studies have demonstrated that the superior temporal gyrus (STG), including the Heschl’s gyrus (HG), plays a vital role in * Corresponding author. Tel.: +49-89-5160-5772x5753. E-mail address: [email protected] (E.M. Meisenzahl). 0022-3956/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0022-3956(03)00078-5
auditory function and language processing (Galaburda & Sanides, 1980). The planum temporale (PT) is a neocortical area at the surface of the posterior superior temporal gyrus within the peri-Sylvian region. It contains auditory association cortex and is localized lateral and posterior to Heschl’s gyrus, as part of Wernicke’s speech area. Electrical stimulation of the STG elicits auditory hallucinations, and lesions including the PT lead to a number of speech comprehension deficits (Shapleske et al., 1999). Therefore, a neurodevelopmentally altered left temporal brain cortex, including the key region of the superior temporal gyrus has been suggested as one model of an underlying key process of schizophrenia (McCarley et al., 1993). The contribution of structural cortical abnormalities to P300 reduction in schizophrenia is still a matter of debate. In the research on the direct spatial relationship between P300 amplitude and the gray matter volumes
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underlying the recording electrode, one approach used to identify neuroanatomical substrates of P300 involves studying patients with focal brain pathology. There is support for the cortical contribution to the P300 from stroke studies, which have revealed that lesions of the superior temporal gyrus diminish auditory P300 amplitude (Woods et al., 1987). Whether the P300 amplitude reflects the integrity of the cortex underlying the recorded elecrodes, or rather reflects the dependancy on the integrity of cortical systems linked to the psychological processes responsible for P300, is not yet clear (Ford et al., 1994a and b). Up to now, only a few studies have combined auditory ERP and structural MRI with the aim to investigate the relationship of auditory P300 and STG volumes in schizophrenic patients (McCarley et al., 1993, 2002; Kawasaki et al., 1997; Havermans et al., 1999). The first and pioneering study on 15 male chronic schizophrenic patients showed a significant association between gray matter volume deficits in the left posterior STG and both temporal P300 amplitude reduction and left < right P300 topographic asymmetry (McCarley et al., 1993). This result was confirmed by a second study of first episode schizophrenic patients (McCarley et al., 2002). Two further investigations that used the combined imaging approach with auditory ERP and structural MRI failed to confirm the relationship between left posterior STG volumes and P300 amplitudes (Kawasaki et al., 1997; Havermans et al., 1999). This investigation therefore examines acoustic eventrelated potentials and structural MRI measurements of the gray matter volume of the anterior, posterior and total STG, as well as STG length in male schizophrenic patients compared to healthy male control subjects. The main aim of the study was to test first the hypothesis that schizophrenic patients show temporal P300 topographic asymmetries and amplitude reductions, as well as volume reductions of the left posterior STG. Furthermore, it was planned to test possible associations between these two measurements. Addi-
tionally, we wanted to investigate the hypothesis that the psychopathological symptom of thought disorder is correlated with the electrode site T3 or with the underlying gray matter volume of the left posterior superior temporal gyrus in schizophrenic male patients. Finally, we also investigated the subgroup of patients with pronounced negative symptoms with respect to possible reductions of ERP and structural MRI measurements.
2. Materials and methods 2.1. Subjects The study was approved by the local ethics committee and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. After complete oral and written description of the study to the patients and control subjects, written informed consent was obtained. Fifty male right-handed schizophrenic patients (age range 18–50 years) who fulfilled DSM-IV and ICD-10 criteria for schizophrenia were recruited over 2 years from the psychiatric hospital of the Ludwig-Maximilians University in Munich. Fifty right-handed male healthy control subjects without a personal history of psychiatric disorder or family history of psychosis were recruited from the local community. They were matched to the patients by age [widest age pairing disparity was 3 years (two pairs)] and educational achievement. Educational achievement was assessed by the number of years of secondary education. Sample characteristics of patients and controls are given in Table 1. Subjects were excluded if they had a current neurological disorder, a history of head injury resulting in loss of consciousness, previous alcohol or substance abuse, metallic objects in their body, or if they had taken cortisol, benzodiazepine or anticonvulsive medication during the three months prior entering in the study.
Table 1 Sociodemographic data of the 50 right-handed male schizophrenic patients and matched healthy controls
Age (years) Height (m) Weight (kg) BPRSa PANSSb PANSS positive subscale PANSS negative subscale Thought disorder index (BPRS) Age of onset (years) Illness duration (years) a b
Patients (n=50)
Healthy controls (n=50)
P-values
30.0 1.79 81.7 42.2 38.4 12.9 25.5 8.8 23.1 6.8
30.2 8.8 1.81 0.06 75.3 9.2 – –
0.92 0.24 0.013
8.4 0.07 15.2 11.3 10.1 4.9 7.5 3.79 6.1 6.9
BPRS, sum score on the Brief Psychiatric Rating Scale. PANSS, sum scores on the Positive and Negative Syndrome Scale.
– – –
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Patients were also excluded if they had any comorbid DSM-IV axis I disorder, or had previously undergone electroconvulsive therapy. 2.2. Assessment Diagnoses were made on the basis of interviews by two trained psychiatrists. The type of medication was recorded: 30 patients were being treated with atypical neuroleptics (clozapine 75–550 mg; risperidone 4–8 mg; olanzapine 5–30 mg) and 12 patients were treated with typical neuroleptics (haloperidol 2–20 mg, fluanxol 2–20 mg). Eight patients were being treated concomitantly with typical and atypical neuroleptics. Age at onset of schizophrenia was based on the age when patients first clearly manifested either delusions or hallucinations. Psychopathology was assessed with the Brief Psychiatric Rating Scale (BPRS) (Overall & Gorham, 1962) and Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). The thought disorder index of the BPRS was applied (Overall & Gorham, 1962). Handedness was determined by the Edinburgh Handedness Inventory (Oldfield, 1971). 2.3. MRI collection and processing MRI images were obtained (1.5 Tesla Magnetom Vision, Siemens) using a coronar T2- and protondensity-weighted Dual-Echo-Sequence (TR 3710 ms/ TE 22/90 ms; total aquisition time: 9 min, number of aquisitions: 1; FOV 230 mm; Matrix 256242, slice thickness 3 mm, voxel 0.90.93 mm) and a 3DMPRAGE sequence (TR/TE 11.6 ms/4.9 ms; total aquisition time: 8 min, number of acquisitions: 1; FOV 230 mm; Matrix 512512, Slice thickness 1.5 mm, voxel 0.450.451.5mm). The commercial software package Analyze was used (ANALYZE, Biomedical Imaging Resource, Mayo Foundation, Rochester, MN) to further process the images of all three sequences, with size reduction from 16 to 8 bit and transformation to a uniform matrix of 256256 on 126 slices of 1.5 mm slice thickness (voxel size 0.90.91.5). Every MRI dataset (consisting in a MPRAGE, T2 and pd-sequence) was segmented with the software program BRAINS (Brain Research: Analysis of Images, Networks, and Systems; developed by NC Andreasen and colleagues) (Andreasen et al., 1992, 1993; Harris et al., 1999). First, every dataset was realigned and resampled three-dimensionally according to the coordinates of Talairach. This was performed by resampling so that the anteroposterior axis of the brain was realigned parallel to the anteroposterior commissural line, and the interhemispheric fissure was aligned on the other two axes. The discriminant analysis technique used to achieve tissue classification required the a priori identification of tissue ‘‘training classes’’ from
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which a classification of all the pixels in the image data set can be generated. This was performed by manual tracing by an experienced technician (E.M.). The operator switched between sequences, and all three sequences were checked before a training class was accepted. The operator defined circular regions of interest in each hemisphere on 16 coronal slices selected to provide thorough spatial representation throughout the brain. Each region contained between five and 15 voxels. The total number of voxels selected for each tissue type was between 150 and 300 voxels. Subsequently, specific tissue volume measurements on every dataset (consisting in a MPRAGE, T2 and pd-sequence) were obtained for the predefined 17 talairachboxes, each with gray matter, white matter and CSF values in ml (Andreasen et al., 1992, 1993). The total brain volume was the sum of all predefined talairach boxes minus the two boxes of the brainstem. STG measurements were performed interactively. 2.4. Definition of the superior temporal gyrus (STG) Images were analyzed using BRAINS, an imaging analysis software program that allows simultaneous viewing of images in three mutually orthogonal planes. Tracings were performed after the entire sample had been collected. Images were mixed and identified only by number so that the investigators were blind to group affilation. Intrarater reliability estimates for the regions of the STG (left, right, anterior, posterior) were based on a random sample of 10 MRI datasets that were measured twice by the same investigator (E.M.) who performed all of the tracings. Estimates of interrater reliability between two raters (E.M.; A.M.) were based on a separate random sample of 10 MRI datasets. The intraclass correlations for the STG regions ranged from 0.89 to 0.93. The borders of the superior temporal gyrus were defined according to the criteria already established in the literature (Shenton et al., 1992) (Fig. 1). STG tracings included gray and white matter tissue. The STG was divided according to Shenton into the anterior and posterior portion. The anterior portion started at the temporal stem, and the posterior boundary of the anterior portion was defined by the first appearance of the mammillary bodies. The adjacent posterior portion was delimited posteriorly by the last appearence of the crux of the fornix (Shenton et al., 1992). The ROIs were determined by summation of the contiguous coronal slices of the defined ROI. The lengths of the anterior and posterior STG were measured by multiplying the number of slices within each ROI by the slice thickness. Asymmetry coefficients (AC) of the gray matter of the four ROIs of the STG measurements (left/right, anterior/posterior, total) were calculated according to Galaburda’s equation:
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AC ¼ ðright STGvolume-left STGvolumeÞ=ð0:5 ðright STGvolume þ left STGvolumeÞ ACs were classified into three groups (categorical lateralization) according to the following definition: leftward asymmetric (AC < 0.05), rightward asymmetric (AC > 0.05) and symmetric (0.054AC40.05) (Galaburda et al., 1987). 2.5. P300 recording P300 recording for all 100 subjects was obtained within 24 h of the MRI scanning. An auditory oddball paradigm was used in which tones (80 dB Sound Pres-
sure Level, 40 ms duration, 10 ms rise/fall time using a fixed 1.5 s interstimulus interval) were presented binaurally via eartips in pseudorandomized order. Twenty percent of these tones were targets (100 sinusoidal tones, 1000 Hz), and 80% were standards (400 sinusoidal tones, 500 Hz). Subjects were seated in a reclining chair with their eyes closed and were instructed to press a button with their dominant hand in response to target stimuli. The average number of correct reactions and mean reaction time was recorded for each subject. Event-related potentials were recorded with 30 channels (29 tin-electrodes of an electro cap and three additional tin-electrodes at the nasion and mastoids, referenced to Cz). The electrodes were positioned precisely according to the international 10–20 system. A coronal line of four electrodes was added between frontal
Fig. 1. Interactive measurement of the left and right superior temporal gyrus: (a) one representative slice of the region of the anterior part of the superior temporal gyrus, (b) one representative slice of the posterior part of the superior temporal gyrus.
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and central electrode locations, and another coronal line of four electrodes was added between central and parietal electrode locations, and one electrode was added at the inion. Electrode impedance was maintained at less than 5 kOhm. The EEG was amplified with bandpass filters of 0.16–70 Hz (sampling rate of 256 Hz). EOG was recorded with electrodes above and lateral to the eyes and at the nasion. To avoid artifacts all trials were excluded if their voltage exceeded 50 mV in any one of the 30 channels at any moment during the averaging epoch (from 200 ms prestimulus to 800 ms poststimulus). Amplitudes were measured with reference to a 200 ms prestimulus baseline. Subchannel analyses were performed in order to obtain data that could be compared with those of McCarley (1993). For the analysis of single channel P300 the data were calculated with reference to linked mastoids. The amplitudes and latencies of the P300 were defined as the most positive point in the P300 time interval (166 ms time window starting 40 ms after the P200 peak).
regarding STG length were also calculated by the ANCOVA design. Laterality was further explored by use of the Asymmetry coefficients (AC) by an independent t-test. For electrophysiological data repeated measurement ANOVA with one between-subject-factor (diagnosis) and two within-subject factors (laterality [mideline (Fz/ Cz/Pz), left (F3/C3/P3), far left (F7/T3/T5), right (F4/ C4/P4), far right (F8/T4/T6)]; topography [frontal (Fz,F3,F4,F7,F8), central (Cz,C3,C4,T3,T4) parietal (Pz,P3,P4,T5,T6)]) on P300 amplitudes were performed. Correlations between morphometric and electrophysiological data were performed by Pearson product moment correlation. Correlations between both the morphometric and the electrophysiological data and psychopathology were examined by Spearman correlation analysis. The subgroup of patients with pronounced negative symptoms was analyzed by median split of the PANSS subscale of negative symptoms.
2.6. Statistical analysis
3. Results
Statistics were performed using the SPSS 11.0 software (statistical package for social sciences, SPSS, Inc., Chicago, 2001). t-Tests were applied to test for differences in sociodemographic variables between healthy controls and patients. Morphometric data (only the segmentation of gray matter tissue was entered into the STG statistics) were analyzed for region and laterality effects by a mixed model analysis of covariance (ANCOVA) with one between-subject factor (diagnosis) and two within-subject factors [laterality, region (anterior vs. posterior STG)]. The covariate intracranial volume was added to the analysis. Group differences
No differences in age (t=0.08, P=0.93), height (t =1.18, P=0.24) or total brain volume (t=1.66, P=0.10) were detected between patients and controls. An overview of the morphometric and electrophysiological data is given in Table 2.
Table 2 Direct comparisons of uncorrected morphometric and electrophysiological data between 50 schizophrenic patients and 50 healthy controls SZ patients
Healthy controls
Total intracranial content (ml) 1347.7 95.6 1383.1 115.9 Left total STG (ml) 9.20 1.30 9.60 1.36 Right total STG (ml) 10.14 1.28 10.47 1.36 Left anterior STG (ml) 2.42 0.61 2.52 0.61 Right anterior STG (ml) 3.16 0.68 3.22 0.59 Left posterior STG (ml) 6.78 1.01 7.25 1.15 Right posterior STG (ml) 6.98 1.07 7.25 1.11 Length, left anterior STG (mm) 9.5 1.6 9.6 1.6 Length, right anterior STG (mm) 11.5 1.8 11.4 1.4 Length, left posterior STG (mm) 22.8 1.9 22.6 2.3 Length, right posterior STG (mm) 22.2 1.6 21.9 2.1 0.099 0.13 0.089 0.12 ACtotalSTG AC posterior STG 0.027 0.15 0.029 0.15 0.25 0.24 0.27 0.23 AC anterior STG P300-amplitude at T3 (m volt) 3.55 1.48 3.75 1.75 P300-amplitude at T4 (m volt) 3.48 1.57 3.13 1.39
3.1. I 3.1.1. STG measurements In the ANCOVA no significant main effect for group with respect to morphometric STG measurements (F=0.40; df=1/97; P=0.53) was detected. There was no significant two-way interaction of diagnosis and laterality (F=0.15; df=1/97; P=0.70) or diagnosis and region (F=0.06; df=1/97; P=0.82), and no significant three-way interaction of diagnosis, laterality, and region (F=0.004, df=1/97, P=0.95). Neither STG length (F=1.5; df=97; P=0.23). nor AC (total STG: t=0.42, P=0.67, anterior STG: t=0.38, P=0.70, posterior STG: t=0.08, P=0.93) differed between patients and healthy controls. Results did not change when ANOVAs were calculated without the covariate total brain volume. 3.1.2. Electrophysiological data of P300 amplitudes The ANOVA on P300 amplitudes did not reveal significant main effects on diagnosis [F (1/98)=0.21, P=0.65] (Fig. 2). The parietal distribution of P300 was significant (anterior–posterior topography [F (1.25/ 445.5)=43.5, P < 0.001] as was the laterality effect [F (1.76/445.5)=207.4, P< 0.001], reflecting larger P300 closer to the midline). The interactions of diagnosis with topography [F (1.25/445.5)=0.75, P=0.42] and laterality
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(F=0.009; df=1/75; P=0.92) was detected. There was no significant two-way interaction of diagnosis and laterality (F=0.19; df=1/75; P=0.65) or diagnosis and region (F=0.008; df=1/75; P=0.93), and no significant three-way interaction of diagnosis, laterality and region (F=0.01, df=1/75, P=0.92). AC did not differ between patients and healthy controls (total STG: t=0.17, P=0.86, anterior STG: t=0.10, P=0.91, posterior STG: t=0.37, P=0.71). No group differences regarding STG length for left anterior (t=0.09, P=0.92) left posterior (t=0.38, P=0.70), right anterior (t=0.32, P=0.74) and right posterior (t=0.38, P=0.70) STG were detected. Results did not change when ANOVAs were calculated without the covariate total brain volume. Fig. 2. Grand average curves of the scalp data measurements are depicted for the electrodes T3 and T4 with reference to linked mastoids for 50 schizophrenic patients and 50 healthy control subjects.
[F (1.76/445.5)=1.2, P=0.29] were not significant. Reaction time (t=0.1.2, P=0.22) and the task performance (t=0.7, P=0.48) did not differ between patients and controls. 3.1.3. Correlations between ERP and the gray matter of the left posterior STG The correlation between the P300 amplitude at T3 and gray matter of the left posterior STG revealed no association in patients (r=0.15; P=0.30) or in healthy controls (r=0.16; P=0.27). 3.2. II 3.2.1. Correlations of thought disorder, ERP (T3) and left posterior STG P300 amplitude at the T3 electrode site was significantly negatively correlated with the formal thought disorder subscore (r=0.47, P=0.001) of the BPRS whereas the left posterior STG (r=0.07, P=0.65) did not correlate. 3.3. III 3.3.1. Subgroup of patients with pronounced negative symptoms This subgroup of patients (N=28 of 50) had higher scores than the mean value of 25.5 on the PANSS subscore for negative symptoms. No differences in age (t=0.498, P=0.62), height (t=0.807, P=0.42) or total brain volume (t=1.73, P=0.08) between this subgroup and the healthy control group were detected. 3.3.2. STG measurements In the ANCOVA no significant main effect for group with respect to morphometric STG measurements
3.3.3. Electrophysiological data of P300 amplitudes The ANOVA on P300 amplitudes did not reveal significant main effects on diagnosis [F (1/76)=0.003, P=0.96]. The parietal distribution of P300 was significant (anterior–posterior topography [F (1.24/ 89.0)=27.1, P < 0.001] as was the laterality effect [F (1.95/140.5)=153.9, P < 0.001], reflecting larger P300 closer to the midline. The interactions of diagnosis with topography [F (1.24/89.0)=0.49, P=0.53] and laterality [F (1.95/140.5)=1.3, P=0.28] were not significant. Reaction time (t=1.3, P=0.21) and task performance time (t=0.75, P=0.45) did not differ between patients and controls. 3.3.4. Correlations between ERP (T3) and the gray matter of the left posterior STG The correlation between the P300 amplitude at T3 and gray matter of the left posterior STG revealed no association in patients (r=0.03; P=0.87) or in healthy controls (r=0.16; P=0.27). 3.3.5. Correlations of thought disorder, ERP (T3) and left posterior STG Again, P300 amplitude at the T3 electrode site was significantly negatively correlated with the formal thought disorder subscore (r=0.52, P=0.004) of the BPRS. Finally, the left posterior STG did not correlate with the formal thought disorder score (r=0.16, P=0.38) of the BPRS scale.
4. Discussion This study aimed to investigate the hypothesis that schizophrenic patients show temporal P300 topographic asymmetries and amplitude reductions as well as volume reductions of the left posterior STG. As our schizophrenic patients did not show either altered P300 amplitudes or asymmetries for electrode sites T3/T4 compared to healthy control subjects, the
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failure to replicate the reduced P300 amplitude component of the event-related potential and altered asymmetry deserves discussion. In the research on the neurobiology of schizophrenia, decrement of the auditory P300 is a robust finding and seems most pronounced in the left temporal region (Ford, 1999). However, some studies failed to demonstrate decreased auditory P300 amplitudes in comparison to controls (Umbricht et al., 1998; Fukuda et al., 1997; Shelley et al., 1996; Strik et al., 1993; Duncan-Johnson et al., 1982; Roth et al., 1981, 1979; Shagass et al., 1978). It must be taken into account that partial remediation of P300 amplitude reduction in schizophrenia was demonstrated with improvement of psychotic symptoms by antipsychotic medication in some studies (Matsubayashi, 1984; Duncan, 1988; Mintz et al., 1995; Gallinat et al., 2001) and by nonpharmacological interventions such as feedback training in others (Fukuda et al., 1989, 1997). Pallanti et al. (1999) found that after a 6-month period of treatment with clozapine, the P300 differences between 22 schizophrenic patients and healthy controls were no longer statistically significant. Furthermore, other studies reported a normalization of previously reduced P300 amplitudes after psychopharmacological treatment (Schall et al., 1998, Umbricht et al., 1998, Coburn et al., 1998). This is in line with our results since the patients participating in our study were medicated and stabilized and had fewer positive symptoms. Their stabilized state might explain why they showed normal P300. In contrast, the patients in McCarley et al.’s studies had been suffering from chronic schizophrenia with continuing productive symptomatology for years (McCarley et al., 1993) or were first episode patients (McCarley et al., 2002), although the patients in the latter study showed slightly less psychopathology on the BPRS scores than our patients. However, our subgroup of patients with pronounced negative symptomatology also failed to show significant reductions of either ERP or STG measurements. It still remains a matter of debate whether P300 amplitude reductions represent state or trait markers in the pathophysiology of the disease. Some data support the trait aspect of P300 deficits because P300 reductions are stable over time despite significant changes in symptomatology (Turetsky et al., 1998; Mathalon et al., 2000) Finally, as our data were not obtained in the study with a longitudinal design, they may not qualify to contribute to the trait/state problem of ERPs in schizophrenia. The STG volume and length measurements did not reveal a difference between schizophrenic patients and healthy control subjects. These were unexpected results in view of the large effect sizes reported by Shenton et al. (1992) when they compared the superior temporal gyrus gray matter volumes of schizophrenic patients with those of healthy controls. Shenton et al. subdivided according to defined anatomical guidelines STG
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measurements into an anterior and posterior portion, guided by the same subcortical landmarks (Shenton et al., 1992) that we applied, in order to replicate the prior findings. However, the use of subcortical landmarks represents a source of potential measurement errors and is a significant source of variability, which might explain in part our negative findings. Nevertheless, our lack of findings cannot not be explained by a general absence of morphometric abnormalities in this group of subjects because patients had significantly larger third ventricles (Meisenzahl et al., 2002b), and bilaterally reduced hippocampal volumes and a reduced anterior cingulate (Meisenzahl et al., submitted for publication). In order to further explore the possibility of reduced superior temporal gyrus laterality, the asymmetry coefficients of the groups were also compared. Although no group differences in AC coefficents were detected, the findings did reveal in all 100 subjects a significant rightward laterality for the anterior part of the gray matter STG, and a symmetric laterality for the posterior part. In line with our findings, Shenton and collegues also failed to detect a leftward asymmetry for the superior temporal gryus in healthy control subjects (Shenton et al., 1992). However, both results are somewhat surprising in view of the literature, which has reported a leftward lateralisation of the posterior superior temporal gyrus for macroscopic parameters of brain anatomy and, more specifically, language function. In this regard, it is of interest that recent investigations of our group on in vivo analysis of the planum temporale in healthy controls (Zetzsche et al., 2001) and schizophrenic patients (Meisenzahl et al., 2002a) by use of three different definitions of PT borders detected that results and the degree of asymmetry between left and right regions of interest were strongly dependent on the definition used for the ROI borders. Our observations leaded us to the conclusion that the influence of the definitions on the investigated ROIs may explain some of the discrepancies between studies. Therefore, the fact that morphometric evaluations of the superior temporal gyrus in patients with schizophrenia are inconsistent may therefore not be that astonishing after all. In the past, several studies have reported unilateral or bilateral left-sided volume deficits in the anterior, posterior or total STG in schizophrenic patients compared to healthy control subjects (Barta et al., 1990; Shenton et al., 1992; Marsh et al., 1997; Hirayasu et al., 1998; Levitan et al., 1999; Rajarethinam et al., 2000). However, a number of studies failed to replicate these findings (DeLisi et al., 1994; Kulynych et al., 1996; Woodruff et al., 1997). In contrast, investigations of patients with chronic, early-onset schizophrenia reported a lower bilateral volume of the STG in patients (Marsh et al., 1997), and a superior temporal gyrus enlargement in adolescents with childhood-onset schizo-
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phrenia (Jacobsen et al., 1996). In another study, adolescents with early-onset schizophrenia showed lower right superior temporal gyrus volumes compared to controls (Matsumoto et al., 2001). One of the two post-mortem studys on STG (Highley et al., 1999; Vogeley et al., 1998) reported an interesting methodological issue: Vogeley and colleagues demonstrated a bilateral volume and length decrease of the left STG in a sample of female schizophrenic patients. The authors pointed out that the detected volume decrease of the left STG in the schizophrenic group was caused by the significantly reduced length of the STG regions (Vogeley et al., 1998). In fact, we agree that additional measurements of the length of the STG compartment seem an often neglected aspect in volumetric studies of the STG. Volumetric reductions of the STG compartment may be caused simply by a reduction of the length of the STG part measured so that study results which do not consider this detail may give a distorted picture of regional brain changes of the STG region. However, in our sample no length differences in the STG compartments, which could have lead to false negative results, emerged. In the group of patients no reductions emerged for either electrophysiological or structural data. Therefore, it can be speculated if the failure to replicate significant associations between P300 amplitude at T3 and the gray matter of the left posterior STG might be explained by the normal amount of gray matter volume in schizophrenic patients. After all, our finding of no association between left temporal ERP amplitude and left gray matter volume of the STG in 50 healthy subjects is in line with recent studies (McCarley et al., 1993, 2002; Ford et al., 1994a) and supports the idea that the P300 in the CNS of healthy controls may not depend on the cortex directly underlying the electrode site (Ford et al. 1994a). Therefore, physiological structure–function relationships seems still difficult to establish, given the dynamic nature of P300 in comparison to the more static nature of brain structure (for review see Ford et al., 1994b; Ford, 1999). Finally, within the groups of patients there was a significant correlation between the psychopathological symptom of thought disorder and the electrode site T3. The hypothesis that a small T3 amplitude is related to a higher amount of thought disorders was confirmed in our sample of schizophrenic patients (Frodl et al., 2002; Hegerl et al., 1995). However, the volume of the left posterior superior STG was not related to a greater number of thought disorders. This is in contrast to prior findings which have indicated that thought disorder is explicitly linked to brain abnormalities in the STG as this area represents one key region of language functioning (Shenton et al., 1992). Therefore, the lack of an relationship between gray matter volume of the left posterior STG and the psychopathological item of
thought disorders may not support the idea of a primary pathology in the STG with regard to this key symptom. Our negative study results necessitate some comments about the patient group. As our study examined a large population of schizophrenic patients, we do not assume that our findings occurred by chance. Our patients comprised stabilized male schizophrenic inpatients who, although severely ill at the time of admission, were mostly showing a good remission of productive psychotic symptoms at the time of the study. Therefore, it cannot be excluded that differences in the clinical course of the disease may at least in part explain our negative findings compared to the two studies of McCarley’s group. This may be further supported by the finding that the the results of analysis of the subgroup of patients with pronounced negative symptoms were not different with respect to the hypotheses investigated in the presented paper. However, the present study suffers from the limitation that only male subjects were investigated and therefore our data cannot give contribute to the question of possible gender effects. In conclusion, our data revealed no evidence for left P300 amplitude and left gray matter volume reductions of the STG, in either male schizophrenic patients or male healthy controls. Our study results may point to the possibility that differences in the clinical course of the disease may at least in part explain the negative findings compared to the ealier two studies of McCarley’s group. Nevertheless, and given the fact that our here presented data support the hypothesis that a higher number of thought disorders is related to a small T3 amplitude but not to a reduced volume of the left posterior superior STG, these findings may demonstrate that the direct spatial relationship between functional and structural data is still a matter of debate and difficult to establish.
Acknowledgements This work was supported by the Deutsche Forschungsgemeinschaft No. 231/96. We would like to thank Prof. Nancy Andreasen and her staff, who provided generous support with the segmentation program BRAINS, and Dr. Strauß, Bernhard Burgermeister and Jacqueline Klesing for technical support.
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