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Corpus callosum size and inter-hemispheric function in schizophrenia
SCHIZOPHRENIA RESEARCH ELSEVIER
Schizophrenia Research 23 (1997) 189-196
Corpus callosum size and inter-hemispheric function in schizophrenia P.W.R. Woodruff *, M.L. Phillips, T. Rushe, I.C. Wright, R.M. Murray, A.S. David Department of Psychological Medicine, Institute of Psychiatry & King's College School of Medicine, London, UK Received 17 June 1996; accepted 29 October 1996
Abstract
We studied the relationship between corpus callosum area and both inter-hemispheric facilitation and interference in schizophrenics and controls. Mid-sagittal sections through the corpus callosum were measured using structural magnetic resonance imaging on 42 patients and 43 normal controls, along with symptom profiles. In a sub-sample, a modified version of the Stroop Test was also performed (27 patients and 29 controls) to assess inter-hemispheric facilitation and interference of colour naming. In the larger sample (total subjects, n = 85), there were no significant differences between patients and controls in CC area but a trend towards smaller values in patients in all but the posterior segment. In the sub-sample, bilateral facilitation was greater, and interference, less in schizophrenics compared with controls. There was a positive correlation between facilitation and posterior CC area, parallelled by a negative correlation between interference and posterior CC area, in both patients and controls, which only reached statistical significance when both groups were combined. These findings suggest that the link, between CC size and neuropsychological processes involving inter-hemispheric transfer of information, is common to both schizophrenics and normal controls. There were significant negative correlations between anterior CC area and psychomotor poverty (avolition, anhedonia and affective flattening), and a suggestion that the negative correlation between age and CC size in controls was not present in patients.
Keywords: Corpus callosum; Magnetic resonance imaging; Stroop; Schizophrenia
1. Introduction
1.1. Corpus callosum structure in schizophrenia The corpus callosum (CC) and its role in mediating inter-hemispheric transfer has been the focus of attention in studies of schizophrenia since the early claim that the CC was larger in post-mortem brains of schizophrenics (Rosenthal and Bigelow, 1972). Initial replication of this finding using in * Corresponding author.
vivo magnetic resonance imaging ( M R I ) of the brain (Nasrallah et al., 1986) was not confirmed in subsequent studies (Kelso et al., 1988; Rossi et al., 1989; Stratta et al., 1989; Gtinther et al., 1991; Woodruff et al., 1993). A recent metaanalysis of published M R I studies on the corpus callosum in schizophrenia (Woodruff et al., 1995) showed that, overall, there was a statistically significant reduction of CC area in schizophrenia compared with normal controls; however, considerable variability existed in the magnitude and direction of CC size differences between schizo-
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phrenics and controls. Such discrepancies may partly be a reflection of factors such as gender and handedness, which appear to separately influence CC size and shape in healthy individuals (De Lacoste-Utamsing and Holloway, 1982; Witelson, 1989; Denenberg et al., 1991), as well as in schizophrenics (Nasrallah et al., 1986; Raine et al., 1990; Hoff et al., 1994). It has been proposed that variability of CC size in schizophrenia may reflect heterogeneity of this condition. For instance, GOnther et al. (1991) found CC size relatively greater in type I, and smaller in type II, schizophrenia. What is the functional significance of alterations of CC size in schizophrenia?
1.2. Structure and function of the corpus eallosum in schizophrenia The corpus callosum permits the integration of cerebral hemispheric activity for higher level attentional and cognitive functions (Hoptman and Davidson, 1994). Functional abnormalities of the CC in schizophrenia can be detected by measuring inter-hemispheric transfer of information, e.g., visual information transfer (Beaumont and Dimond, 1973; Eaton et al., 1979; David, 1987), tactile information transfer (Green, 1978; Dimond et al., 1979; Carr, 1980), and dichotic listening (Green and Koteno, 1980; Hallet and Green, 1983). We wished to use the Stroop Test as a functional measure of inter-hemispheric integration in schizophrenia. The Stroop Test is a test of selective attention (McCleod, 1991). The subject can be presented with a colour-word written in either the same colour ink as the colour-word (congruent condition), or in a different colour (incongruent condition). The subject is asked to name either the colour ink in which the word is written or the colour word itself. The response to the incongruent condition is slower or more error-prone than that to the congruent condition. A modified version of the Stroop test has been devised in order to study components of the task that depend on inter-hemispheric communication (David, 1992, 1993). The modified version uses a colour strip paired with either an incongruent or congruent colour-word which are presented tachistoscopi-
cally with the two components either separated across the midline (bilateral presentation) or presented to a single visual half-field (unilateral presentation). The difference in reaction time to an incongruent compared with a congruent colourword pairing is referred to as the Combined Stroop Effect, and has been found to be larger in the bilateral presentation for schizophrenics compared with that for normal controls or subjects with affective disorder (David, 1993). This was interpreted as evidence for increased inter-hemispheric transfer in schizophrenics compared with control subjects. The extent to which abnormal inter-hemispheric function in schizophrenic subjects was the result of either increased interference for incongruent stimuli or increased facilitation for congruent stimuli remained unresolved. Lindsay and Jacoby (1994) demonstrated that interference and facilitation were independent processes. By incorporating a neutral condition in addition to the interfering (incongruent) and facilitating (congruent) conditions, Phillips et al. (1996) have been able to demonstrate the presence of relatively reduced inter-hemispheric interference and increased inter-hemispheric facilitation in schizophrenic subjects. We aimed in this study to investigate the relationship between corpus callosal area and interhemispheric function in schizophrenic subjects using MRI structural imaging and the version of the Stroop test of Phillips et al. (1996) described above. The corpus callosum shape and size differs between males and females in both healthy controls (Burke and Yeo, 1994) and schizophrenics (Raine et al., 1990). Because of this and our wish to limit the number of comparisons we chose only righthanded males. We predicted that: (1) CC size would be reduced in schizophrenic patients, (2) posterior CC area (thought to be preferentially involved in the visual Stroop task) would be positively associated with inter-hemispheric facilitation and negatively associated with inter-hemispheric interference in both patient and control groups. In addition, we explored the relationship between CC size and the symptoms of schizophrenia.
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2. Method
2.1. Subjects and assessment Patients were recruited from the Camberwell Psychosis Follow-up Study (van Os et al., 1994). Forty-two right-handed males with < 1 left-handed item on the Annett scale and who fulfilled DSMIII-R (American Psychiatric Association, 1987) criteria for schizophrenia consented to undergo MRI scanning and interview. Exclusion criteria (in addition to those in general for having MRI scans) included: age >55 years, alcohol intake > 50 units/week in the past year, a history of illicit injectable drugs or steroids in the past year, and documented unconsciousness or neurosurgery. Duration of illness was taken from the time in months from the date of first inpatient admission to date of scanning. The National Adult Reading Test (NART) (Nelson, 1982) was used as an estimate of premorbid IQ. Controls, recruited from a local unemployment agency and local staff, were similarly screened and assessed. Clinical measures included the Scales for Assessment of Positive Symptoms (SAPS) and Scales for Assessment of Negative Symptoms (SANS) (Andreasen, 1982). A past history of symptoms and their severity was assessed from interview and note review using the SAPS scale. In order to examine whether subsyndromes of schizophrenia had separate associations with CC measures, patients were scored on psychomotor poverty, disorganisation and reality distortion (Liddle, 1987).
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for total CC area measures for 10 subjects were >0.97. Intra-rater reliabilities determined on all sub-regions of the CC for 10 subjects were > 0.84, except for the mid-anterior section (0.71). CC measures were correlated with ventricular volumes, measured on the same subjects and reported separately in a larger MRI study (Woodruff et al., submitted). Measures of bilateral facilitation and interference were determined from Stroop measures previously described by Phillips et al. (1996) using a divided visual field tachistoscopic technique. We used a sub-group of subjects from this study on whom MRI scans had been obtained. Within group measures of association were performed using Pearson correlation coefficients and between group comparisons were made using Student ttests. The facilitation measure was the reaction time (RT) saving calculated by subtracting colour naming of a neutral word from colour naming of a colour-word, congruent with the colour patch. The interference measure was the RT lost calculated by subtracting the neutral condition from colour naming of a colour word incongruent with the colour patch.
3. Results
Mean age of patients was 32.4_7.2years (25-53) and of controls, 30.2 + 7.4 (18-52). Mean duration of illness in patients was 11.10_ 7.54 years (2-36) and mean number of hospital admissions was 5.8 _ 5.5 (1-25).
2.2. Scanning and corpus callosum measurement 3.1. Corpus callosumstructure A 1.5 Tesla Philips Gyroscan scanner was used to obtain a T-1 weighted spin-echo sagittal sequence of 5-mm thick slices orientated in the midline (TR = 235 ms, TE = 20 ms, FOV = 240 mm, four signal averages). With the aid of 'Analyze' software (Robb, 1990), the CC was measured on the mid-sagittal slice. The CC was also divided into four sections by lines drawn perpendicular to its antero-posterior length as previously described (Woodruff et al., 1993). Reliability was assessed using intra-class correlation coefficients. Intra- and inter-rater reliabilities
Corpus callosum areas in schizophrenics (n= 43) versus controls (n=42) were not statistically significant (CCTOT, 577.6 (108.8) versus 585.2 (96.5)mm2; CCA, 189.7 (40.8) versus 194.9 (39.0)mm2; CCAM, 101.6 (20.5) versus 102.5 (21.1)mm2; CCAP, 91.7 (22.2) versus 92.3 (18.7)mm2; CCP, 196.5 (40.6) versus 195.9 (29.5) mm2). There was a trend for negative correlations between age and CC areas in controls, but not in patients (Table 1). There was a negative correla-
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Table 1 Correlations between corpus callosum area measurements and age in patients and controls CCA
CCAM CCAP
CCP
CCTOT
Controls -0.25 -0.28 -0,04 0.03 -0.17 (0.10) (0.06) ( 0 , 8 0 ) ( 0 . 9 4 ) (0.27) Patients 0.12 0.09 0,004 -0.01 0.06 (0.44) (0.56) ( 0 . 9 8 ) ( 0 . 9 3 ) (0.72) Correlation coefficientswith p values in brackets. tion between length of illness and posterior CC area ( r = - 0 . 2 8 , p =0.07). 3.2. Corpus callosum structure and interhemispheric function
MRI scans of the corpus callosum and performance on the Stroop test were both assessed on 27 patients (mean age 32.9 + 6.6) and 29 controls who agreed to the additional assessment (mean age 31.5_+8.2). In this sub-group, patients had fewer total years of education than controls (12.2_+2.8 versus 14.3_+3.3; p = 0 . 0 1 , t-test). N A R T score was lower in patients than controls (107.2+_10.3 versus 113.8_+8.5). Also, mean weekly alcohol consumption was less in patients than controls (7.7_+ 12.5 versus 9.6_+ 9.3 units). In order to ascertain any bias in sampling we compared characteristics of subjects who had been scanned only and those who had additionally performed the Stroop test. Controls who had both MRI scans and Stroop tests performed ( n = 2 9 ) , compared with those for whom only MRI scans were available (n=14), were slightly older (31.3 + 8.1 versus 27.9 __5.2 years, p = 0.17, t-test). There was no difference in N A R T scores (113.8_+8.5 versus 113.7_+6.9; p = 0 . 9 7 , t-test). A similar comparison for patients revealed no difference in ages (32.4_+6.3 versus 32.3+8.7) but significantly higher N A R T scores in those patients on whom both M R I scans and Stroop tests were performed (107.3-+ 10.1 versus 100.9-+9.3). Bilateral facilitation was marginally greater in the 27 cases than 29 controls (41.7_+18.3 versus 26.6_+ 6.6; p = 0.43, t-test). Bilateral interference was significantly less in cases than controls (40.3 + 14.5 versus 79.5 _+9.9; p = 0.028, t-test). In
patients, there was a positive correlation between delusions and bilateral interference (r=0.53, p = 0.02). The relationship between CC area and performance on the Stroop task is shown in Table 2. There were negative correlations between total CC area and SANS scores for avolition (r = - 0 . 4 6 , p = 0 . 0 0 8 ) , anhedonia ( r = - 0 . 3 7 , p = 0 . 0 4 ) and affective flattening ( r = - 0 . 3 2 , p = 0 . 0 7 ) , that is, the smaller the CC the more these negative symptoms. These correlations were greatest for anterior CC regions (CCA and avolition, r = - 0 . 4 7 , p = 0.007; CCA and anhedonia, r = - 0 . 4 2 , p=0.018; CCA and affective flattening, r = - 0.41, p = 0.02). In a multiple regression model accounting for the effect of whole cerebral volume, the strongest associations were between total CC area and avolition (B = - 0 . 3 4 , p = 0.06), and CCA and avolition (B = - 0.35, p = 0.05 ), neither of which would reach statistical significance if a Bonferroni correction was applied. These respective correlations were not significant for posterior CC areas. There were no significant correlations between SAPS scores and CC areas. The only significant correlation between the three syndrome scores and CC areas was between CCA and psychomotor poverty ( r = -0.39, p=0.01). There were no significant correlations between CC areas and lateral, temporal horn, IIIrd or IVth ventricular volumes in patients. In controls, however, there were significant correlations between IVth ventricular volume and CCA (r=0.39, p = 0.009) and CCAM (r=0.47, p=0.001).
4. Discussion 4.1. Corpus callosum size in schizophrenia
Conclusions are limited to the right-handed male groups studied. Our first hypothesis that CC area would be significantly reduced in male schizophrenics was not confirmed in contrast to a previous study in a separate group of male and female patients with prominent positive symptoms (Woodruff et al., 1993). The mean reduction of 7 . 6 m m 2 is, however, within the 95% confidence intervals of 3.45-53.4 mm 2 calculated from the
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Table 2 Correlation coefficients(p values) between bilateral interference(bilatint) and bilateral facilitation (bilatfac) and corpus callosum measurements for patients and controls (n = 56)
Bilatint
Controls Patients Both
Bilatfac
Controls Patients Both
CCTOT
CCA
CCAM
CCAP
CCP
- 0.03 (0.89) -0.21 (0.28) -0.16 (0.24) 0.06 (0.76) 0.23 (0.24) 0.18 (0.19)
- 0.04 (0.82) -0.16 (0.43) -0.12 (0.37) - 0.03 (0.89) 0.12 (0.54) 0.08 (0.58)
0.07 (0.72) -0.13 (0.53) -0.05 (0.72) - 0.12 (0.54) 0.17 (0.39) 0.07 (0.58)
- 0.05 (0.78) -0.13 (0.52) -0.12 (0.364) 0.17 (0.37) 0.21 (0.29) 0.19 (0.15)
- 0.09 (0.61) -0.32 (0.10) -0.27 (0.047)* 0.19 (0.31) 0.33 (0.09) 0.29 (0.03)*
*p= <0.05. meta-analysis of previous studies (Woodruff et al., 1995). Since that meta-analysis, there have been several further reports. Hoff et al. (1994), in a relatively young first-onset sample found that females rather than males may have smaller corpora callosa than sex-matched controls. Although statistically non-significant, male schizophrenics had larger CC areas than male controls. Similarly, in a more heterogeneous sample but of relatively short duration of illness, only anterior CC areas were larger in male schizophrenics than controls (Colombo et al., 1994). The present study (like most included in the meta-analysis) included a relatively heterogeneous sample including those with chronic illness, so if CC size varies according to clinical sub-types (see later), this may have reduced our chance to detect significant differences. However, the main strength of this study was the comparison of structure, symptoms and function within subjects. 4.2. Age and corpus callosum size
The association between age and smaller anterior CC area in controls was less in patients. It may be that the age-related changes in CC size in schizophrenics in our study are too subtle to reach statistical significance, or that it represents a divergence in ageing effects on the CC between this group of schizophrenics and controls. Such a diver-
gence would be consistent with the findings of Bagwell et al. (1995) who reported that age was highly correlated with CC size in 18 controls ( r = 0.74, p = 0 . 0 0 0 1 ) but not in 22 schizophrenics (r=0.21, p = 0 . 3 3 ) . One possible explanation includes defective axonal elimination during early childhood development (Clarke et al., 1989) which would result in a larger CC before ageing effects took hold. If so, CC size should be greater in schizophrenics, which was not the case in our study, although this has been reported in others (Nasrallah, 1985). Alternatively axonal myelination of the CC (which increases throughout normal adulthood (Giedd et al., 1996) in schizophrenia might continue un-abated at a time when axonal loss due to ageing usually predominates. In a healthy age group over 60, Burke and Yeo (1994) found negative correlations between age and CC area particularly striking in males rather than females, and the anterior region was most susceptible to these age-related changes. In addition maturational increases are less marked in the anterior versus posterior CC (Giedd et al., 1996), which might result in its greater sensitivity to degenerative effects of age. 4.3. Corpus callosum size and schizophrenic symptoms
Nasrallah (1985) argued that Schneiderian first-rank symptoms, such as delusions, may result
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from abnormal integration of inter-hemispherically transmitted information such that the left hemisphere became 'conscious' of processes normally confined to the right. The correlation between bilateral interference and delusions is consistent with this and suggests that excessive transfer of incongruent information contributes towards this erroneous integration of inter-hemispheric information. It has been suggested that schizophrenics with early onset of illness and negative symptomatology may have excessive inter-hemispheric transfer, whilst those with later onset and positive symptomatology have reduced inter-hemispheric transfer (Coger and Serafetinides, 1990). In this study of patients with predominantly chronic illness, we found an association of negative symptoms with smaller CC area, particularly of the anterior segments, consistent with Giinther et al. (1991) who demonstrated that schizophrenics with smaller CC area had predominantly type II schizophrenia. Although, unlike Glinther et al. (1991) we did not select patients specifically on the basis of symptoms, of the three sub-syndrome scores of Liddle (1987), only psychomotor poverty correlated inversely with anterior CC area. Negative symptoms of schizophrenia are thought to originate from poorly functioning frontal lobe regions (Andreasen et al., 1990), and reduced volumes of these regions have been demonstrated in structural MRI studies (Woodruff and Murray, 1994). It is possible that these frontal lobe abnormalities are additionally associated with dysfunctional communication between the hemispheres. In support of this is the demonstration of GOnther et al. (1991) of an association between reduced cerebral blood flow and reduced CC area in schizophrenics with negative symptoms. A!though we did not find an association between positive symptoms and CC area in this schizophrenic group, it is possible that a more homogeneous group of patients with acute onset may have shown this association, such as that described by David et al. (1995) of an association between anterior CC area and auditory hallucinations. Larger studies (or the combination of several smaller ones) are required to accurately determine these apparently subtle effects of CC size on symptoms.
4.4. Corpus callosum size and inter-hemispheric function Results from Table 2 show that there was a positive association between corpus callosum area and bilateral facilitation for all regions (especially the posterior section) of the corpus callosum in patients and controls. This positive association between posterior CC area and bilateral facilitation became statistically significant when results from both groups were combined. There was likewise a negative association found between posterior corpus callosum area and bilateral interference. We have demonstrated that CC size in both schizophrenics and controls is directly related to inter-hemispheric facilitation and that there is a reciprocal relationship between CC size and inter-hemispheric interference as we predicted. Facilitation allows transfer of congruent information across the CC. Interference on the other hand allows transfer of incongruent information. We have confirmed the existence of a reciprocal relationship between facilitation and interference. As we predicted (hypothesis 2), the relationship between size and facilitation and the reverse association with interference applied only to the posterior CC, the area most likely to be involved in transfer of visual information used in the Stroop test. The implication is that facilitation and lack of interference is associated either with greater numbers or more myelination of small diameter inter-hemispheric fibres. It supports the hypothesis that CC size reflects greater flow of congruent, at the expense of incongruent, information. The findings also support the role of the CC in facilitating cognitive functioning (Hoff et al., 1994; Sauerwein and Lassonde, 1994). There have been relatively few studies investigating structure and function of the corpus callosum jointly in the same subjects, and none to our knowledge that have related CC size with interhemisheric facilitation and interference. Raine et al. (1990) used a variety of auditory and somatosensory inter-hemispheric tasks and found performance on these did not parallel CC abnormalities, although they did not directly correlate structural and functional measures. Similar but not directly comparable with our study is that of Hoff et al.
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(1994), w h o f o u n d a relationship between larger C C size and better performance on a range o f neuropsychological tasks in healthy controls a n d a tendency for this association to be reversed in schizophrenics. In schizophrenics C C size had a reduced effect on cognition because, they argued, the fibres are dysfunctional. O u r data does not support this conclusion, at least in a g r o u p o f m o r e chronic patients. The fact that the Stroop test we employed relies on posterior C C visual fibres where the structurefunction associations were strongest adds neuroanatomical validity to our findings. They are consistent with the findings in n o r m a l controls that interference (as determined from performance on a right hemispheric m o t o r task during left hemispheric verbal activity) was inversely correlated with corpus callosal size (Yazgan et al., 1995), and in schizophrenics o f an association between interhemispheric transfer and anterior callosal size ( D a v i d et al., 1995).
5. Conclusions There appears to be a link between corpus callosum size and neuropsychological processes involving inter-hemispheric transfer that is comm o n to b o t h schizophrenics and healthy controls. Age-related changes o f the corpus callosum m a y differ between schizophrenics and controls. Studies need to assess specific structure/function relationships in patient and control groups separately over time. The data support the existence o f an inverse relationship between anterior corpus callosum area and negative s y m p t o m s in schizophrenia. Future studies might usefully explore the functional correlations o f activity in brain regions connected via the corpus callosum to m o r e fully understand the role o f the corpus callosum in mechanisms underlying schizophrenic symptoms.
Acknowledgment We wish to thank Mrs. P. Graves and the R a d i o g r a p h i c Staff at G u y ' s Hospital for technical help with scanning, and Dr. Paul Summers, G u y ' s
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Hospital for technical help. M.L.P. was supported by the M R C ( U K ) . This study was supported in part by the Psychiatry Research Trust and the Stanley Foundation.
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Nelson, H.E. (1982) The National Adult Reading Test. Windsor: NFER-Nelson. Phillips, M.L., Woodruff, P.W.R and David, A.S. (1996) Stroop interference and facilitation in the cerebral hemispheres in schiozophrenia. Schizophr. Res. 20, 57-68. Raine, A., Harrison, G.N., Reynolds, G.P., Sheard, C., Cooper, J.E. and Medley, I. (1990) Structural and functional characteristics of the corpus callosum in schizophrenics, psychiatric controls, and normal controls. Arch. Gen. Psychiatry 47, 1060-1063. Robb, R.A. (1990) A software system for interactive and quantitative analysis of biomedical images. In: Hohne, K.H., Fuchs, H. and Pizer, S.M. (Eds.), 3D Imaging in Medicine. NATA ASI Series, Vol. F 60. Rosenthal, R. and Bigelow, L.B. (1972) Quantitative brain measurements in chronic schizophrenia. Br. J. Psychiatry 121,259-264. Rossi, A., Stratta, P., Gallucci, M., Passariello, R. and Casacchia, M. (1989) Quantification of corpus callosum and ventricles in schizophrenia with nuclear magnetic resonance imaging: a pilot study. Am. J. Psychiatry 146(1), 99-101 Sauerwein, H.C. and Lassonde, M. (1994) Cognitive and sensoft-motor functioning in the absence of the corpus callosum: neuropsychological studies in callosal agenesis and callosotomized patients. Behav. Brain Res. 64, 229-240. Stratta, P., Rossi, A., Gallucci, M., Amicarelli, I., Passariello, R. and Casacekia, M. (1989) Hemispheric asymmetries and schizophrenia: a preliminary magnetic resonance imaging study. Biol Psychiatry 25, 275-284. van Os, J., Fahy, T.A., Bebbibgton, P. et al. (1994) The influence of life-events on the subsequent course of psychotic illness: a prospective follow-up of the Camberwell Collaborative Psychosis Study. Psychol. Med. 24, 503-513. Witelson, S.F. (1989) Hand and sex differences in the isthmus and genu of the human corpus callosum. A postmortem morphological study. Brain 112, 799-835. Woodruff, P.W.R. and Murray, R.M. (1994) The aetiology of brain abnormalities in schizophrenia. In: Ancill, R., Higenbottam, J. and Holliday, S. (Eds.), Schizophrenia 1994: A State of the Art. John Wiley & Sons, Chichester. Woodruff, P.W.R., Pearlson, G.D., Geer, M.J. and Chilcoat, H.D. (1993) A computerized magnetic resonance imaging of corpus callosum morphology in schizophrenia. Psychol. Med. 23, 45-56. Woodruff, P.W.R., McMannus, I.C. and David, A.S. (1995) A meta-anaiysis of corpus callosum size in schizophrenia. J. Neurol. Neurosurg. Psychiatry 58, 457-461. Woodruff, P.W.R., Wright, I.C., Shuriquie, N., Russouw, H., Howard, R.J., Graves, M., Bullmore, E.T. and Murray, R.M. Structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation. Psychol Med (submitted). Yazgan, M.Y., Wexler, B.E., Kinsbourne, M., Peterson, B. and Leckman, J.F. (1995) Functional significance of individual variations in callosal area. Neuropsychologia 33(6), 769-779.
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Corpus callosum size and inter-hemispheric function in schizophrenia P.W.R. Woodruff *, M.L. Phillips, T. Rushe, I.C. Wright, R.M. Murray, A.S. David Department of Psychological Medicine, Institute of Psychiatry & King's College School of Medicine, London, UK Received 17 June 1996; accepted 29 October 1996
Abstract
We studied the relationship between corpus callosum area and both inter-hemispheric facilitation and interference in schizophrenics and controls. Mid-sagittal sections through the corpus callosum were measured using structural magnetic resonance imaging on 42 patients and 43 normal controls, along with symptom profiles. In a sub-sample, a modified version of the Stroop Test was also performed (27 patients and 29 controls) to assess inter-hemispheric facilitation and interference of colour naming. In the larger sample (total subjects, n = 85), there were no significant differences between patients and controls in CC area but a trend towards smaller values in patients in all but the posterior segment. In the sub-sample, bilateral facilitation was greater, and interference, less in schizophrenics compared with controls. There was a positive correlation between facilitation and posterior CC area, parallelled by a negative correlation between interference and posterior CC area, in both patients and controls, which only reached statistical significance when both groups were combined. These findings suggest that the link, between CC size and neuropsychological processes involving inter-hemispheric transfer of information, is common to both schizophrenics and normal controls. There were significant negative correlations between anterior CC area and psychomotor poverty (avolition, anhedonia and affective flattening), and a suggestion that the negative correlation between age and CC size in controls was not present in patients.
Keywords: Corpus callosum; Magnetic resonance imaging; Stroop; Schizophrenia
1. Introduction
1.1. Corpus callosum structure in schizophrenia The corpus callosum (CC) and its role in mediating inter-hemispheric transfer has been the focus of attention in studies of schizophrenia since the early claim that the CC was larger in post-mortem brains of schizophrenics (Rosenthal and Bigelow, 1972). Initial replication of this finding using in * Corresponding author.
vivo magnetic resonance imaging ( M R I ) of the brain (Nasrallah et al., 1986) was not confirmed in subsequent studies (Kelso et al., 1988; Rossi et al., 1989; Stratta et al., 1989; Gtinther et al., 1991; Woodruff et al., 1993). A recent metaanalysis of published M R I studies on the corpus callosum in schizophrenia (Woodruff et al., 1995) showed that, overall, there was a statistically significant reduction of CC area in schizophrenia compared with normal controls; however, considerable variability existed in the magnitude and direction of CC size differences between schizo-
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phrenics and controls. Such discrepancies may partly be a reflection of factors such as gender and handedness, which appear to separately influence CC size and shape in healthy individuals (De Lacoste-Utamsing and Holloway, 1982; Witelson, 1989; Denenberg et al., 1991), as well as in schizophrenics (Nasrallah et al., 1986; Raine et al., 1990; Hoff et al., 1994). It has been proposed that variability of CC size in schizophrenia may reflect heterogeneity of this condition. For instance, GOnther et al. (1991) found CC size relatively greater in type I, and smaller in type II, schizophrenia. What is the functional significance of alterations of CC size in schizophrenia?
1.2. Structure and function of the corpus eallosum in schizophrenia The corpus callosum permits the integration of cerebral hemispheric activity for higher level attentional and cognitive functions (Hoptman and Davidson, 1994). Functional abnormalities of the CC in schizophrenia can be detected by measuring inter-hemispheric transfer of information, e.g., visual information transfer (Beaumont and Dimond, 1973; Eaton et al., 1979; David, 1987), tactile information transfer (Green, 1978; Dimond et al., 1979; Carr, 1980), and dichotic listening (Green and Koteno, 1980; Hallet and Green, 1983). We wished to use the Stroop Test as a functional measure of inter-hemispheric integration in schizophrenia. The Stroop Test is a test of selective attention (McCleod, 1991). The subject can be presented with a colour-word written in either the same colour ink as the colour-word (congruent condition), or in a different colour (incongruent condition). The subject is asked to name either the colour ink in which the word is written or the colour word itself. The response to the incongruent condition is slower or more error-prone than that to the congruent condition. A modified version of the Stroop test has been devised in order to study components of the task that depend on inter-hemispheric communication (David, 1992, 1993). The modified version uses a colour strip paired with either an incongruent or congruent colour-word which are presented tachistoscopi-
cally with the two components either separated across the midline (bilateral presentation) or presented to a single visual half-field (unilateral presentation). The difference in reaction time to an incongruent compared with a congruent colourword pairing is referred to as the Combined Stroop Effect, and has been found to be larger in the bilateral presentation for schizophrenics compared with that for normal controls or subjects with affective disorder (David, 1993). This was interpreted as evidence for increased inter-hemispheric transfer in schizophrenics compared with control subjects. The extent to which abnormal inter-hemispheric function in schizophrenic subjects was the result of either increased interference for incongruent stimuli or increased facilitation for congruent stimuli remained unresolved. Lindsay and Jacoby (1994) demonstrated that interference and facilitation were independent processes. By incorporating a neutral condition in addition to the interfering (incongruent) and facilitating (congruent) conditions, Phillips et al. (1996) have been able to demonstrate the presence of relatively reduced inter-hemispheric interference and increased inter-hemispheric facilitation in schizophrenic subjects. We aimed in this study to investigate the relationship between corpus callosal area and interhemispheric function in schizophrenic subjects using MRI structural imaging and the version of the Stroop test of Phillips et al. (1996) described above. The corpus callosum shape and size differs between males and females in both healthy controls (Burke and Yeo, 1994) and schizophrenics (Raine et al., 1990). Because of this and our wish to limit the number of comparisons we chose only righthanded males. We predicted that: (1) CC size would be reduced in schizophrenic patients, (2) posterior CC area (thought to be preferentially involved in the visual Stroop task) would be positively associated with inter-hemispheric facilitation and negatively associated with inter-hemispheric interference in both patient and control groups. In addition, we explored the relationship between CC size and the symptoms of schizophrenia.
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2. Method
2.1. Subjects and assessment Patients were recruited from the Camberwell Psychosis Follow-up Study (van Os et al., 1994). Forty-two right-handed males with < 1 left-handed item on the Annett scale and who fulfilled DSMIII-R (American Psychiatric Association, 1987) criteria for schizophrenia consented to undergo MRI scanning and interview. Exclusion criteria (in addition to those in general for having MRI scans) included: age >55 years, alcohol intake > 50 units/week in the past year, a history of illicit injectable drugs or steroids in the past year, and documented unconsciousness or neurosurgery. Duration of illness was taken from the time in months from the date of first inpatient admission to date of scanning. The National Adult Reading Test (NART) (Nelson, 1982) was used as an estimate of premorbid IQ. Controls, recruited from a local unemployment agency and local staff, were similarly screened and assessed. Clinical measures included the Scales for Assessment of Positive Symptoms (SAPS) and Scales for Assessment of Negative Symptoms (SANS) (Andreasen, 1982). A past history of symptoms and their severity was assessed from interview and note review using the SAPS scale. In order to examine whether subsyndromes of schizophrenia had separate associations with CC measures, patients were scored on psychomotor poverty, disorganisation and reality distortion (Liddle, 1987).
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for total CC area measures for 10 subjects were >0.97. Intra-rater reliabilities determined on all sub-regions of the CC for 10 subjects were > 0.84, except for the mid-anterior section (0.71). CC measures were correlated with ventricular volumes, measured on the same subjects and reported separately in a larger MRI study (Woodruff et al., submitted). Measures of bilateral facilitation and interference were determined from Stroop measures previously described by Phillips et al. (1996) using a divided visual field tachistoscopic technique. We used a sub-group of subjects from this study on whom MRI scans had been obtained. Within group measures of association were performed using Pearson correlation coefficients and between group comparisons were made using Student ttests. The facilitation measure was the reaction time (RT) saving calculated by subtracting colour naming of a neutral word from colour naming of a colour-word, congruent with the colour patch. The interference measure was the RT lost calculated by subtracting the neutral condition from colour naming of a colour word incongruent with the colour patch.
3. Results
Mean age of patients was 32.4_7.2years (25-53) and of controls, 30.2 + 7.4 (18-52). Mean duration of illness in patients was 11.10_ 7.54 years (2-36) and mean number of hospital admissions was 5.8 _ 5.5 (1-25).
2.2. Scanning and corpus callosum measurement 3.1. Corpus callosumstructure A 1.5 Tesla Philips Gyroscan scanner was used to obtain a T-1 weighted spin-echo sagittal sequence of 5-mm thick slices orientated in the midline (TR = 235 ms, TE = 20 ms, FOV = 240 mm, four signal averages). With the aid of 'Analyze' software (Robb, 1990), the CC was measured on the mid-sagittal slice. The CC was also divided into four sections by lines drawn perpendicular to its antero-posterior length as previously described (Woodruff et al., 1993). Reliability was assessed using intra-class correlation coefficients. Intra- and inter-rater reliabilities
Corpus callosum areas in schizophrenics (n= 43) versus controls (n=42) were not statistically significant (CCTOT, 577.6 (108.8) versus 585.2 (96.5)mm2; CCA, 189.7 (40.8) versus 194.9 (39.0)mm2; CCAM, 101.6 (20.5) versus 102.5 (21.1)mm2; CCAP, 91.7 (22.2) versus 92.3 (18.7)mm2; CCP, 196.5 (40.6) versus 195.9 (29.5) mm2). There was a trend for negative correlations between age and CC areas in controls, but not in patients (Table 1). There was a negative correla-
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Table 1 Correlations between corpus callosum area measurements and age in patients and controls CCA
CCAM CCAP
CCP
CCTOT
Controls -0.25 -0.28 -0,04 0.03 -0.17 (0.10) (0.06) ( 0 , 8 0 ) ( 0 . 9 4 ) (0.27) Patients 0.12 0.09 0,004 -0.01 0.06 (0.44) (0.56) ( 0 . 9 8 ) ( 0 . 9 3 ) (0.72) Correlation coefficientswith p values in brackets. tion between length of illness and posterior CC area ( r = - 0 . 2 8 , p =0.07). 3.2. Corpus callosum structure and interhemispheric function
MRI scans of the corpus callosum and performance on the Stroop test were both assessed on 27 patients (mean age 32.9 + 6.6) and 29 controls who agreed to the additional assessment (mean age 31.5_+8.2). In this sub-group, patients had fewer total years of education than controls (12.2_+2.8 versus 14.3_+3.3; p = 0 . 0 1 , t-test). N A R T score was lower in patients than controls (107.2+_10.3 versus 113.8_+8.5). Also, mean weekly alcohol consumption was less in patients than controls (7.7_+ 12.5 versus 9.6_+ 9.3 units). In order to ascertain any bias in sampling we compared characteristics of subjects who had been scanned only and those who had additionally performed the Stroop test. Controls who had both MRI scans and Stroop tests performed ( n = 2 9 ) , compared with those for whom only MRI scans were available (n=14), were slightly older (31.3 + 8.1 versus 27.9 __5.2 years, p = 0.17, t-test). There was no difference in N A R T scores (113.8_+8.5 versus 113.7_+6.9; p = 0 . 9 7 , t-test). A similar comparison for patients revealed no difference in ages (32.4_+6.3 versus 32.3+8.7) but significantly higher N A R T scores in those patients on whom both M R I scans and Stroop tests were performed (107.3-+ 10.1 versus 100.9-+9.3). Bilateral facilitation was marginally greater in the 27 cases than 29 controls (41.7_+18.3 versus 26.6_+ 6.6; p = 0.43, t-test). Bilateral interference was significantly less in cases than controls (40.3 + 14.5 versus 79.5 _+9.9; p = 0.028, t-test). In
patients, there was a positive correlation between delusions and bilateral interference (r=0.53, p = 0.02). The relationship between CC area and performance on the Stroop task is shown in Table 2. There were negative correlations between total CC area and SANS scores for avolition (r = - 0 . 4 6 , p = 0 . 0 0 8 ) , anhedonia ( r = - 0 . 3 7 , p = 0 . 0 4 ) and affective flattening ( r = - 0 . 3 2 , p = 0 . 0 7 ) , that is, the smaller the CC the more these negative symptoms. These correlations were greatest for anterior CC regions (CCA and avolition, r = - 0 . 4 7 , p = 0.007; CCA and anhedonia, r = - 0 . 4 2 , p=0.018; CCA and affective flattening, r = - 0.41, p = 0.02). In a multiple regression model accounting for the effect of whole cerebral volume, the strongest associations were between total CC area and avolition (B = - 0 . 3 4 , p = 0.06), and CCA and avolition (B = - 0.35, p = 0.05 ), neither of which would reach statistical significance if a Bonferroni correction was applied. These respective correlations were not significant for posterior CC areas. There were no significant correlations between SAPS scores and CC areas. The only significant correlation between the three syndrome scores and CC areas was between CCA and psychomotor poverty ( r = -0.39, p=0.01). There were no significant correlations between CC areas and lateral, temporal horn, IIIrd or IVth ventricular volumes in patients. In controls, however, there were significant correlations between IVth ventricular volume and CCA (r=0.39, p = 0.009) and CCAM (r=0.47, p=0.001).
4. Discussion 4.1. Corpus callosum size in schizophrenia
Conclusions are limited to the right-handed male groups studied. Our first hypothesis that CC area would be significantly reduced in male schizophrenics was not confirmed in contrast to a previous study in a separate group of male and female patients with prominent positive symptoms (Woodruff et al., 1993). The mean reduction of 7 . 6 m m 2 is, however, within the 95% confidence intervals of 3.45-53.4 mm 2 calculated from the
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Table 2 Correlation coefficients(p values) between bilateral interference(bilatint) and bilateral facilitation (bilatfac) and corpus callosum measurements for patients and controls (n = 56)
Bilatint
Controls Patients Both
Bilatfac
Controls Patients Both
CCTOT
CCA
CCAM
CCAP
CCP
- 0.03 (0.89) -0.21 (0.28) -0.16 (0.24) 0.06 (0.76) 0.23 (0.24) 0.18 (0.19)
- 0.04 (0.82) -0.16 (0.43) -0.12 (0.37) - 0.03 (0.89) 0.12 (0.54) 0.08 (0.58)
0.07 (0.72) -0.13 (0.53) -0.05 (0.72) - 0.12 (0.54) 0.17 (0.39) 0.07 (0.58)
- 0.05 (0.78) -0.13 (0.52) -0.12 (0.364) 0.17 (0.37) 0.21 (0.29) 0.19 (0.15)
- 0.09 (0.61) -0.32 (0.10) -0.27 (0.047)* 0.19 (0.31) 0.33 (0.09) 0.29 (0.03)*
*p= <0.05. meta-analysis of previous studies (Woodruff et al., 1995). Since that meta-analysis, there have been several further reports. Hoff et al. (1994), in a relatively young first-onset sample found that females rather than males may have smaller corpora callosa than sex-matched controls. Although statistically non-significant, male schizophrenics had larger CC areas than male controls. Similarly, in a more heterogeneous sample but of relatively short duration of illness, only anterior CC areas were larger in male schizophrenics than controls (Colombo et al., 1994). The present study (like most included in the meta-analysis) included a relatively heterogeneous sample including those with chronic illness, so if CC size varies according to clinical sub-types (see later), this may have reduced our chance to detect significant differences. However, the main strength of this study was the comparison of structure, symptoms and function within subjects. 4.2. Age and corpus callosum size
The association between age and smaller anterior CC area in controls was less in patients. It may be that the age-related changes in CC size in schizophrenics in our study are too subtle to reach statistical significance, or that it represents a divergence in ageing effects on the CC between this group of schizophrenics and controls. Such a diver-
gence would be consistent with the findings of Bagwell et al. (1995) who reported that age was highly correlated with CC size in 18 controls ( r = 0.74, p = 0 . 0 0 0 1 ) but not in 22 schizophrenics (r=0.21, p = 0 . 3 3 ) . One possible explanation includes defective axonal elimination during early childhood development (Clarke et al., 1989) which would result in a larger CC before ageing effects took hold. If so, CC size should be greater in schizophrenics, which was not the case in our study, although this has been reported in others (Nasrallah, 1985). Alternatively axonal myelination of the CC (which increases throughout normal adulthood (Giedd et al., 1996) in schizophrenia might continue un-abated at a time when axonal loss due to ageing usually predominates. In a healthy age group over 60, Burke and Yeo (1994) found negative correlations between age and CC area particularly striking in males rather than females, and the anterior region was most susceptible to these age-related changes. In addition maturational increases are less marked in the anterior versus posterior CC (Giedd et al., 1996), which might result in its greater sensitivity to degenerative effects of age. 4.3. Corpus callosum size and schizophrenic symptoms
Nasrallah (1985) argued that Schneiderian first-rank symptoms, such as delusions, may result
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from abnormal integration of inter-hemispherically transmitted information such that the left hemisphere became 'conscious' of processes normally confined to the right. The correlation between bilateral interference and delusions is consistent with this and suggests that excessive transfer of incongruent information contributes towards this erroneous integration of inter-hemispheric information. It has been suggested that schizophrenics with early onset of illness and negative symptomatology may have excessive inter-hemispheric transfer, whilst those with later onset and positive symptomatology have reduced inter-hemispheric transfer (Coger and Serafetinides, 1990). In this study of patients with predominantly chronic illness, we found an association of negative symptoms with smaller CC area, particularly of the anterior segments, consistent with Giinther et al. (1991) who demonstrated that schizophrenics with smaller CC area had predominantly type II schizophrenia. Although, unlike Glinther et al. (1991) we did not select patients specifically on the basis of symptoms, of the three sub-syndrome scores of Liddle (1987), only psychomotor poverty correlated inversely with anterior CC area. Negative symptoms of schizophrenia are thought to originate from poorly functioning frontal lobe regions (Andreasen et al., 1990), and reduced volumes of these regions have been demonstrated in structural MRI studies (Woodruff and Murray, 1994). It is possible that these frontal lobe abnormalities are additionally associated with dysfunctional communication between the hemispheres. In support of this is the demonstration of GOnther et al. (1991) of an association between reduced cerebral blood flow and reduced CC area in schizophrenics with negative symptoms. A!though we did not find an association between positive symptoms and CC area in this schizophrenic group, it is possible that a more homogeneous group of patients with acute onset may have shown this association, such as that described by David et al. (1995) of an association between anterior CC area and auditory hallucinations. Larger studies (or the combination of several smaller ones) are required to accurately determine these apparently subtle effects of CC size on symptoms.
4.4. Corpus callosum size and inter-hemispheric function Results from Table 2 show that there was a positive association between corpus callosum area and bilateral facilitation for all regions (especially the posterior section) of the corpus callosum in patients and controls. This positive association between posterior CC area and bilateral facilitation became statistically significant when results from both groups were combined. There was likewise a negative association found between posterior corpus callosum area and bilateral interference. We have demonstrated that CC size in both schizophrenics and controls is directly related to inter-hemispheric facilitation and that there is a reciprocal relationship between CC size and inter-hemispheric interference as we predicted. Facilitation allows transfer of congruent information across the CC. Interference on the other hand allows transfer of incongruent information. We have confirmed the existence of a reciprocal relationship between facilitation and interference. As we predicted (hypothesis 2), the relationship between size and facilitation and the reverse association with interference applied only to the posterior CC, the area most likely to be involved in transfer of visual information used in the Stroop test. The implication is that facilitation and lack of interference is associated either with greater numbers or more myelination of small diameter inter-hemispheric fibres. It supports the hypothesis that CC size reflects greater flow of congruent, at the expense of incongruent, information. The findings also support the role of the CC in facilitating cognitive functioning (Hoff et al., 1994; Sauerwein and Lassonde, 1994). There have been relatively few studies investigating structure and function of the corpus callosum jointly in the same subjects, and none to our knowledge that have related CC size with interhemisheric facilitation and interference. Raine et al. (1990) used a variety of auditory and somatosensory inter-hemispheric tasks and found performance on these did not parallel CC abnormalities, although they did not directly correlate structural and functional measures. Similar but not directly comparable with our study is that of Hoff et al.
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(1994), w h o f o u n d a relationship between larger C C size and better performance on a range o f neuropsychological tasks in healthy controls a n d a tendency for this association to be reversed in schizophrenics. In schizophrenics C C size had a reduced effect on cognition because, they argued, the fibres are dysfunctional. O u r data does not support this conclusion, at least in a g r o u p o f m o r e chronic patients. The fact that the Stroop test we employed relies on posterior C C visual fibres where the structurefunction associations were strongest adds neuroanatomical validity to our findings. They are consistent with the findings in n o r m a l controls that interference (as determined from performance on a right hemispheric m o t o r task during left hemispheric verbal activity) was inversely correlated with corpus callosal size (Yazgan et al., 1995), and in schizophrenics o f an association between interhemispheric transfer and anterior callosal size ( D a v i d et al., 1995).
5. Conclusions There appears to be a link between corpus callosum size and neuropsychological processes involving inter-hemispheric transfer that is comm o n to b o t h schizophrenics and healthy controls. Age-related changes o f the corpus callosum m a y differ between schizophrenics and controls. Studies need to assess specific structure/function relationships in patient and control groups separately over time. The data support the existence o f an inverse relationship between anterior corpus callosum area and negative s y m p t o m s in schizophrenia. Future studies might usefully explore the functional correlations o f activity in brain regions connected via the corpus callosum to m o r e fully understand the role o f the corpus callosum in mechanisms underlying schizophrenic symptoms.
Acknowledgment We wish to thank Mrs. P. Graves and the R a d i o g r a p h i c Staff at G u y ' s Hospital for technical help with scanning, and Dr. Paul Summers, G u y ' s
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Hospital for technical help. M.L.P. was supported by the M R C ( U K ) . This study was supported in part by the Psychiatry Research Trust and the Stanley Foundation.
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