Materials and methods

MRI studies

Demographic variables for the subjects appear in Table 1. For the schizophrenia group, diagnoses were made according to DSM-IV criteria. The subgroup that were first-episode patients (schizophrenia n=6, schizophreniform n=2, schizoaffective n=1) were treated for a mean of 5 months (range 1–12 months) at the time of imaging. Medications used were olanzapine (n=6), risperidone (n=2), and quetiapine (n=1). The subgroup with chronic illness (n=21) generally was moderately to markedly ill. Medications included olanzapine (n=4), risperidone (n=5), clozapine (n=10), quetiapine (n=1), depot fluphenazine, or pipotiazine (n=1 each); some patients were taking more than one antipsychotic. Healthy comparison subjects were recruited from hospital staff and the local community, with the goal of matching the patient group for age, gender distribution, parental education, and smoking history. Subjects with a history of recent significant substance abuse (aside from cigarettes), history of head trauma or other neurological disorder were excluded. All subjects provided written informed consent and the protocol was approved by the UBC Clinical Research Ethics Committee.

Table 1 - Demographic and clinical features of patients and healthy comparison subjects participating in the MRI studies.

Full table

We used a T2 relaxation technique to assess myelin water fraction, using a General Electric Signa 1.5 T MR scanner.^25,26 Briefly, a sagittal scout scan was used first to establish anatomical landmarks. Next, an axial slice was positioned through the base of the genu and splenium of the corpus callosum for T2 relaxation measurements. A single-slice 32-echo MRI pulse sequence was used. Sequence parameters were repetition time TR=3 s, echo spacing 10 ms, slice thickness 10 mm, field of view 220 mm, bandwidth 32 kHz, matrix 256 128. The slice obtained appeared like a normal T2 slice (see Figure 1), and was used to outline anatomical regions of interest, done interactively by two individuals. Care was taken to use narrowly defined regions, to limit the possibility of volume-averaging effects. The regions of interest were frontal white matter, the genu of the corpus callosum, the posterior internal capsule, the splenium of the corpus callosum, and the posterior white matter. Inspection of axial slices 1.02 mm in thickness obtained with an SPGR sequence and bracketing the T2 relaxation slice indicated that the ROIs contained nearly exclusively white matter.

Figure 1.

The central image illustrates a 10 mm thick T2-weighted slice used for outlining the anatomical regions of interest. From top to bottom, these are frontal white matter, genu of corpus callosum, internal capsule, splenium of corpus callosum, posterior white matter. The images to the left and right are 1.02 mm thick SPGR slices, and represent respectively the inferior and superior bounds of the thicker T2 slice. The white matter regions of interest outlined on the T2 slice are quite homogeneous in composition.

Full figure and legend (43K)

The outlined regions were then analysed by averaging the decay curves from each pixel.³⁷ The average curve was then decomposed into three peaks, a small, fast-relaxing (0–50 ms) signal assigned to water trapped in the hydrophobic space between myelin bilayers, a large signal near 70 ms assigned to intra- and extracellular tissue water, and a small peak with T2 greater than 1 s assigned to cerebrospinal fluid. The myelin water fraction was calculated as the ratio of the area of the fast-relaxing peak to the total T2 distribution area.

To determine if the size of the corpus callosum contributed to the comparison of myelin water fraction between groups, the corpus callosum area was measured on a single sagittal slice from volumetric SPGR scans (1.02 mm slice thickness). Mid-sagittal slice inclusion criteria were an easily distinguishable cerebral aqueduct and either a distinct anterior commissure or presence of the interhemispheric falx of dura. The corpus callosum was divided into seven regions,³⁸ including the genu and splenium.

Post-mortem studies

Samples of anterior prefrontal cortex were dissected from frozen coronal sections of patients with schizophrenia (n=6 males, 7 females), and comparison subjects with no history of mental disorder (n=8 males, 3 females). Grey matter was used as white matter samples were not available, and previous studies of oligodendrocyte-related mRNA and proteins were also performed on grey matter. The mean age at the time of death did not differ between groups (control 46.2 years, SD 17.0 vs schizophrenia 47.9 years, SD 17.4), nor did post-mortem interval (control 17.8 h, SD 4.8 vs schizophrenia 13.8 h, SD 6.0) or duration of storage (control 97.0 months, SD 26.8 vs schizophrenia 110.0 months, SD 46.1). All cases of schizophrenia were likely to have been treated with antipsychotic drugs; however, these were detected at post-mortem in only two cases. Samples were obtained from brain tissue banks, in accord with policies of each Institutional Review Board. These samples were used in previous studies, and descriptions of individual cases are available.^31,39

We used well-characterized antibodies reactive with MAG (Boehringer Mannheim, Laval, Canada)⁴⁰ and with CNPase (SMI-91, Sternberger, Lutherville, MD, USA).³⁴ Prior to using an ELISA to quantify the oligodendrocyte-associated proteins MAG and CNPase, we performed immunoblotting studies of human brain homogenates, which confirmed the expected single band at approximately 100 kDa for MAG and the doublet band at approximately 45–50 kDa for CNPase. For the ELISA, antibodies were used at dilution 1 : 100 for anti-MAG, and 1 : 500 for anti-CNPase. All samples were studied together in the same run, in duplicate, blinded to diagnosis. A four-step (MAG) or six-step (CNPase), 1 : 1 serial dilution curve was generated for each sample.³¹ Blank values were subtracted, and the integrated sum of optical density for each sample over the dilution range was used for comparisons.⁴¹ Using a study of synaptophysin, a more abundant antigen, we confirmed that this approach yields similar results to the traditional determination of antigen concentration (integrated compared with concentration, r=0.94).

Statistical analysis

The MRI and myelin protein measures were examined for deviations from the normal distribution using the Kolmogorov–Smirnov test. The data appeared to be normally distributed, so parametric statistics were used. We first performed an omnibus comparison of overall white matter myelin water fraction between all healthy subjects and all patients with schizophrenia using a repeated measures ANOVA, with side (left, right) as a within-subjects factor, diagnosis as a between-subjects factor, and age as a covariate. Using the same approach, we next examined five anatomically distinct areas of white matter: frontal (forceps minor), genu and splenium of corpus callosum, internal capsule, and posterior (forceps major). For this comparison, the value for statistical significance was set at P<0.01.

We next studied the relations between myelin water fraction, age and education using correlation, and examined the control group and the total schizophrenia group separately. A secondary analysis compared the control group and the total schizophrenia group using both age and education as covariates.

A series of exploratory comparisons was then made between healthy subjects under the age of 30 years and the first-episode psychosis subgroup, and between healthy male subjects and the chronic schizophrenia subgroup (all males).

Intracranial volumes were obtained from axial slices to use as a covariate in the analyses of callosal areas. Inter-rater reliability measures were acceptable for all myelin and corpus callosum regions of interest, with intraclass correlation coefficients ranging from 0.84 to 0.98.

For analysis of the ELISA data, we considered the possible complicating effects of age, post-mortem, and storage times. All correlations between potentially confounding variables and antigen values were P>0.1, so t-tests were used for comparisons.

Results

Subject groups for MRI studies

We compared demographic variables of healthy subjects and patients recruited for the MRI studies (Table 1). The only significant difference between groups was personal level of education (total healthy vs total schizophrenia t=3.80, df=55, P=0.0004; subset male healthy vs chronic schizophrenia t=3.26, df=42, P=0.002). Personal education did not differ between younger healthy subjects and the first-episode psychosis group. Completion of schooling was likely affected by the onset of illness in patients with the more chronic form of schizophrenia. Parental education did not differ between any groups, suggesting comparable potential for educational achievement in the absence of illness.

Myelin water fraction: total schizophrenia group vs controls

The T2 relaxation technique allows images to be generated where the intensity of a pixel represents the myelin water fraction in that pixel (myelin maps, Figure 2). For overall white matter myelin water fraction, the mean value in the total schizophrenia group was approximately 12% lower compared with healthy subjects (F=4.89, df=1, 54, P=0.031, Figure 3). The regional distribution of myelin water fraction in schizophrenia compared with healthy subjects is illustrated in Figure 3. The frontal lobe white matter (mean 20% lower in schizophrenia, F=4.08, df=1, 54, P=0.048) and the genu of the corpus callosum (mean 19% lower in schizophrenia, F=4.37, df=1, 54, P=0.041) showed the largest differences, but neither met criteria for statistical significance after correcting for multiple comparisons. However, myelin water fraction in the genu was 36% lower on the left in schizophrenia compared with healthy subjects, but only 2% lower on the right. This resulted in a significant side-by-diagnosis interaction for myelin water fraction in the genu in the overall sample (F=10.08, df=1, 54, P=0.002). All statistically significant findings with parametric tests were also observed with nonparametric tests.

Figure 2.

Myelin water fraction maps in healthy comparison subjects and patients with schizophrenia. These maps are for illustrative purposes only, and are created from the T2 slice as shown in Figure 1. The intensity of these images is proportional to the myelin water fraction. The first series of three myelin maps are from a 27-year-old healthy male (a), a 27-year-old male with first-episode psychosis (b), and a 25-year-old male with chronic schizophrenia (c). The second three myelin maps are from a 19-year-old healthy male (d), a 19-year-old male with first-episode psychosis (e), and a 22-year-old male with chronic schizophrenia (f).

Full figure and legend (87K)

Figure 3.

Left panel: Scattergrams of overall white matter myelin water fraction in healthy subjects compared with patients with schizophrenia. Myelin water fraction was smaller in schizophrenia overall (P=0.031). Con: controls; Sch: schizophrenia. Right panel: Box plot of distribution of T2 myelin water fraction between brain regions, separated according to diagnostic group: healthy controls (Con) and schizophrenia (Sch). The top, internal bar, and bottom of the boxes represent the 75th, 50th, and 25th percentiles, respectively. The whiskers extend from the 10th percentile to the 90th percentile. The smaller black boxes represent the mean values. Int cap: internal capsule.

Full figure and legend (26K)

We compared the areas of two corpus callosum regions to determine if differences in myelin water fraction could be attributed to differences in size of the corpus callosum. For 47 scans (23 schizophrenia, 24 healthy subjects), a sagittal slice was available for the measurement of corpus callosum area. No differences in area between groups were observed for the genu (healthy 139.3 mm², SD=28.2; schizophrenia 139.8 mm², SD=22.6, F=0.01, df=1, 43, P=0.92) or for the splenium (healthy 163.0 mm², SD=31.8; schizophrenia 161.2 mm², SD=26.3, F=0.01, df=1, 43, P=0.91) of the corpus callosum in an analysis covarying for age and intracranial volume. The intracranial volume did not differ between groups.

Myelin water fraction and education in the total schizophrenia group and controls

Ongoing brain maturation during adolescence and early adulthood could contribute to myelin water fraction. We examined correlations between age, education, and myelin water fraction in white matter overall, and in the left genu (Table 2). Since the overall frontal lobe white matter might be expected to show ongoing maturation during early adulthood, this region was also examined. Age and myelin water fraction showed statistically significant correlations in overall white matter and frontal white matter, but only in control subjects. Education and myelin water fraction were correlated in frontal white matter, again, only in the control subjects (Figure 4). The magnitude of the correlations for these variables in control subjects differed significantly from correlations in patients with schizophrenia (P0.05).

Figure 4.

Plots of frontal myelin water fraction in relation to age and to education in healthy comparison subjects (control) and patients with schizophrenia. While statistically significant relations between frontal myelin water fraction and both age (P=0.01) and education (P=0.006) were observed in healthy subjects, no statistically significant relations were seen in patients with schizophrenia.

Full figure and legend (41K)

Table 2 - Correlations between myelin water fraction and age, and education in regions showing differences between controls and patients with schizophrenia.

Full table

Control subjects and patients with schizophrenia did not differ on parental education, but did demonstrate statistically significant differences in personal education (Table 1). The range of education in this sample was 9–21 years in controls, and 9–18 years in subjects with schizophrenia. It is likely that the prodrome of schizophrenia interfered with education in some patients. We performed secondary analyses of covariance to determine if myelin water fraction differed between diagnostic groups when both age and education were used as covariates (Table 3). For the left genu, the statistically significant difference between diagnostic groups remained after controlling for both age and education. This may suggest an abnormality of myelin water fraction, which precedes illness onset. For overall white matter and frontal white matter, differences related to diagnostic group were not statistically significant when both age and education were controlled for. In the context of no significant correlation between myelin water fraction and age or education in these regions, a possible interpretation is that the onset of schizophrenia disrupted a normal pattern of maturation, resulting in secondary changes.

Table 3 - Analysis of covariance on myelin water fraction.

Full table

Myelin water fraction in chronic schizophrenia and in first-episode patient subsets

Exploratory analyses were carried out in subsets of patients. In the subset of patients with chronic schizophrenia (n=21, all males), overall myelin water fraction was approximately 13% lower compared with male healthy subjects (n=23) of a comparable age (F=4.16, df=1, 41, P=0.048). Regional analyses did not demonstrate any significant differences related to diagnostic subgroup. For the genu, the same pattern of results was observed as in the overall sample, with the left side being affected (interaction F=7.05, df=1, 41, P=0.011, Figure 5).

Figure 5.

Scattergram of myelin water fraction in the left genu of the corpus callosum in young healthy subjects (yCon), first-episode psychosis (FEP), healthy male subjects (mCon), and males with chronic schizophrenia (Sch). The myelin water fraction was smaller in each group of patients with schizophrenia (*P<0.05).

Full figure and legend (19K)

In the subset of first-episode psychosis (n=9), overall myelin water fraction was not significantly different compared with healthy subjects of a similar age (n=10). Regional analyses did not demonstrate any significant differences related to diagnostic subgroup. For the genu, the same pattern of differences from controls as observed in the chronic cases was demonstrated (interaction F=5.30, df=1, 16, P=0.035), indicating that some of the disturbances in myelin water fraction appear to be present near the initial presentation of illness. It is also of interest to note that there was no significant difference in educational attainment between the first-episode patients and the comparison healthy subject subgroup. Although limited educational experience may have contributed to the lower myelin water fraction in the chronic patients compared with healthy subjects, this was less likely to be a factor in the first-episode subset.

Myelin water fraction was not correlated with duration of treatment in the first-episode psychosis group, or with duration of illness in the chronic group.

Post-mortem studies

Two oligodendrocyte-associated proteins were studied in post-mortem samples of the anterior frontal cortex (Figure 6). The mean value of CNPase immunoreactivity was 33% lower in schizophrenia (t=2.07, df=22, P=0.05). This finding was also statistically significant using a Mann–Whitney test (Z=2.00, P=0.046). The mean value for MAG immunoreactivity was 27% lower in schizophrenia; however, this difference was not statistically significant (t=1.54, df=22, P=0.14). Unfortunately, educational attainment was not known for the samples used in the post-mortem study.

Figure 6.

Scattergram of immunoreactivity of oligodendrocyte-associated proteins MAG and CNPase in anterior prefrontal cortex samples from cases of schizophrenia (Sch) and comparison subjects with no known mental illness (Con). CNPase immunoreactivity was less in schizophrenia (P=0.05).

Full figure and legend (19K)

Discussion

The MRI and post-mortem results support the hypothesis of abnormalities of myelination in schizophrenia. An interesting finding in healthy subjects was an association between age, education, and myelin water fraction in frontal lobe white matter. These relations may be disturbed in schizophrenia.

The MRI results indicate a diffusely smaller myelin water fraction in schizophrenia, with the left genu of the corpus callosum showing more prominent effects. In the active phases of illness, schizophrenia is associated with prominent psychotic symptoms, which are likely related to excessive dopaminergic transmission.¹ Additionally, the illness is often complicated by chronic disability. Disruption of the integrity of myelinated pathways, particularly in anterior regions, could contribute to this poorly understood component of the illness. The consequences of abnormalities of myelination in schizophrenia may share some similarities with MS, even though the mechanisms are likely to be very different. In MS, standard MRI techniques depict lesions as macroscopic areas of abnormality in white matter, as well as normal-appearing white matter (NAWM). In MS patients, the myelin water fraction using T2 relaxation analysis is abnormal in lesions, but is also approximately 10% lower in NAWM.²⁷ This is quantitatively comparable to the smaller myelin water fraction observed in schizophrenia in the present study. Subtle MRI abnormalities in NAWM in MS are highly correlated with cognitive dysfunction,⁴² and with disability.⁴³ Further investigation of the functional correlates of smaller myelin water fraction in schizophrenia may be similarly illuminating.

The preliminary results presented here concerning relations between myelin water fraction, age, and education suggest differences in the strength of these correlations in schizophrenia. Prospective studies of patients early in the course of illness with repeated scans, and a larger cohort with a broader range of educational achievement will be needed to understand the significance of these findings. The observation of lower myelin water fraction in the left genu in first-episode patients suggests that subtle abnormalities are present at illness onset. The more diffuse abnormalities in the subset of chronic patients may be related to a progressive process. Alternatively, they could be a secondary consequence of the illness, related to reduced opportunity for education and other experiences. Induction of myelination is in part dependent on neural signal traffic in axons,⁴⁴ and reduced neural impulse traffic in schizophrenia could be a contributing factor. Whether the lower myelin water fraction in chronic patients is primary or secondary, it will be of interest to investigate the possibility that this abnormality may limit the potential for functional recovery and rehabilitation.

The MRI component of the present study has certain limitations. A single slice was available for the myelin water fraction analysis, and the thickness could result in partial volume effects. If not carefully controlled for consistent anatomical positioning, single-slice approaches can lead to difficulty in reproducing the results. In the present study, use of a single slice was due to the practical consideration of the time necessary to obtain the image (25 min). There are also technical considerations concerning multi-slice approaches, which limit such an approach to T2 relaxation studies.²⁶ First, multi-slice sequences require slice-selective 180° pulses, which may be less effective than rectangular pulses. Second, multi-slice images can be corrupted by magnetization transfer effects due to off-resonance radiofrequency irradiation. Third, multiple, intense 180° pulses could lead to unacceptable heating.

An additional limitation was the use of the ratio or myelin water fraction rather than the absolute myelin water content. As a consequence of using a ratio, changes in numerator, denominator or both could result in the lower water fraction as we observed in schizophrenia. The advantage of the ratio approach is the consistency of ratio values from subject to subject, while the absolute values of all the T2 peaks are quite variable. We measured both myelin water fraction and absolute total water content of various tissues in a previous study.²⁶ This required a phantom T2 decay curve, as well as correcting each of the tissue T2 distribution peaks for T1 relaxation. The measured total water content was similar to that expected from post-mortem studies, and did not differ between white matter regions. However, as expected from the anatomical distribution of myelin, the myelin water fraction did differ between regions.^26,27 We also demonstrated that the myelin water fraction (as calculated in the present study) was highly correlated with immunostaining or classical histopathological stains in post-mortem brain.³⁶ For these reasons, we feel it is likely that the myelin water fraction does represent a difference in this component of the signal rather that the total water content. However, if the total water content in the left genu were increased in schizophrenia (yet unaltered in other white matter regions), this would be a theoretically possible explanation for the present results.

The effects of antipsychotic medications must also be considered. All patients in the present sample were treated with antipsychotic drugs. Treatment duration for the first-episode psychosis group was for a mean of 18 weeks, and was with risperidone, olanzapine, or quetiapine. None of these medications is known to be myelotoxic. Within the FEP group there was no correlation between myelin water fraction and duration of treatment, which ranged from 9 weeks (three patients) to 52 weeks (one patient). This is similar to the result of a post-mortem study, which found no relation between abnormalities of oligodendrocytes and duration of antipsychotic drug treatment.³⁰

Putative cellular and molecular correlates of myelination abnormalities include altered expression of oligodendrocyte-associated genes and disturbances in their protein products. We observed less of the oligodendrocyte-associated protein CNPase in schizophrenia, which is complementary to a report of less expression of the gene coding for this molecule.³² It should be noted that in both the present study and in the study of Hakak et al,³² assays were made of oligodendrocyte-related proteins or mRNA in grey matter, not in white matter. Different results could be observed when post-mortem studies of white matter are carried out. In white matter, loss of CNPase immunostaining is a marker of abnormalities of myelination, and was correlated with the MRI finding of lower myelin water fraction in a post-mortem study of MS.³⁶ Abnormalities of glial cells are increasingly reported in serious mental disorders.^45,46 These include signs of apoptosis and necrosis of oligodendrocytes,³⁰ and damage to the lamellae of the myelin sheath.^28,29,30 Oligodendrocyte dysfunction and abnormalities of myelination could be secondary to axonal dysfunction, as detailed studies of NAWM in MS reveal abnormalities of axonal proteins such as loss of neurofilament protein phosphorylation.⁴⁷

In summary, the onset of schizophrenia in late adolescence or early adulthood could interrupt the process of normal maturation myelinated pathways. Alternatively, the illness process could result in secondary loss of complete myelination following onset. Disruption of myelinated pathways might help explain the long duration of time necessary for functional recovery and rehabilitation in schizophrenia, particularly for patients with repeated episodes of illness.

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Acknowledgements

WGH was supported by a Scientist Award from the Canadian Institutes of Health Research. Grant support was provided by CIHR (MT14037), NARSAD and the National Institutes of Mental Health (MT46745, MH40210 and MH60877). Drs Joel Kleinman and Manuel Casanova provided tissue samples. Ms C Chen provided technical support.