Magnetic resonance imaging in schizophrenia: relationship with clinical measures

SCHIZOPHRENIA RESEARCH Schizophrenia Research 12 (1994) 195-203

Magnetic resonance imaging in schizophrenia: relationship with clinical measures P. David Mozley a,b*, Raquel E. Gur a,b, Susan M. Resnick a, Derri L. Shtasel a, Jeffrey Richards a, Mark Kohn b, Robert Grossman b, Gabor Herman b, and Ruben C. Gur a,b a Departments

of Psychiatry, Neuropsychiatry Section, Mental Health Clinical Research Center, 10th Floor Gates Bldg, 3500 Spruce Street, University of Pennsylvania, Philadelphia, PA 19104, USA and Department of Radiology, University of Pennsylvania Philadelphia, Pennsylvania Received

2 February

1993; revision received

19 September

1993; accepted

20 September

1993

Abstract Relationships were examined between clinical features of schizophrenia and cerebrospinal fluid (CSF) volume in brain obtained by magnetic resonance imaging (MRI) in a sample of 59 patients. The volumes of the cerebral hemispheres and CSF were measured with a computer program designed to separate reliably neural tissue from CSF. The CSF to cranial volume ratios were related to history, symptom profile and outcome functioning. Earlier age of onset was associated with higher sulcal CSF ratio, r= -0.40. The anatomic measures were unrelated to symptom severity. However, patient subtypes differed in the laterality of measures. Higher left hemispheric ratios were seen in patients with severe negative symptoms, and left predominance of ventricular relative to sulcal ratios was associated with the presence of hallucinations and delusions. The results suggest that while higher CSF is related to earlier age of onset, the clinical symptoms are more related to its lateralization. This is consistent with the hypothesis that schizophrenia is a lateralized brain disease. Key words: Magnetic

resonance

imaging;

Clinical features;

1. Introduction

In search of neural substrates for schizophrenia, studies using CT or MRI have related ventricular enlargement to clinical variables (Pfefferbaum et al., 1990). Ventricular brain ratio (VBR) has been the most frequently studied anatomic variable ever since Johnstone et al. (1976) have first reported that it may be larger in patients with schizophrenia than in controls. VBR has been related to history, clinical profile and level of functioning. * Corresponding author Elsevier Science B.V. SSDZ 0920-9964(94)E0074-4

Lateralization;

(Schizophrenia)

Concerning history, ventricular enlargement has been associated with poor premorbid adjustment in some studies (Pearlson et al., 1984; Williams et al., 1985), but not others (Kemali et al., 1986; Johnstone et al., 1986). Weinberger et al. (1980) have found no significant difference between patients with enlarged and normal ventricles in age of onset. Johnstone et al. (1989), however, have suggested a relationship between VBR and age of onset, manifested by impaired social behavior. Phenomenologic correlates of VBR have been obtained from measures of clinical profile. Negative symptoms have been associated with

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increased VBR in some investigations (Pearlson et al., 1984; Williams et al., 1985; Kemali et al., 1986; Johnstone et al., 1976; Andreasen et al., 1982, 1986, 1990ab; Takahashi et al., 1981), but not others (e.g., Mathew et al., 1985; Kolakowska et al., 1985; Farmer et al., 1987; Ota et al., 1987; Romani et al., 1986; Losonczy et al., 1986; Pfefferbaum et al., 1988). Correlations between VBR and positive symptom severity, but not negative symptom severity (Farmer et al., 1987), and between VBR and both positive and negative symptoms (Besson et al., 1987), have also been observed. There have been reports of an inverse correlation between VBR and outcome functioning (Pearlson et al., 1984; Williams et al., 198.5; Weinberger et al., 1980; Schulz et al., 1983; Luchins et al., 1984) which have not been consistently replicated (Johnstone et al., 1986; Kolakowska et al., 1985; Losonczy et al., 1986). Several clinical and methodologic factors may have contributed to some of the inconsistencies in the literature. Early neuroanatomic studies have calculated VBR with linear or planimetric measures of a single tomographic slice. The application of computerized volumetric MRI procedures in well characterized prospective samples can help clarify some of the inconsistencies. We have described the validation of an MRI based, semiautomated image analysis program that can reliably segment CSF from brain tissue (Kohn et al., 1991). In a normative sample, both ventricular and sulcal CSF to cranial volume ratios have been shown sensitive to effects of age and gender (Gur et al., 1991a). In comparing patients with schizophrenia to controls, we have reported higher ventricular and sulcal ratios in patients (Gur et al., 1991b). Here we present the relationship between these neuroanatomic measures and clinical features in an extended sample which has been followed prospectively with standardized assessment of history, clinical profile and level of functioning. These measures are used to examine the relation between anatomy and clinical features. We also test the hypothesis that schizophrenia reflects a lateralized brain abnormality (Crow, 1990; Flor-Henry, 1976; Gur, 1977, 1978). This hypothesis has been supported by correlations between symptom severity

and lateralized physiologic indices (Gur et al., 1983, 1985, 1987b, 1989). Although lateralized anatomic abnormalities in schizophrenia have been described (Barta et al., 1990; Crow, 1990; Suddath et al., 1990), symptom severity has not been related to lateralized anatomic indices.

2. Subjects and methods 2.1. Subjects The sample included 59 patients (40 men, 19 women) of whom 42 were presented in Gur et al. (1991b), who also outlined procedures for evaluation and criteria for inclusion. Patients were consecutive admissions to the MHCRC with DSMIII-R diagnosis of schizophrenia. Age was 29.3 f 7.4 (range 18844 years), education 12.7_+ 1.8, and maternal and paternal education were 12.5k2.8 and 13.2k2.7, respectively. All subjects received a medical, neurologic and psychiatric evaluation, and laboratory tests including toxic screen. Participants had no history of any disorder or event which can potentially affect brain function (Gur et al., 1991ab). Exclusion criteria were: ( 1) Medical: history of hypertension, cardiac disease, renal, liver, endocrine and pulmonary disorders and treatment with steroids. (2) Neurological: history of disorder or event which may affect brain function such as head trauma with loss of consciousness, seizure, cerebral palsy, Parkinson’s dissclerosis, Huntington’s disease, ease, multiple vascular headaches, central nervous system infection, learning disability and cerebrovascular disease. (3) Psychiatric: any other Axis I disorder including substance abuse and history of electroconvulsive therapy. Age of onset of illness, i.e. clear deterioration of functioning, was 22.5 + 5.3 (range 16-41) years, duration was < 1 year for 8 patients and for the remainder it was 7.9Ifr 5.0 (range 1-19) years. For 22 patients the enrollment in the study was during first hospitalization, and number of previous hospitalizations for the remaining was 4.4 + 5.2 (range l-25). There were 50 right-handed, 1 ambidextrous, and 8 left-handed patients (Rackzowski et al. 1974). Weight and height were 74.7 f 10.9 kg and 173.9k8.5 cm for men and 61.4f9.6 kg and

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et al/Schizophrenia

165.1+ 5.0 cm for women. Informed consent obtained prior to participation in the study.

was

2.2. Clinical assessment andphenomenology Procedures of assessment and scoring were detailed elsewhere (Gur et al., 1991~). The assessment was done by research psychiatrists of the Accrual and Assessment Core of the MHCRC following standard clinical research procedures. Information was gathered from clinical interviews and observations, structured interview (SCID-P; Spitzer et al., 1986), review of medical records, and interviews with family members and professionals most familiar with the patient. For each instrument the recommended procedures for obtaining data were followed. Rating scales were completed by investigators of the assessment team trained to a criterion reliability of 0.90 (intraclass correlation). The ratings were reviewed by the entire assessment team, and disagreements were resolved by consensus independent of the MRI. Assessment of history included the Premorbid Adjustment Scale (assessing social, scholastic, interpersonal functioning from childhood to adulthood; Harris, 1975), age of onset, duration of illness and number of previous hospitalizations. Symptom profile was measured with the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1980), the Scale for Assessment of Negative Symptoms (SANS; Andreasen, 1982ab, 1983), the Scale for Assessment of Positive Symptoms (SAPS; Andreasen, 1982b, 1984), defitit-nondeficit typology (Carpenter et al., 1988), the Hamilton depression scale (HAM-D; Hamilton, 1960), and the Abnormal Involuntary Movement Scale (AIMS; Simpson et al., 1979). The Strauss-Carpenter outcome scale (Strauss and Carpenter, 1972) was applied for summary of clinical outcome for a period ranging from 6 months to 2 years, and the Quality of Life Scale (QOL; Lawton et al., 1982) provided a measure of psychosocial functioning. 2.3. A4RI measurement MRIs were acquired on a GE Signa 1.5 T scanner (Milwaukee, WI). Transaxial images were obtained in planes parallel to the orbitomeatal line. Each slice was 5 mm thick and there were no

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interslice gaps. A multiecho acquisition sequence was used, TR 3000, TE 30 and 80 ms. This double echo protocol allowed two independent properties of the tissue in each pixel to be measured simultaneously based on the same radio frequency stimulus: proton density and T2 weighted value. The segmentation program (Kohn et al., 1991) uses minimal operator interaction which includes initiating an automatic boundary tracing program which identifies the interior of the skull for drawing regions of interest, and identifying the general regions of the tissues to be segmented. Regions of interest and midline can be defined manually by line tracing using the mouse, and these region definitions are saved with the volume and segmentation data. The proton densities are plotted against T2 weighted values of each pixel within an operator-defined region of interest (ROI). The brightness of this plot at an (x, y) location is proportional to the frequency of occurrence of pixels within the ROI with a proton density of x and the T2 value of y. The CSF and neural tissue form discrete clusters of brightness which can be identified and separated. Field inhomogeneity (‘shading artifact’) distorts the shape of the clusters but preserves ability to segment CSF and brain, even in severe shading. For cluster separation the user identifies to the program the general location of the peaks of the clusters to be segmented. The program then performs a regions-growing operation, gathering local statistics of each cluster until it can reliably separate them. Volume calculation is performed based upon the segmented slice data without further operator interaction. The images were analyzed by two operators (P.D.M. and S.M.R.), who were unaware of the subject’s diagnosis. There was high interrater reliability (intraclass correlation of 0.99 for whole brain and 0.94 for CSF volume; Kohn et al., 1991), and the average value between the two operators was used. All supratentorial slices were analyzed and the infratentorial CSF and tissue were excluded by placing a boundary around the posterior fossa on each slice. The infra-tentorial CSF and brain tissue were excluded from the analysis by placing a boundary around the posterior fossa on each slice. The caudal brain stem structures below the level of the cerebral peduncles

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of the midbrain were excluded. The hypothalamic and chiasmatic cisterns were retained, but the pituitary, the carotid cistern, the ambient cistern, and the quadrigeminal plates were excluded. 2.4. Data analysis Clinical measures. These were quantified in 3 categories: (1) History: Premorbid functioning, age of onset, duration of illness, number of previous hospitalizations. (2) Symptom profile: BPRS, SANS and SAPS total scores. Patients were grouped on the basis of severity of symptoms in the 3 SANS-SAPS factors described in Gur et al. (1991~): Factor 1 (Negative) includes four of the SANS scales (Apathy, Anhedonia, Affective Flattening, AlogiaaAvolition); Factor 2 (Disinhibition) includes the Attention subscale of the SANS and the Bizarre Behavior and Positive Formal Thought Disorder of the SAPS; Factor 3 (Reality testing) includes the Hallucinations and Delusions subscales of the SAPS. Patients with scores >,4 (Marked) on all subscales of the factor were grouped as ‘High severity’ for that factor, and they were compared to ‘Others’. There were 14 patients who satisfied criteria for high severity on Factor 1, 15 on Factor 2, and 16 on Factor 3. Only two patients overlapped across two factor groupings and they were retained. In addition, the deficit-nondeficit classification (Carpenter et al., 1988) was used for grouping patients into subtypes. (3) Level of functioning: Strauss-Carpenter outcome scale, Quality of life, total scores. Anatomic measures. Two CSF ratio indices were computed as described in Gur et al. (1991b): VCR (ventricular CSF volume/cranial volume) and SCR (same for sulcal CSF). The formula used was: SCR = SULC/(SULC +VENT + BRAIN), where SCR=sulcal CSF ratio, SULC =sulcal CSF volume, VENT = ventricular CSF volume, BRAIN = brain volume (all in ml). The complementary formula was used for VCR. The CSF volumes were calculated from the voxel counts for all slices containing ventricular CSF (the analyses were repeated on all available

slices, with nearly identical results except as noted below), and sulcal CSF was defined as all CSF outside the ventricles. There are significant effects of age and gender (Gur et al., 1991a) on the anatomic indices, but the truncated age range and the number of women precluded stratified analysis by these variables. Therefore, age and sex were regressed on the anatomic variables using coefficients (/I weights) derived from the control sample of 42 normal subjects reported in Gur et al. ( 1991a). For each anatomic index the p weight of the corresponding adjusting variable (e.g., age) was multiplied by each subject’s value for that adjusting variable standardized to a mean of zero (based on normative sample). The resulting values for each adjusting variable were then subtracted from the original scores. (See Saykin et al. ( 1991) for a further discussion of this technique). Thus, the anatomic data submitted for statistical analysis were not influenced by effects of age and sex on normal brain anatomy. The corrected values were used as dependent measures. Analyses were repeated using the patients’ own b weights with the same significant effects and will not be reported. The focus of the analysis was on slices containing ventricles, since these measures showed differences between patients and controls in previous studies using planimetry. The data for the whole brain as well as the slice containing the largest ventricular space (the basis for most earlier studies) were also analyzed, with similar results. To test the hypotheses on associations between CSF indices and clinical features, Pearson product moment correlations were computed between the three clinical measures (BPRS, SANS, SAPS) total scores and the anatomic measures VCR and SCR. Likewise, for the hypothesis on relationships with history and level of functioning the four history scores and the two functioning scores specified above were correlated with the anatomic indices. To examine the hypothesis that clinical subtypes may differ in the anatomic measures and their laterality, MANOVA was performed for the patient groupings described above: High Factor 1 vs Others, High Factor 2 vs Others, High Factor 3 vs Others, and Deficit-Nondeficit. These served as grouping factors, and laterality (left, right) and

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VCR vs SCR were measures) factors.

within-group

FACTOR

(repeated-

1

FACTOR

2

FACTOR

3

3. Results Of the four history variables, only age of onset correlated significantly with SCR, higher sulcal CSF ratios were associated with earlier age of onset, Y(57) = - 0.40, p < 0.001, one-tailed. None of the clinical or outcome measures correlated significantly with either VCR or SCR (range - 0.24 to -0.25). The hypothesis of an association between symptom subtypes and anatomy was tested for the 3 factor classifications and the deficit-nondeficit types as described above. The analysis of the three patient groupings based on the SANS and SAPS factors showed different effects for each grouping. For patients high on Factor 1 (Negative) compared there was a significant group x to ‘Others’, laterality interaction, F( 1,57) = 5.21, p = 0.026, reflecting relatively higher left hemispheric indices in the high severity group. This was not significant for the VCR alone, but highly significant for SCR, F(1,57)=8.32, p=O.O05. For Factor 2 (Disinhibition) grouping no effects or interactions were significant. For Factor 3 (Reality testing) grouping, there was a significant group x laterality x ventricles vs sulci interaction, F( 1,57) = 6.00, p = 0.017, with high severity patients having higher left hemispheric VCR relative to SCR laterality. Fig. 1 illustrates these interactions with laterality by showing the groupings of patients into high and low severity on each of the factors. To highlight the laterality effects data are shown for a laterality index defined as Left-Right hemispheric volume ratios. No main effects or interactions were significant for the deficit-nondeficit classification for the entire sample. However, when excluding lefthanders from the analysis containing the whole brain, there was a deficit-nondeficit x VCR vs SCR interaction F( 1,48) = 4.22, p < 0.05 (it was marginal for the main analysis of slices containing ventricles, F( 1,48) = 3.26, p = 0.07). Deficit patients had higher sulcal CSF relative to ventricular ratios.

-0

5

VCR

SCR

VCR

SCR

VCR

SCR

Fig. 1. Means *SEM of laterality (left-right) for VCR and SCR in patients with high and low severity of symptoms included in Factor 1: negative symptoms, Factor 2: disinhibition, and Factor 3: reality testing, derived from the SANS and SAPS. Black triangle, high severity; white triangle, low severity.

Comparing first episode patients (n = 22) to the other patients did not show significant main effects or interactions.

4. Discussion Our results suggest that, out of all history and functioning measures, increased CSF ratio is associated only with earlier age of onset and for sulcal CSF. The lack of an association between ventricular enlargement and earlier age of onset differs from Johnstone et al. (1989) and accords with Weinberger et al. (1980). Sulcal CSF, which showed such an association in our data, was not examined in earlier studies. There was no evidence for an association between the anatomic indices and duration of illness. This is corroborated by the lack of a difference between first episode patients and the others. This result too is consistent with several studies (e.g., Weinberger et al., 1980; Woods et al., 1990). Examination of the clinical profile showed no correlation between symptom severity and the anatomic indices. However, the laterality of these indices was related to clinical subtypes, with different effects for ventricular and sulcal measures. Higher left hemispheric CSF in sulci relative to

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ventricles was observed in patients with severe negative symptoms. By contrast, higher left ventricular relative to sulcal CSF was seen in the cluster of patients characterized by impaired reality testing (hallucinations and delusions factor). The finding of greater severity associated with relatively higher left hemispheric values accords with other studies reporting lateralized anatomic (Barta et al., 1990; Crow, 1990; Suddath et al., 1990), physiologic (Gur et al., 1987ab; DeLisi et al., 1989), and neurobehavioral abnormalities (Saykin et al., 199 1; Cassens et al., 1990) in schizophrenia. There is a growing body of neuroanatomic evidence for the hypothesis that schizophrenia is a lateralized brain disorder (Gur, 1977; Southard, 1915; Flor-Henry, 1969). As Crow (1990) pointed out, schizophrenia seems to involve the brain hemisphere which regulates language, the most distinct evolutionary leap of humans. The present findings suggest further that the extent of lateralized asymmetry relates to symptom severity. Our conclusions are limited to hemispheric ratios and do not preclude more regionally circumscribed effects. For example, there is evidence for reduced volume and morphologic abnormalities of the temporal lobe in schizophrenia (Barta et al., 1990; Crow, 1990; Suddath et al., 1990; Shenton et al., 1992). Consistent with temporal lobe dysfunction, we found that the area of differential deficit in schizophrenia is memory (Saykin et al., 1991), which is regulated by temporal lobe regions (Squire and Butters, 1984; Milner, 1970). The association between temporal lobe abnormalities examination. requires symptomatology and Similarly, the specificity of the effects for ventricular compared to sulcal CSF measures merits further scrutiny. Differential effects for ventricular and sulcal CSF were not hypothesized since there were no prior data on sulcal volumetric measurements. However, it is likely that ventricular CSF reflects abnormalities of limbic structures while sulcal CSF is related to reduced neuronal volume in cortical tissue (DeLisi et al., 1991; Barta et al., 1990; Jernigan et al., 1991). The analysis of the data on the deficit-nondeficit classification showed no effects for the entire sample but a significant interaction suggesting higher sulcal CSF in the subgroup of right-handed

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deficit patients. These results should be considered preliminary and require replication. It should also be pointed out that the sample included only 19 women and was not large enough to warrant analysis of gender differences. This merits specific scrutiny in a larger sample (Gur et al., in press). On the basis of behavioral and neurophysiologic data, we have proposed that schizophrenia is associated not only with dysfunction of the left hemisphere, but also with overactivation of the dysfunctional hemisphere (Gur, 1978; Gur et al., 1985, 1987a,b). Unlike what is seen in ischemic, traumatic and neurodegenerative brain disorders, where neural activity is reduced in damaged regions, in schizophrenia there is evidence that symptom severity is associated with greater left hemisphere physiologic activity (Gur et al., 1987a,b). Increased neural activity against a background of reduced neuronal volume may occur in epileptiform diseases (Engel, 1987). Possibly, subtypes of patients may be identified, some with predominance of anatomic asymmetries and others with predominance of physiologic asymmetries. Alternatively, the underlying anatomic abnormalities may affect regional physiologic activity through changing availability of neuroreceptors. Such hypotheses could be tested by crossregistration of anatomic and physiologic data obtained from the same subjects. This is becoming increasingly feasible with neuroimaging methods, and would enable better understanding of the relationships among anatomic indices, neuroreceptors, and metabolism, and how they affect phenomenology and neurobehavioral deficits.

5. Acknowledgements This investigation was supported by NIMH grant MH-4219 1, Mental Health Clinical Research Center MH-43880, and a Research Scientist Development Award (REG) MH-00.586 and NIH grant CA-5081. We thank Helen Mitchell-Sears, BA, for assistance and Larry Muenz, PhD, for statistical consultation.

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