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Enlargement of the fornix in early-onset schizophrenia: a quantitative MRI study
Neuroscience Letters 301 (2001) 163±166
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Enlargement of the fornix in early-onset schizophrenia: a quantitative MRI study D.C. Davies a,*, A.M.J. Wardell b, R. Woolsey a, A.C.D. James c a
Department of Anatomy and Developmental Biology, St George's Hospital Medical School, Cranmer Terrace, Tooting, London SW17 0RE, UK b Department of Child Mental Health, St. George's Hospital Medical School, London SW17 0RE, UK c The Warneford Hospital, Oxford OX3 7JX, UK Received 3 December 2000; accepted 29 January 2001
Abstract Abnormalities of temporal lobe structure and frontal lobe function occur in schizophrenia. There have been few studies of young people with schizophrenia and little is known about temporo-frontal connectivity in the disease. Therefore, the cross-sectional area of the body of the fornix was measured on MR images from 17 young people with schizophrenia, nine with other serious psychiatric illnesses and eight without illness. The mean age of each group was 16±17 years. The mean cross-sectional fornix area in subjects with schizophrenia was signi®cantly larger than that in subjects without illness (<40%) and psychiatric controls (<26%). There was no such signi®cant difference between subjects without illness and psychiatric controls. The nature of the larger fornix in early-onset schizophrenia, whether it persists and whether it occurs in schizophrenia presenting in adulthood, remain to be elucidated. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Early-onset schizophrenia; Fornix; Hippocampal formation; Limbic system; Prefrontal cortex
Post mortem studies have revealed reductions in hippocampal and parahippocampal gyrus volumes in schizophrenia [5,9]. Cytoarchitectural disarray and cell loss from these structures have also been reported to occur in the disease [4,14,16,19,22,24]. Such abnormalities alone are unlikely to be able to account directly for the wide variety of symptoms associated with schizophrenia, many of which appear to be prefrontal in origin. However, these hippocampal abnormalities may also affect the function of brain structures with which the hippocampal formation/parahippocampal gyrus are connected. The fornix is the major ®bre tract connecting the hippocampal formation with sub-cortical brain regions and provides an indirect connection between the hippocampal formation and the prefrontal cortex. It is a large discrete bundle that lends itself to in vivo measurement. The association between schizophrenia and the size of the fornix was therefore investigated in young people using magnetic resonance imaging (MRI). Early-onset schizophrenia (presentation between 13±18 years) is considered to be * Corresponding author. Tel.: 144-20-8725-5211; fax: 144-208725-3326. E-mail address: [email protected] (D.C. Davies).
phenomenologically and epidemiologically continuous with adult-onset schizophrenia. It is particularly attractive for investigation of the psychiatric, psychological and anatomical markers of schizophrenia because (1) the structural markers are already likely to be present, (2) early-onset patients may well be severely affected and (3) they present opportunities to follow-up cohorts throughout their lives. Young people presenting with suspected schizophrenia (but no other neurological or psychiatric disorder) to Child and Adolescent Psychiatrists in the former Oxford and South West Thames regions, were recruited as they presented and MR images of their brains were obtained soon afterwards. Following diagnosis ful®lling DSM-IV criteria [1], there were 17 patients (11 male, six female) with schizophrenia (mean age 16 years 11 months ^ 5 months SEM, range 14 years 10 months±20 years 5 months). Although the subjects with schizophrenia had received neuroleptic medication before they were scanned, none had received long-term treatment. Eight subjects (four male, four female) with no history of psychiatric or neurological illness, recruited as volunteers through general practitioners, served as normal controls. They were scanned at a mean age of 16 years 11 months ^ 7 months SEM (range 14
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 01 63 7- 8
164
D.C. Davies et al. / Neuroscience Letters 301 (2001) 163±166
years 0 months±18 years 4 months). Further individuals (six male, three female) without schizophrenia or any neurological abnormality, but presenting with a serious psychiatric illness, were scanned soon after presentation. According to DSM-IV criteria, these patients were suffering from major depressive disorders: with psychotic features (three), major depressive disorder (two); bipolar I disorder (two); bipolar II disorder (one) and psychotic disorder-drug induced (one). This psychiatric control group of patients had a mean age of 16 years 3 months ^ 6 months SEM (range 12 years 9 months±17 years 9 months) at scanning. All subjects in this study were in full-time, mainstream education prior to the onset of any illness, although one subject with schizophrenia had an IQ of 70 and another was described as having mild learning dif®culties. This study received approval from the Oxford Psychiatry Research Ethics Committee and the St George's Healthcare Ethics Committee. All subjects and their parents gave written informed consent. Magnetic resonance images (MRI) were obtained using a General Electric SIGNA 1.5 Tesla machine. The subject's chin was elevated so that the scanned volume was perpendicular to the long axis of the temporal lobe to minimise partial volume effects. Two initial scans were performed to ensure correct patient orientation, i.e. the anterior part of the genu of the corpus callosum and the clivus followed a vertical line. Coronal volumetric T1-weighted gradient-echo images (TE 5 ms, TR 35 ms, ®eld of view 20 £ 20 cm and 256 £ 256 image matrix) were employed. For the majority of subjects, the brain was covered by 60 slices of 3.0 mm thickness. The brains of four subjects were covered by 124 slices of 1.5 mm thickness. A MR scan was selected for each subject at the level of the mammillary bodies, where the fornices from each side of the brain were contiguous forming the body of the fornix, the long axis of which was orientated perpendicular to the plane of the coronal image. The cross-sectional outline of the body of the fornix was traced together with the small area of associated septum pellucidum on a computer monitor, using a mouse-driven cursor. The upper boundary of the septum pellucidum was taken to follow the natural curve of the corpus callosum. The cross-sectional area of the body of the fornix was then measured by planimetry using ANALYZE e software (Mayo Foundation) running on a Sun Sparc Station 2 computer. The measurement of each fornix was repeated three times, on each of three separate days and a mean value obtained from the nine measurements. All MR images were analysed `blind'. Statistical analysis of the data was performed by means of multivariate analysis of variance with the factors diagnosis, age at scanning and sex. The correlation between the crosssectional area of the body of the fornix and diagnosis was then investigated by multiple regression analysis. Multivariate analysis of variance revealed that there was a signi®cant effect of diagnosis on the mean cross-sectional area of the body of the fornix at the level of the mammillary bodies (F2;29 5:55, P 0:009). There was no signi®cant
effect of either age (F1;29 1:93, P 0:176) or sex (F1;29 1:11, P 0:301) on the mean cross-sectional area of the body of the fornix. Breaking down the data by diagnosis, multiple regression analysis revealed that the mean (^SEM) cross-sectional area of the body of the fornix of subjects with schizophrenia (17.78 ^ 0.81 mm 2) was signi®cantly larger (39.69%) than that of normal controls (12.73 ^ 1.04 mm 2; regression coef®cient, 4.88, P , 0:005). The mean cross-sectional area of the body of the fornix of subjects with schizophrenia was also signi®cantly larger (26.23%) than that of psychiatric controls (14.08 ^ 1.67 mm 2; regression coef®cient, 3.38, P , 0:036). There was no signi®cant difference between the mean cross-sectional area of the body of the fornix of normal control and psychiatric control subjects (regression coef®cient, 1.50, P . 0:417). The diagnosis, age at scanning, sex and cross-sectional area of the body of the fornix for each subject are given in Table 1. The ®nding that the mean cross-sectional area of the body Table 1 The cross-sectional area (mm 3) of the fornices of the subjects a Subject No.
Diagnosis
Sex
Age at Scan
X-sectional Area
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
S S S S S S S S S S S S S S S S S C C C C C C C C PC PC PC PC PC PC PC PC PC
M M M M F M M M F M F M F M F F M M M F F M F M F F M M F F M M M M
20.5 18.10 16.3 18.2 15.1 19.9 14.10 17.5 16.2 16.2 16.2 18.3 17.11 15.1 15.7 15.0 16.0 17.0 14.0 18.3 18.4 18.4 17.2 14.7 17.11 12.9 16.7 17.9 17.2 17.7 16.0 15.9 15.11 16.11
23.50 19.35 18.55 19.36 16.79 14.65 13.15 20.57 11.66 23.46 15.06 18.13 16.98 15.34 15.69 20.20 19.78 15.72 11.40 12.14 10.45 18.49 9.63 11.97 12.01 16.54 15.50 21.69 9.56 20.61 7.82 12.52 8.54 13.97
a
Subjects with schizophrenia (S), normal controls (C) and psychiatric controls (PC), measured from MR scans at the level of the mamillary bodies. Age at scan is given in years and months; M, male; F, female.
D.C. Davies et al. / Neuroscience Letters 301 (2001) 163±166
of the fornix in young people with schizophrenia was significantly larger than both those in normal control and psychiatric control subjects of a similar age, suggests a speci®c effect of schizophrenia rather than a non-speci®c effect of psychiatric illness. Drug-abuse was not a prominent feature of the subjects in this study, nor did it appear to be a factor in presenting. Although the subjects with schizophrenia had received some neuroleptic treatment before scanning, the fact that the subjects were scanned soon after presentation meant that this treatment was limited at the time of scanning. Thus, it is unlikely that drug-abuse or neuroleptic treatment contributed to the enlarged cross-sectional area of the fornices observed in patients with schizophrenia in the current study. The signal to noise ratios of both 1.5 mm and 3.0 mm MR images were such that the outline of the body of the fornix was clearly and similarly de®nable. No partial volume effects were apparent on any image measured. Magnetic resonance imaging studies have previously indicated that cortical volume in the mesial temporal cortex in the region of the rostral hippocampus is smaller in subjects with schizophrenia than in healthy subjects [7,8,17]. Moreover, the hippocampus itself has been reported to have a smaller volume in schizophrenia [6], due at least in part to a lower number of hippocampal pyramidal neurons [14,20]. Abnormal dendritic organisation [24] and aberrant orientation of hippocampal pyramidal neurons [12,22] have been reported to occur in schizophrenia. However, other authors [11] failed to replicate these ®ndings and concluded that hippocampal out¯ow through CA1 to the subiculum (and thence to widespread cortical and sub-cortical areas) is unaffected in schizophrenia. Cytoarchitectural abnormalities in the hippocampal formation appear to be more pronounced in CA3 and CA4 than in CA1 and the subicular complex [4,14]. Abnormalities in CA3 and CA4 may result in alterations in the output from these regions. The primary efferent axons from CA3 pyramids project into the fornix, while their Schaffer collaterals project to CA1. Cytoarchitectural abnormalities in CA3 could result in a failure of axonal collateral branching or in collaterals not following their normal trajectories, resulting in more axons in the fornix. CA3 projects via the precommissural fornix to the lateral septal nucleus and efferents from the septum project to the mediodorsal thalamic nucleus, which in turn projects widely to prefrontal cortex. An abnormal input to this system could have profound effects on cerebral function. Separation of the mediodorsal thalamus from the prefrontal cortex by sectioning the anterior limb of the anterior capsule in frontal lobotomy, results in behavioural changes (a reduction in interpersonal behaviour, emotional blunting and socially inappropriate behaviour) that resemble the negative symptoms of schizophrenia. It is also conceivable that an increased number of hippocampal efferents in the fornix may be driven by abnormalities in its target regions. Histological abnormalities in the septal nuclei [3], reduced size and neuronal number in the mediodorsal thalamic nucleus
165
[23] and reduced size of the prefrontal cortex [25] have all been reported to occur in schizophrenia and these de®ciencies may stimulate compensatory innervation by hippocampal efferents in the fornix. The fornix does not only carry hippocampal efferents. It also contains prominent inputs from the medial septal complex and the posterior hypothalamus. Thus, the possibility exists that an increased number of axons in the fornix could be due to an increased number of afferents, in an attempt to compensate for a dysfunctional hippocampal formation. However, since swollen neurons with granular accumulations (that are presumably degenerating) have been reported to be present in the septal nuclei in schizophrenia [3], this would seem to be unlikely. It is also unlikely that the greater mean cross-sectional area of the body of the fornix observed in the current study is due to gliosis, since there is little evidence that gliosis is a feature of schizophrenia (see [18]). The entorhinal cortex gives rise to the major cortical input to the hippocampal formation. It is also a major recipient of hippocampal out¯ow. The results of both neuropathology [9,14] and MR imaging studies [13,21] have revealed the parahippocampal/entorhinal area to be smaller than normal in schizophrenia. Abnormal lamina II pre-a neuron clusters and lower neuron densities have been reported to occur in the super®cial layers of the entorhinal cortex [2,19]. These lamina II pre-a neuron clusters were subsequently shown to be poorly developed and to lie at a deeper level within the cortex than in normal control subjects [15]. These authors suggested that the neuronal abnormalities they described were due to arrested migration, whereby neurons generated late in cortical development failed to reach the super®cial laminae and remained in the deeper laminae. Disruption of layer II of the entorhinal cortex would be likely to affect adversely the perforant path input to the hippocampal formation and pre-a neuron clusters lying at a deeper level than normal may also disrupt hippocampal output from the subiculum/CA1 to layer IV of the entorhinal cortex. Thus, the evidence suggests that the connections between the entorhinal cortex and the hippocampal formation are compromised in schizophrenia, resulting in impaired cortical input to the hippocampal formation. Furthermore, since the subicular complex projects to the anterior thalamic nuclear complex via the postcommissural fornix, this could result in a re-routing of some subicular efferents (normally destined for the entorhinal cortex) to join others in the fornix, thus contributing to its larger size in early-onset schizophrenia. The current results showing a larger cross-sectional area of the body of the fornix in early-onset schizophrenia are of importance because they are derived from a well-de®ned, relatively homogeneous group of subjects. A recent study of post-mortem material failed to ®nd any difference between adults with schizophrenia and an age-matched comparison group, in the cross-sectional area of the anterior columns of the fornix [10]. There are several possible reasons for this
166
D.C. Davies et al. / Neuroscience Letters 301 (2001) 163±166
discrepancy: (1) early-onset and adult-onset schizophrenia are different, (2) the larger fornix in early-onset schizophrenia does not persist into adulthood and (3) long-term drug treatment/substance abuse affects the size of the fornix. All of these possibilities require investigation and reinforce the need to study the structural abnormalities in the brains of populations of subjects with schizophrenia over time. The structural basis of the larger fornix in early-onset schizophrenia also requires investigation as it is not known whether it is due to a larger number/size of axons or to some other component of the fornix. Once the histological nature of the larger fornix and the population in which it occurs are known, then the functional signi®cance of the larger fornix in schizophrenia can be investigated more effectively. We thank Jeremy Turk for constructive criticism of the manuscript, Peter Hill for support of the project, Martin Graves and Maria Schmidt for expert assistance with the analysis of MR images. This work was supported by a grant from the Oxford Regional Health Authority. [1] American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th, American Psychiatric Press, Washington, DC, 1994, pp. 285±286. [2] Arnold, S.E., Hyman, B.T., Van Hoesen, G.W. and Damasio, A.R., Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia, Arch. Gen. Psychiatry, 48 (1991) 625±632. [3] Averback, P., Structural lesions of the brain in young schizophrenics, Can. J. Neurol. Sci., 8 (1981) 73±76. [4] Benes, F.M., Sorensen, I. and Bird, E.D., Reduced neuronal size in posterior hippocampus of schizophrenic patients, Schizophrenia Bull., 17 (1991) 597±608. [5] Bogerts, B., Meertz, E. and SchoÈnfeldt-Bausch, R., Basal ganglia and limbic system pathology in schizophrenia. A morphometric study of brain volume and shrinkage, Arch. Gen. Psychiatry, 42 (1985) 784±791. [6] Bogerts, B., Falkai, P., Haupts, M., Greve, B., Ernst, S., Tapernon-Franz, U. and Heinzmann, U., Post-mortem volume measurements of the limbic system and basal ganglia structures in chronic schizophrenics. Initial results from a new brain collection, Schizophrenia Res., 3 (1990) 295±301. [7] Bogerts, B., Lieberman, J.A., Ashtari, M., Bilder, R.M., DeGreef, G., Lerner, G., Johns, C. and Masiar, S., Hippocampus-amygdala volumes and psychopathology in chronic schizophrenia, Biol. Psychiatry, 33 (1993) 236±245. [8] Breier, A., Buchanan, R.W., Elkashef, A., Munson, R.C., Kirkpatrick, B. and Gellad, F., Brain morphology in schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures, Arch. Gen. Psychiatry, 49 (1992) 921±926. [9] Brown, R., Colter, N., Corsellis, J.A.N., Crow, T.J., Frith, C.D., Jagoe, R., Johnstone, E.C. and Marsh, L., Postmortem evidence of structural brain changes in schizophrenia. Differences in brain weight, temporal horn area, and parahippocampal gyrus compared with affective disorder, Arch. Gen. Psychiatry, 43 (1986) 36±42.
[10] Chance, S.A., Highley, J.R., Esiri, M.M. and Crow, T.J., Fiber content of the fornix in schizophrenia: lack of evidence for a primary limbic encephalopathy, Am. J. Psychiatry, 156 (1999) 1720±1724. [11] Christison, G.W., Casanova, M.F., Weinberger, D.R., Rawlings, R. and Kleinman, J.E., A quantitative investigation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia, Arch Gen. Psychiatry, 46 (1989) 1027±1032. [12] Conrad, A.J., Abebe, T., Austin, R., Forsythe, S. and Scheibel, A.B., Hippocampal pyramidal cell disarray in Schizophrenia as a bilateral phenomenon, Arch. Gen. Psychiatry, 48 (1991) 413±417. [13] DeLisi, L.E., Hoff, A.L., Schwartz, J.E., Shields, G.W., Halthore, S.N., Gupta, S.M. and Henn, F.A., Brain morphology in ®rst-episode schizophrenic-like psychotic patients: a quantitative magnetic resonance imaging study, Biol. Psychiatry, 29 (1991) 159±175. [14] Falkai, P. and Bogerts, B., Cell loss in the hippocampus of schizophrenics, Eur. Arch. Psychiatry Neurol. Sci., 236 (1986) 154±161. [15] Falkai, P. and Bogerts, B., Qualitative and quantitative assessment of pre-alpha-cell clusters in the entorhinal cortex of schizophrenics. A neurodevelopmental model of schizophrenia? Schizophrenia Res., 4 (1991) 357±360. [16] Falkai, P., Bogerts, B. and Rozmek, M., Limbic pathology in schizophrenia: the entorhinal region-a morphometric study, Biol. Psychiatry, 24 (1988) 515±521. [17] Fukuzako, H., Fukuzako, T., Hashiguchi, T., Hokazono, Y., Takeuchi, K., Hirakawa, K., Ueyama, K., Takigawa, M., Kajiya, Y., Nakajo, M. and Fujimoto, T., Reduction in hippocampal volume is caused mainly by its shortening in chronic schizophrenia: assessment by MRI, Biol. Psychiatry, 39 (1996) 938±945. [18] Harrison, P.J., On the neuropathology of schizophrenia and its dementia: neurodevelopmental, neurodegenerative, or both? Neurodegeneration, 4 (1995) 1±12. [19] Jacob, W. and Beckmann, H., Prenatal disturbances in the limbic allocortex in schizophrenics, J. Neur. Trans., 65 (1986) 303±326. [20] Jeste, D.V. and Lohr, J.B., Hippocampal pathologic ®ndings in schizophrenia. A morphometric study, Arch. Gen. Psychiatry, 46 (1989) 1019±1024. [21] Kawasaki, Y., Maeda, Y., Urata, K., Higashima, M., Yamaguchi, N., Suzuki, M., Takashima, T. and Ide, Y., A quantitative magnetic resonance imaging study of patients with schizophrenia, Eur. Arch. Psychiatry Clin. Neurosci., 242 (1993) 268±272. [22] Kovelman, J.A. and Scheibel, A.B., A neurohistological correlate of schizophrenia, Biol. Psychiatry, 19 (1984) 1601±1621. [23] Pakkenberg, B., Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics, Arch. Gen. Psychiatry, 47 (1990) 1023±1028. [24] Scheibel, A.B. and Kovelman, J.A., Disorientation of the hippocampal pyramidal cell and its processes in the schizophrenic patient, Biol. Psychiatry, 16 (1981) 101±102. [25] Seidman, L.J., Yurgelun-Todd, D., Kremen, W.S., Woods, B.T., Goldstein, J.M., Faraone, S.V. and Tsuang, M.T., Relationship of prefrontal and temporal lobe MRI measures to neuropsychological performance in chronic schizophrenia, Biol. Psychiatry, 35 (1994) 235±246.
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Enlargement of the fornix in early-onset schizophrenia: a quantitative MRI study D.C. Davies a,*, A.M.J. Wardell b, R. Woolsey a, A.C.D. James c a
Department of Anatomy and Developmental Biology, St George's Hospital Medical School, Cranmer Terrace, Tooting, London SW17 0RE, UK b Department of Child Mental Health, St. George's Hospital Medical School, London SW17 0RE, UK c The Warneford Hospital, Oxford OX3 7JX, UK Received 3 December 2000; accepted 29 January 2001
Abstract Abnormalities of temporal lobe structure and frontal lobe function occur in schizophrenia. There have been few studies of young people with schizophrenia and little is known about temporo-frontal connectivity in the disease. Therefore, the cross-sectional area of the body of the fornix was measured on MR images from 17 young people with schizophrenia, nine with other serious psychiatric illnesses and eight without illness. The mean age of each group was 16±17 years. The mean cross-sectional fornix area in subjects with schizophrenia was signi®cantly larger than that in subjects without illness (<40%) and psychiatric controls (<26%). There was no such signi®cant difference between subjects without illness and psychiatric controls. The nature of the larger fornix in early-onset schizophrenia, whether it persists and whether it occurs in schizophrenia presenting in adulthood, remain to be elucidated. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Early-onset schizophrenia; Fornix; Hippocampal formation; Limbic system; Prefrontal cortex
Post mortem studies have revealed reductions in hippocampal and parahippocampal gyrus volumes in schizophrenia [5,9]. Cytoarchitectural disarray and cell loss from these structures have also been reported to occur in the disease [4,14,16,19,22,24]. Such abnormalities alone are unlikely to be able to account directly for the wide variety of symptoms associated with schizophrenia, many of which appear to be prefrontal in origin. However, these hippocampal abnormalities may also affect the function of brain structures with which the hippocampal formation/parahippocampal gyrus are connected. The fornix is the major ®bre tract connecting the hippocampal formation with sub-cortical brain regions and provides an indirect connection between the hippocampal formation and the prefrontal cortex. It is a large discrete bundle that lends itself to in vivo measurement. The association between schizophrenia and the size of the fornix was therefore investigated in young people using magnetic resonance imaging (MRI). Early-onset schizophrenia (presentation between 13±18 years) is considered to be * Corresponding author. Tel.: 144-20-8725-5211; fax: 144-208725-3326. E-mail address: [email protected] (D.C. Davies).
phenomenologically and epidemiologically continuous with adult-onset schizophrenia. It is particularly attractive for investigation of the psychiatric, psychological and anatomical markers of schizophrenia because (1) the structural markers are already likely to be present, (2) early-onset patients may well be severely affected and (3) they present opportunities to follow-up cohorts throughout their lives. Young people presenting with suspected schizophrenia (but no other neurological or psychiatric disorder) to Child and Adolescent Psychiatrists in the former Oxford and South West Thames regions, were recruited as they presented and MR images of their brains were obtained soon afterwards. Following diagnosis ful®lling DSM-IV criteria [1], there were 17 patients (11 male, six female) with schizophrenia (mean age 16 years 11 months ^ 5 months SEM, range 14 years 10 months±20 years 5 months). Although the subjects with schizophrenia had received neuroleptic medication before they were scanned, none had received long-term treatment. Eight subjects (four male, four female) with no history of psychiatric or neurological illness, recruited as volunteers through general practitioners, served as normal controls. They were scanned at a mean age of 16 years 11 months ^ 7 months SEM (range 14
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 01 63 7- 8
164
D.C. Davies et al. / Neuroscience Letters 301 (2001) 163±166
years 0 months±18 years 4 months). Further individuals (six male, three female) without schizophrenia or any neurological abnormality, but presenting with a serious psychiatric illness, were scanned soon after presentation. According to DSM-IV criteria, these patients were suffering from major depressive disorders: with psychotic features (three), major depressive disorder (two); bipolar I disorder (two); bipolar II disorder (one) and psychotic disorder-drug induced (one). This psychiatric control group of patients had a mean age of 16 years 3 months ^ 6 months SEM (range 12 years 9 months±17 years 9 months) at scanning. All subjects in this study were in full-time, mainstream education prior to the onset of any illness, although one subject with schizophrenia had an IQ of 70 and another was described as having mild learning dif®culties. This study received approval from the Oxford Psychiatry Research Ethics Committee and the St George's Healthcare Ethics Committee. All subjects and their parents gave written informed consent. Magnetic resonance images (MRI) were obtained using a General Electric SIGNA 1.5 Tesla machine. The subject's chin was elevated so that the scanned volume was perpendicular to the long axis of the temporal lobe to minimise partial volume effects. Two initial scans were performed to ensure correct patient orientation, i.e. the anterior part of the genu of the corpus callosum and the clivus followed a vertical line. Coronal volumetric T1-weighted gradient-echo images (TE 5 ms, TR 35 ms, ®eld of view 20 £ 20 cm and 256 £ 256 image matrix) were employed. For the majority of subjects, the brain was covered by 60 slices of 3.0 mm thickness. The brains of four subjects were covered by 124 slices of 1.5 mm thickness. A MR scan was selected for each subject at the level of the mammillary bodies, where the fornices from each side of the brain were contiguous forming the body of the fornix, the long axis of which was orientated perpendicular to the plane of the coronal image. The cross-sectional outline of the body of the fornix was traced together with the small area of associated septum pellucidum on a computer monitor, using a mouse-driven cursor. The upper boundary of the septum pellucidum was taken to follow the natural curve of the corpus callosum. The cross-sectional area of the body of the fornix was then measured by planimetry using ANALYZE e software (Mayo Foundation) running on a Sun Sparc Station 2 computer. The measurement of each fornix was repeated three times, on each of three separate days and a mean value obtained from the nine measurements. All MR images were analysed `blind'. Statistical analysis of the data was performed by means of multivariate analysis of variance with the factors diagnosis, age at scanning and sex. The correlation between the crosssectional area of the body of the fornix and diagnosis was then investigated by multiple regression analysis. Multivariate analysis of variance revealed that there was a signi®cant effect of diagnosis on the mean cross-sectional area of the body of the fornix at the level of the mammillary bodies (F2;29 5:55, P 0:009). There was no signi®cant
effect of either age (F1;29 1:93, P 0:176) or sex (F1;29 1:11, P 0:301) on the mean cross-sectional area of the body of the fornix. Breaking down the data by diagnosis, multiple regression analysis revealed that the mean (^SEM) cross-sectional area of the body of the fornix of subjects with schizophrenia (17.78 ^ 0.81 mm 2) was signi®cantly larger (39.69%) than that of normal controls (12.73 ^ 1.04 mm 2; regression coef®cient, 4.88, P , 0:005). The mean cross-sectional area of the body of the fornix of subjects with schizophrenia was also signi®cantly larger (26.23%) than that of psychiatric controls (14.08 ^ 1.67 mm 2; regression coef®cient, 3.38, P , 0:036). There was no signi®cant difference between the mean cross-sectional area of the body of the fornix of normal control and psychiatric control subjects (regression coef®cient, 1.50, P . 0:417). The diagnosis, age at scanning, sex and cross-sectional area of the body of the fornix for each subject are given in Table 1. The ®nding that the mean cross-sectional area of the body Table 1 The cross-sectional area (mm 3) of the fornices of the subjects a Subject No.
Diagnosis
Sex
Age at Scan
X-sectional Area
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
S S S S S S S S S S S S S S S S S C C C C C C C C PC PC PC PC PC PC PC PC PC
M M M M F M M M F M F M F M F F M M M F F M F M F F M M F F M M M M
20.5 18.10 16.3 18.2 15.1 19.9 14.10 17.5 16.2 16.2 16.2 18.3 17.11 15.1 15.7 15.0 16.0 17.0 14.0 18.3 18.4 18.4 17.2 14.7 17.11 12.9 16.7 17.9 17.2 17.7 16.0 15.9 15.11 16.11
23.50 19.35 18.55 19.36 16.79 14.65 13.15 20.57 11.66 23.46 15.06 18.13 16.98 15.34 15.69 20.20 19.78 15.72 11.40 12.14 10.45 18.49 9.63 11.97 12.01 16.54 15.50 21.69 9.56 20.61 7.82 12.52 8.54 13.97
a
Subjects with schizophrenia (S), normal controls (C) and psychiatric controls (PC), measured from MR scans at the level of the mamillary bodies. Age at scan is given in years and months; M, male; F, female.
D.C. Davies et al. / Neuroscience Letters 301 (2001) 163±166
of the fornix in young people with schizophrenia was significantly larger than both those in normal control and psychiatric control subjects of a similar age, suggests a speci®c effect of schizophrenia rather than a non-speci®c effect of psychiatric illness. Drug-abuse was not a prominent feature of the subjects in this study, nor did it appear to be a factor in presenting. Although the subjects with schizophrenia had received some neuroleptic treatment before scanning, the fact that the subjects were scanned soon after presentation meant that this treatment was limited at the time of scanning. Thus, it is unlikely that drug-abuse or neuroleptic treatment contributed to the enlarged cross-sectional area of the fornices observed in patients with schizophrenia in the current study. The signal to noise ratios of both 1.5 mm and 3.0 mm MR images were such that the outline of the body of the fornix was clearly and similarly de®nable. No partial volume effects were apparent on any image measured. Magnetic resonance imaging studies have previously indicated that cortical volume in the mesial temporal cortex in the region of the rostral hippocampus is smaller in subjects with schizophrenia than in healthy subjects [7,8,17]. Moreover, the hippocampus itself has been reported to have a smaller volume in schizophrenia [6], due at least in part to a lower number of hippocampal pyramidal neurons [14,20]. Abnormal dendritic organisation [24] and aberrant orientation of hippocampal pyramidal neurons [12,22] have been reported to occur in schizophrenia. However, other authors [11] failed to replicate these ®ndings and concluded that hippocampal out¯ow through CA1 to the subiculum (and thence to widespread cortical and sub-cortical areas) is unaffected in schizophrenia. Cytoarchitectural abnormalities in the hippocampal formation appear to be more pronounced in CA3 and CA4 than in CA1 and the subicular complex [4,14]. Abnormalities in CA3 and CA4 may result in alterations in the output from these regions. The primary efferent axons from CA3 pyramids project into the fornix, while their Schaffer collaterals project to CA1. Cytoarchitectural abnormalities in CA3 could result in a failure of axonal collateral branching or in collaterals not following their normal trajectories, resulting in more axons in the fornix. CA3 projects via the precommissural fornix to the lateral septal nucleus and efferents from the septum project to the mediodorsal thalamic nucleus, which in turn projects widely to prefrontal cortex. An abnormal input to this system could have profound effects on cerebral function. Separation of the mediodorsal thalamus from the prefrontal cortex by sectioning the anterior limb of the anterior capsule in frontal lobotomy, results in behavioural changes (a reduction in interpersonal behaviour, emotional blunting and socially inappropriate behaviour) that resemble the negative symptoms of schizophrenia. It is also conceivable that an increased number of hippocampal efferents in the fornix may be driven by abnormalities in its target regions. Histological abnormalities in the septal nuclei [3], reduced size and neuronal number in the mediodorsal thalamic nucleus
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[23] and reduced size of the prefrontal cortex [25] have all been reported to occur in schizophrenia and these de®ciencies may stimulate compensatory innervation by hippocampal efferents in the fornix. The fornix does not only carry hippocampal efferents. It also contains prominent inputs from the medial septal complex and the posterior hypothalamus. Thus, the possibility exists that an increased number of axons in the fornix could be due to an increased number of afferents, in an attempt to compensate for a dysfunctional hippocampal formation. However, since swollen neurons with granular accumulations (that are presumably degenerating) have been reported to be present in the septal nuclei in schizophrenia [3], this would seem to be unlikely. It is also unlikely that the greater mean cross-sectional area of the body of the fornix observed in the current study is due to gliosis, since there is little evidence that gliosis is a feature of schizophrenia (see [18]). The entorhinal cortex gives rise to the major cortical input to the hippocampal formation. It is also a major recipient of hippocampal out¯ow. The results of both neuropathology [9,14] and MR imaging studies [13,21] have revealed the parahippocampal/entorhinal area to be smaller than normal in schizophrenia. Abnormal lamina II pre-a neuron clusters and lower neuron densities have been reported to occur in the super®cial layers of the entorhinal cortex [2,19]. These lamina II pre-a neuron clusters were subsequently shown to be poorly developed and to lie at a deeper level within the cortex than in normal control subjects [15]. These authors suggested that the neuronal abnormalities they described were due to arrested migration, whereby neurons generated late in cortical development failed to reach the super®cial laminae and remained in the deeper laminae. Disruption of layer II of the entorhinal cortex would be likely to affect adversely the perforant path input to the hippocampal formation and pre-a neuron clusters lying at a deeper level than normal may also disrupt hippocampal output from the subiculum/CA1 to layer IV of the entorhinal cortex. Thus, the evidence suggests that the connections between the entorhinal cortex and the hippocampal formation are compromised in schizophrenia, resulting in impaired cortical input to the hippocampal formation. Furthermore, since the subicular complex projects to the anterior thalamic nuclear complex via the postcommissural fornix, this could result in a re-routing of some subicular efferents (normally destined for the entorhinal cortex) to join others in the fornix, thus contributing to its larger size in early-onset schizophrenia. The current results showing a larger cross-sectional area of the body of the fornix in early-onset schizophrenia are of importance because they are derived from a well-de®ned, relatively homogeneous group of subjects. A recent study of post-mortem material failed to ®nd any difference between adults with schizophrenia and an age-matched comparison group, in the cross-sectional area of the anterior columns of the fornix [10]. There are several possible reasons for this
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discrepancy: (1) early-onset and adult-onset schizophrenia are different, (2) the larger fornix in early-onset schizophrenia does not persist into adulthood and (3) long-term drug treatment/substance abuse affects the size of the fornix. All of these possibilities require investigation and reinforce the need to study the structural abnormalities in the brains of populations of subjects with schizophrenia over time. The structural basis of the larger fornix in early-onset schizophrenia also requires investigation as it is not known whether it is due to a larger number/size of axons or to some other component of the fornix. Once the histological nature of the larger fornix and the population in which it occurs are known, then the functional signi®cance of the larger fornix in schizophrenia can be investigated more effectively. We thank Jeremy Turk for constructive criticism of the manuscript, Peter Hill for support of the project, Martin Graves and Maria Schmidt for expert assistance with the analysis of MR images. This work was supported by a grant from the Oxford Regional Health Authority. [1] American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th, American Psychiatric Press, Washington, DC, 1994, pp. 285±286. [2] Arnold, S.E., Hyman, B.T., Van Hoesen, G.W. and Damasio, A.R., Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia, Arch. Gen. Psychiatry, 48 (1991) 625±632. [3] Averback, P., Structural lesions of the brain in young schizophrenics, Can. J. Neurol. Sci., 8 (1981) 73±76. [4] Benes, F.M., Sorensen, I. and Bird, E.D., Reduced neuronal size in posterior hippocampus of schizophrenic patients, Schizophrenia Bull., 17 (1991) 597±608. [5] Bogerts, B., Meertz, E. and SchoÈnfeldt-Bausch, R., Basal ganglia and limbic system pathology in schizophrenia. A morphometric study of brain volume and shrinkage, Arch. Gen. Psychiatry, 42 (1985) 784±791. [6] Bogerts, B., Falkai, P., Haupts, M., Greve, B., Ernst, S., Tapernon-Franz, U. and Heinzmann, U., Post-mortem volume measurements of the limbic system and basal ganglia structures in chronic schizophrenics. Initial results from a new brain collection, Schizophrenia Res., 3 (1990) 295±301. [7] Bogerts, B., Lieberman, J.A., Ashtari, M., Bilder, R.M., DeGreef, G., Lerner, G., Johns, C. and Masiar, S., Hippocampus-amygdala volumes and psychopathology in chronic schizophrenia, Biol. Psychiatry, 33 (1993) 236±245. [8] Breier, A., Buchanan, R.W., Elkashef, A., Munson, R.C., Kirkpatrick, B. and Gellad, F., Brain morphology in schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures, Arch. Gen. Psychiatry, 49 (1992) 921±926. [9] Brown, R., Colter, N., Corsellis, J.A.N., Crow, T.J., Frith, C.D., Jagoe, R., Johnstone, E.C. and Marsh, L., Postmortem evidence of structural brain changes in schizophrenia. Differences in brain weight, temporal horn area, and parahippocampal gyrus compared with affective disorder, Arch. Gen. Psychiatry, 43 (1986) 36±42.
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