Section of Cognitive Psychopharmacology, Institute of Psychiatry, London
Correspondence: Dr Dominic Fannon, Department of Psychiatry, Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK. Tel: 020 7919 2066; fax: 020 7252 3172; e-mail: d.fannon{at}iop.kcl.ac.uk
Declaration of interest Financially supported by Grosvenor House Group Estates and Psychmed Ltd.
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ABSTRACT |
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Aims To investigate the developmental correlates of ventricular enlargement.
Method Information on childhood development and magnetic resonance images in 1.5-mm contiguous sections were collected on 21 patients experiencing a first episode of psychosis.
Results Patients (n=21) had significantly less whole brain volume and enlarged third and lateral ventricles compared to controls (n=25). Third ventricle (r=0.48, P<0.03) and lateral ventricle (r=0.65, P<0.01) volumes correlated with developmental score. Patients with developmental delay had significantly larger third and lateral ventricles than those without.
Conclusions Enlargement of both third and lateral ventricles is found in first-episode psychosis and is related to developmental delay in childhood. Insult to periventricular areas is relevant to the neurobiology of the disease. These findings support the view that schizophrenia involves disturbance of neurodevelopmental processes in some patients.
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INTRODUCTION |
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METHOD |
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Subjects who had a DSM-IV diagnosis of substance abuse or dependence, mental retardation, neurological disorder or had a medical condition that may affect brain structure or function were excluded from the study. In addition, control subjects were excluded if there was a personal history of any Axis I or II disorder or a family history of psychosis. Symptom measures were performed using the Positive and Negative Syndrome Scale (PANSS; Kay et al, 1987). Detailed childhood developmental information was collected from the mothers of 21 patients (15 men and 6 women) using the schedule outlined in Table 1. Classification of developmental status was a priori. Developmental delay was deemed present if developmental score was either 1 (problems reported by mothers in one or more areas but no professional advice sought) or 2 (professional advice sought by mother or referral to educational psychologist or speech therapist by school for at least one of the above')). Those patients with no developmental problems reported by mother were classified as having no developmental delay. Developmental information was not available for the remaining 16 patients, whose mothers did not consent or were not contactable. Ethical approval was obtained from the Bethlem and Maudsley Ethics Committee (Research). After a complete description of the proposed study was discussed with each participant, written informed consent was obtained.
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Image acquisition
Magnetic resonance imaging (MRI) scanning was performed on a 1.5-T G.E.
Signa system at the Maudsley Hospital, London. Initially, a series of sagittal
and axial scout views were acquired to correct for head tilt and to localise
imaging coordinates. Next, the whole brain was scanned with a
three-dimensional inversion-recovery-prepared fast-spoiled GRASS (SPGR)
T1-weighted data-set. These T1-weighted images were obtained in the axial
plane with 1.5-mm contiguous sections; TR was 11.3 ms, TI was 300 ms, TE was
2.2 ms and the flip angle was 20° with one data average and a 256 x
256 x 128 pixel matrix.
Measurements
Brain images were reoriented parallel to the anterior
commissureposterior commissure (AC-PC) line and the interhemispheric
fissure prior to measurement. Volumetric measurements were obtained by
stereological assessment using the MEASURE program
(Barta et al, 1997).
All ratings were performed (by A.S. and J.L.) blind to diagnosis, with high
interrater and intrarater reliability. Intraclass correlations ranged from
0.95 to 0.99 for measurements of whole brain and lateral and third
ventricles.
Regions of interest
The lateral ventricular volume was that bounded anteriorly by the frontal
lobe, medially by the septum pellucidum, intraventricular foramen and corpus
callosum and posteriorly by the occipital lobe. The third ventricular volume
was that bounded by the anterior commissure, the fornix, the stria medullaris,
the pineal body, the superior and inferior colliculi, the midbrain and
mamillary body, the thalamus and hypothalamus. Whole brain volume was measured
as the area defined as the entire brain excluding ventricles, cerebrospinal
fluid, cerebellum, dura mater and brainstem.
Statistical analysis
Data analysis was performed using the Statistical Package for the Social
Sciences (SPSS). Chi-squared analyses were used to look for differences in
socio-economic status, handedness and gender distribution. Analyses of
variance (ANOVAs) were used to examine for differences in age, years of
education and height. Comparisons of regional volumes between groups were
performed using the General Linear Model in SPSS. The ANOVA used whole brain
volume or ventricular volume as dependent variables and height, age, gender
and diagnosis as independent variables. Age was used to control for possible
age-related changes in the subjects
(Cowell et al, 1994).
Height was used as the independent variable to control for body and head size.
Covariation with height alone did not change our findings. Height, instead of
total brain volume, was used because it has been shown to be a predictor of
general head size (Andreasen et
al, 1994b). Covarying for height has been used
previously in MRI studies of schizophrenia
(Bilder et al, 1994;
Tibbo et al, 1998)
and depression (Sheline et al,
1999). Spearman's correlations were used to test for relationships
between ventricular volumes and developmental scores. All analyses used a
two-tailed estimation of significance, P<0.05 was regarded as
significant.
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RESULTS |
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Follow-up comparisons between patients with and without developmental delay showed significantly greater third ventricular (F=5.3, P<0.03) and lateral ventricular (F=11.9, P<0.01) enlargement in those with a history of childhood developmental delay (see Table 3). There were no group differences in positive (F=0.05, P<0.32) or negative (F=0.08, P<0.78) symptom scores or age of onset (F=0.48, P<0.50).
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DISCUSSION |
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We set out to test the hypothesis that MRI-detected structural abnormality in schizophrenia is related to the preclinical course of the illness by investigating the developmental correlates of ventricular enlargement. We examined a group of subjects with adult-onset psychosis early in their first episode on whom information regarding childhood development was available. The neurodevelopmental model of schizophrenia attributes its cause to early disturbance of brain development before the presentation of psychotic symptoms. Therefore, the patient group was examined for differences in maternally recalled delay in developmental milestones. Those with a history of delayed development were compared with those without in terms of volumes of lateral and third ventricles. Ventricular volumes were used because they provide the most consistent evidence of structural abnormality in schizophrenia. The analysis reported here included only three brain regions because developmental information was not available on all subjects and the smallest possible number of regions of interest was chosen for analysis. The larger patient group had, in addition, significant deficits in cortical grey matter, temporal lobe grey matter and reduced thalamic volume. Future publications will report on these findings in more detail. Ventricular abnormality is the most robust structural finding in schizophrenia, although the third ventricle has been studied to a lesser extent. Therefore, investigation of the structural correlates of developmental delay was conducted with reference to ventricular volumes alone.
The results of our study indicate that enlargement of the third and lateral ventricles is present close to the onset of schizophrenia and is not attributable to the effects of the illness itself or to treatment. Our findings lend support to the view that schizophrenia involves disturbance of neurodevelopmental processes in some patients. The integration of MRI findings and premorbid findings may thus provide a greater understanding of the aetiology and pathogenesis of schizophrenia. Essentially, our findings are consistent with a neurodevelopmental model of schizophrenia involving localised periventricular deficiency of critical neuronal pathways. We suggest that maldevelopment of such pathways may be evidenced initially by delayed achievement of developmental milestones in association with ventricular enlargement and later by the emergence of psychotic symptoms.
Specificity of findings
Developmental delay was not correlated exclusively with either third or
lateral ventricular volume. Both lateral and third ventricular volumes showed
a significant association with the developmental measure. The absence of a
specific association between third ventricle volume and a measure of
developmental delay may be interpreted in a number of ways. First, contrary to
previous reports (Bornstein et al,
1992), third ventricle enlargement may not be a more specific
finding in schizophrenia relative to lateral ventricle enlargement. Such a
finding in previous studies may have been confounded by inconsistent
measurement of ventricular volumes or atypical patient samples. Jones et
al (1994b) have
suggested that third ventricle enlargement may be more specific to affective
psychosis than schizophrenia or schizoaffective psychosis. Second, specific
associations may exist between third and lateral ventricle volumes and
disparate aetiological factors in schizophrenia, but these processes may not
have an impact on the developmental characteristics measured in this study.
Third, our study may have lacked sufficient power to detect a true difference
in the relationships between third and lateral periventricular pathology and
developmental aspects of the early prepsychotic phase of the illness. Our
findings are consistent with a common periventricular mechanism affecting both
third and lateral ventricles and associated with developmental disturbance in
childhood. Abnormality in periventricular structures early in childhood may
result in both ventricular enlargement and disturbed development, perhaps
owing to aberrant development of proximate neural pathways. This discussion
focuses on the significance of third ventricle abnormality.
Behaviour and cognition
Previous computed tomography (CT) studies have shown contradictory findings
in relation to third ventricle changes and are of uncertain clinical
relevance. However, in this study we show preliminary evidence that among
patients with first-episode psychosis, enlargement of ventricles detected in
adulthood is related to developmental delay in childhood. This is consistent
with earlier work showing that behavioural abnormalities in childhood,
analogous to negative schizophrenic symptomatology, are associated with third
ventricle widening in people who have a high genetic risk of the illness
(Dykes et al, 1992).
Third ventricle enlargement has been shown to be correlated significantly with
poor neuropsychological performance (especially on tests of frontal lobe
function, attention and concentration) and may be found in a more severely ill
subgroup of patients (Bornstein et
al, 1992).
Genetics
The possible aetiological significance of third ventricle abnormality is
evident in the results of family studies. Sharma et al
(1997) have shown
significantly increased third ventricle volume in obligate carriers among
families multiply affected with schizophrenia. Keshavan et al
(1997) demonstrated that
first-degree relatives of patients with schizophrenia have enlarged third
ventricles. More recent work has shown enlargement of the third ventricle to
be correlated with epithalamus calcifications and cortical atrophy, suggestive
of a lesion of the third periventricular region
(Caputo et al, 1998).
The origin of this finding is suggested by the association of third
ventricular pathology with the absence of the adhesio interthalamica in
first-episode patients, indicative of early developmental disturbance
(Snyder et al,
1998).
Neurodevelopmental disorder
An association between ventricular enlargement and developmental delay in
childhood is consistent with a neurodevelopmental disorder and in keeping with
other lines of evidence pointing to disturbance of normal brain maturation in
schizophrenia. Such evidence includes the first presentation of illness
typically occurring in adolescence or early adulthood and the presence of
structural and functional abnormalities close to or prior to the onset of
illness. Similarly, premorbid intellectual deficits
(Jones et al,
1994a) point to early developmental disturbance, as do
minor physical anomalies (Lane et
al, 1997) and markers of aberrant prenatal growth
(Davis & Bracha, 1996). The finding of more normal third and lateral ventricle volumes,
relative to controls, in those patients without a history of developmental
delay is consistent with a model of schizophrenia that includes
neurodevelopmental and non-developmental sub-types
(Murray et al, 1992).
The most plausible interpretation of our findings is that abnormality of
periventricular brain structure and associated childhood developmental
disturbance are both attributable to altered neurological development much
earlier in life. Paus et al
(1999) reported evidence for
protracted structural maturation of fibre pathways supporting motor and speech
functions during childhood and adolescence. The proposed model hypothesises
that insult to neurodevelopment results in a lesion to periventricular brain
structure and malfunction of cognitive and neurological function presenting as
developmental delay in childhood.
Periventricular lesion?
Magnetic resonance imaging findings have not been generalised to all
patients with schizophrenia and structural abnormalities may arise through
different mechanisms. With regard to ventricular enlargement, no consistent
correlation has been demonstrated between the degree of enlargement and loss
of contiguous brain volume. This may be explained by the limitations of
current methods of measurement or by the involvement of independent
pathological processes in the disease. It may also be due to disproportionate
volume loss in localised, periventricular structures
(Harrison, 1999). Disturbance
of the autonomic nervous system (ANS) has been shown to be associated with
negative symptom schizophrenia (Frith
et al, 1979) and with widening of the third ventricle
(Cannon et al, 1988).
Widening of the third ventricle has been shown to be associated with negative
symptoms (Andreasen et al,
1982). It has been suggested, therefore, that damage to the third
periventricular area (which accommodates ANS centres) is involved in the
neurobiology of schizophrenia (Dykes
et al, 1992). Third ventricle enlargement may be
indicative of disruption of cortico-striato-thalamo-cortical circuitry
critical to limbic functioning (Bornstein
et al, 1992) or cortico-subcortical feedback circuits
(Caputo et al, 1998).
Such a model of the disorder is consistent with the view that vulnerability to
and expression of schizophrenia are dependent on the disturbance of a number
of interconnected brain systems (Bullmore
et al, 1997).
The nature of the putative insult to periventricular areas is subject to debate. The critical process may relate to axon diameter or myelination or to excessive neuronal pruning. Defects in limbic circuits may account for aberrant functioning, evident as symptoms of schizophrenia such as disruption of higher cognitive processing (attention and memory as well as changes in drive, motility and affect). Diencephalic structures close to or bordering on the third ventricle are prominent relays in the limbic pathways. Third ventricle enlargement may index abnormalities of these surrounding structures. Abnormality of cortico-striato-thalamic circuits caused by loss of cortical efferents or caudate volume might account for lateral ventricular enlargement because frontal and temporal horns are adjacent to limbic circuits. Sensorimotor pathways may be more specifically affected by pathology surrounding the lateral ventricles. Abnormal development of such pathways provides a possible explanation for the findings of our study.
Our data support a model of increased ventricular volume secondary to reduced periventricular matter caused by a lesion of cortico-subcortical circuitry. The specific cause of these deficits is unclear but is evidenced in the cognitive and psychotic features of the disease. A relationship between both lateral and third ventricle volumes and developmental delay may reflect abnormal function in those periventricular pathways serving higher cognitive processes required for normal neurological and psychosocial functioning. Pathways involving midline structures may be especially susceptible in schizophrenia, as indicated by previous work and highlighted by the results of the current study.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication December 14, 1999. Revision received May 18, 2000. Accepted for publication May 18, 2000.