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Cited by 573Schizophrenia research and treatmentMental Health and PsychiatryNeural and Behavioral Psychology Studies

Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia

Open access
Pantelis, C.·2005·Schizophrenia Bulletin
DOI 10.1093/schbul/sbi034
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Abstract

The underlying neurobiology of emerging psychotic disorders is not well understood. While there is evidence from structural imaging and other studies supporting the popular notion that schizophrenia arises as a consequence of an "early neurodevelopmental" lesion, more recent findings challenge this notion. Evidence, including our own data, suggests that dynamic brain changes occur during the earliest stages of a psychotic illness, including around the time of transition to illness. In this article we review the available longitudinal and relevant cross-sectional structural neuroimaging studies focusing on both the very early neurodevelopmental markers (pre- or perinatal origin) and the later markers (late neurodevelopmental) around the period of transition to illness. Based on our review of recent findings, we suggest that the onset of psychosis is a time of active brain changes, wherein, for a proportion of individuals, (i) an early (pre- and perinatal) neurodevelopmental lesion renders the brain vulnerable to anomalous late (particularly postpubertal) neurodevelopmental processes, as indicated by evidence for accelerated loss of gray matter and aberrant connectivity particularly in prefrontal regions; and (ii) these anomalous neurodevelopmental processes interact with other causative factors associated with the onset of psychosis (e.g., substance use, stress, and dysregulation of the hypothalamic-pituitary-adrenal axis function), which together have neuroprogressive sequelae involving medial temporal and orbital prefrontal regions, as suggested by imaging studies around transition to active illness. However, the pathological processes underlying such progressive changes during "late neurodevelopment" remain unclear but may reflect anomalies of synaptic plasticity, abnormal brain maturation, the adverse effects of stress, or other environmental factors. In this context, the features of schizophrenia, including the neuropsychological deficits and behavioral manifestations, can be understood as direct effects of these multiple pathological processes at various neurodevelopmental stages, including genetic and nongenetic etiological factors.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that schizophrenia reflects multiple pathological processes across different neurodevelopmental stages, not a single static early lesion. It synthesizes longitudinal and cross-sectional structural imaging evidence for early pre/perinatal vulnerability, anomalous late postpubertal development, and active brain changes around psychosis onset.

Key findings

  • Longitudinal MRI studies consistently show progressive ventricular enlargement and brain volume reductions in schizophrenia; the authors’ first-episode psychosis cohort showed whole-brain volume reduction at 1–2% per year, with no change in temporal or hippocampal volumes.
  • In first-episode schizophrenia, cortical surface contraction was found in frontal (especially dorsolateral prefrontal) and parietal regions; the pattern was similar to controls but amplified by a factor of almost 3, while chronic schizophrenia showed no difference from controls.
  • In ultra-high-risk (UHR) individuals followed through transition, both UHR-P and UHR-NP showed left cerebellar gray matter reduction, but UHR-P additionally showed reductions in left inferior frontal, left medial temporal (parahippocampal/fusiform), and bilateral cingulate regions.
  • Pituitary volume, an HPA-axis index, was 12% larger at baseline in UHR subjects who later developed psychosis (p = .001), and psychosis risk increased by 20% for every 10% increase in baseline pituitary volume (p = .002); first-episode patients had 10% larger pituitaries, while chronic schizophrenia patients had 17% smaller pituitaries.

Methods

  • Narrative review of longitudinal and relevant cross-sectional structural neuroimaging studies in schizophrenia and early psychosis, including a detailed summary of the authors’ own cohort work; Table 1 summarizes recent longitudinal MRI/CT studies.
  • Own datasets include a UHR cohort of 63 males compared with 75 healthy males, with 21 UHR subjects developing psychosis over 12 months; a larger hippocampal/amygdala study of 473 subjects (89 chronic schizophrenia, 162 first-episode psychosis, 135 UHR, 87 controls); and longitudinal first-episode/chronic/control samples.
  • Main analyses across cited studies include region-of-interest volumetry, voxel-based morphometry, cortical surface contraction/expansion mapping, and pituitary, hippocampal, and amygdala volume measurements.

Limitations

  • The paper states that longitudinal studies generally have small samples, especially controls; methodologies vary; illness stages examined are limited; many “first-episode” patients have already been ill for years; medication remains a confounding factor; substance use is often not accounted for; and clinical heterogeneity complicates interpretation.
  • The paper also notes that the initial cross-sectional UHR-P finding may reflect sampling and may not be representative of the whole pre-psychotic population, and that follow-up periods may be inadequate to detect some changes.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis, with no formal search strategy or quality assessment, and several cited findings are preliminary, unpublished, or from heterogeneous cohorts.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/schbul/sbi034

Cites

215 of 215 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 157 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    There was no difference in any ACC morphological measures between UHR subjects who subsequently developed psychosis and those who did not.

    “However, there was no difference in any of the ACC mor-phological measures between those UHR subjects who subsequently developed a psychosis and those who did not.”
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  • Findingown data

    The normal leftward bias in paracingulate folding observed in healthy controls was not observed in the UHR group.

    “The pattern of paracingulate folding again showed the ''normal'' leftward bias in the healthy controls, which (akin to the case for chronically ill patients) was not observed in the UHR group.”
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  • Findingown data

    The ACC folding differences were over and above differences in cortical folding across the entire left hemisphere.

    “These differences were over and above differences in cortical folding across the entire left hemisphere.”
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  • Findingown data

    No change was found in temporal or hippocampal volumes in our own longitudinal study.

    “No change was found in temporal or hippocampal volumes, consistent with a number of studies, 16,99 although reductions in parts of the temporal lobe, specifically the superior temporal gyrus, have been reported in other studies during the early course of the illness.15,[56][57]”
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  • Findingown data

    There is no difference in the rate of cortical change between chronic schizophrenia and control groups.

    “There was no difference in the rate of change between the chronic schizophrenia and control groups”
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  • Classified as probably not a substantial claim. 4
  • The quote only partly states this claim. 3

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    Findingown data

    Compared with controls, male patients with schizophrenia were less likely to show the normal leftward ACC sulcal asymmetry, explained by reduced gyral folding in the left ACC.

    “Compared with controls, male patients with schizophrenia were less likely to show the ''normal'' leftward ACC sulcal asymmetry, which was explained by reduced gyral folding in the left ACC.”
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    Findingcitation

    Compared with UHR individuals having a positive family history of schizophrenia, those without a family history had significantly smaller left hippocampal volume and a trend toward anomalous left cingulate morphology, with reduced paracingulate folding and more cingulate sulcus interruptions.

    “Compared with the UHR group having a positive family history of schizophrenia, those without a family history had significantly smaller left hippocampal volume and a trend toward anomalous left cingulate morphology, with reduced paracingulate folding and more cingulate sulcus interruptions.”
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    Findingown data

    Compared with healthy controls, the UHR group was more likely to have interruptions in the course of the cingulate sulcus and less likely to have a well-developed paracingulate sulcus in the left hemisphere.

    “Compared with healthy controls, the UHR group was more likely to have interruptions in the course of the cingulate sulcus and less likely to have a well-developed paracingulate sulcus in the left hemisphere.”
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    Findingcitation

    The pattern of cortical change was very similar in all 3 groups but was amplified by a factor of almost 3 in both hemispheres in the first-episode patients.

    “The pattern of change was very similar in all 3 groups but was amplified by a factor of almost 3 in both hemispheres in the first-episode patients.”
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    Findingown data

    In our own longitudinal study over 1-4 years, progressive reduction in whole brain volume was identified in patients at a rate of 1-2% per year but not control subjects.

    “By examining the rate of change in volumes over the variable follow-up period, progressive reduction in whole brain volume was identified in patients (at a rate of 1-2% per year) but not control subjects.”
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    Findingcitation

    In the UHR-P group, an additional 3 regions of the left hemisphere were reduced: a left inferior frontal region, a left medial temporal region including the parahippocampal gyrus and fusiform gyrus, and the cingulate bilaterally.

    “However, in the UHR-P group, an additional 3 regions of the left hemisphere were reduced (a left inferior frontal region, a left medial temporal region that included the parahippocampal gyrus and the fusiform gyrus, and the cingulate bilaterally).”
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    Findingcitation

    In the first Melbourne study, UHR-NP individuals had smaller left hippocampal volumes at intake and were more similar to first-episode psychosis subjects, while UHR-P individuals did not differ from a comparable normal sample.

    “Contrary to expectation, it was the UHR-NP who had smaller left hippocampal volumes at intake (and were more similar to first-episode psychosis subjects), while the UHR-P group did not differ from a comparable normal sample.”
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    Findingcitation

    In the Melbourne study, accelerated gray matter retraction was identified in UHR-P individuals over the transition to psychosis in the same regions as in first-episode patients, with additional retraction in orbital-prefrontal regions.

    “In this study, we have identified accelerated gray matter retraction in UHR-P individuals over the transition to psychosis in the same regions as in first-episode patients, although there was additional retraction in orbital-prefrontal regions, consistent with the earlier findings.”
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    Findingown data

    In the larger Melbourne study, hippocampi were of normal size in patients with affective psychoses or psychosis not otherwise specified, while amygdala volumes were significantly larger in this group.

    “Further, hippocampi were of normal size in patients with affective psychoses or psychosis not otherwise specified, while amygdala volumes were significantly larger in this group.”
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    Findingown data

    In a larger Melbourne study, patients with chronic schizophrenia had bilaterally smaller hippocampi, while first-episode schizophrenia patients had smaller left hippocampi.

    “As before, patients with chronic schizophrenia had bilaterally smaller hippocampi, while first-episode schizophrenia patients had smaller left hippocampi.”
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    Findingcitation

    In never-medicated UHR individuals, UHR-P subjects had a significantly larger (12%) baseline pituitary volume compared with UHR-NP subjects, while UHR-NP subjects had smaller pituitaries (6%) compared with control subjects.

    “UHR subjects who later went on to develop psychosis (UHR-P, n = 31) had a significantly larger (þ12%; p = .001)baseline pituitary volume compared with UHR-NP subjects, while the latter also had smaller pituitaries compared with control subjects (ÿ6%; p = .032).”
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    Findingcitation

    In the first study, first-episode patients showed a 10% increase in pituitary size compared with 59 normal controls, while chronic schizophrenia patients had a 17% smaller pituitary.

    “In the first study we found that in comparison with 59 normal controls, first-episode patients (n = 24) showed a 10% increase in the size of the pituitary, while the pituitary in chronic schizophrenia patients (n = 51) was 17% smaller, 177”
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    Interpretationnone given

    The nature of any structural abnormalities observed in adulthood, after illness onset, may depend on an interaction between the nature of the insult and the neurodevelopmental stage of the fetus from early gestation to birth.

    “However, an issue not adequately dealt with in the available literature is that the nature of any structural abnormalities observed in adulthood, after illness onset, may depend on an interaction between the nature of the insult and the neurodevelopmental stage of the fetus from early gestation to birth.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning

    These findings are consistent with the notion of an early insult of nongenetic origin and may render this region susceptible to later progressive changes.

    “These findings are consistent with the notion of an early insult of nongenetic origin and may render this region susceptible to later progressive changes as shown recently in longitudinal volumetric studies in high-risk subjects.[17][18]”
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    Premisecitation

    Early longitudinal studies are equivocal regarding progressive brain changes in schizophrenia, while better-controlled and more sophisticated studies conducted more recently have more consistently, though not universally, demonstrated such change.

    “While the early longitudinal studies are equivocal regarding progressive brain changes in schizophrenia, 92 the better-controlled and more sophisticated studies conducted more recently have more consistently (though not universally) demonstrated such change.”
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    Interpretationcitation

    The presence of enlarged cerebrospinal fluid spaces, particularly extracerebral CSF, together with findings of reduced brain tissue volume in schizophrenia suggests that progressive changes are occurring, as brain and skull growth are complete early in life before the onset of schizophrenia.

    “As eloquently argued by Woods, 13 the presence of enlarged cerebrospinal fluid (CSF) spaces, particularly extracerebral CSF, together with findings of reduced brain tissue volume in schizophrenia suggests that progressive changes are occurring, as brain and skull growth are complete early in life before the onset of schizophrenia.”
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    • Rests on an assumption: Brain and skull growth are complete early in life before the onset of schizophrenia.

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    Premisecitation

    Enlargement of the CSF spaces is evident from illness onset, with further progressive changes suggested in cross-sectional studies.

    “Enlargement of the CSF spaces is evident from illness onset, [83][84][85][86][87] with further progressive changes suggested in cross-sectional studies.[88][89]”
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    Premisecitation

    The paracingulate sulcus is a tertiary sulcus and is less likely to be under genetic control, as suggested by twin studies of sulci and gyri.

    “Further, the paracingulate sulcus is a tertiary sulcus and is therefore less likely to be under genetic control, as suggested by twin studies of sulci and gyri.73”
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    Premisecitation

    In DeLisi et al. 10-year follow-up, further ventricular enlargement was observed, and increased size of ventricles was associated with better outcome.

    “In their 10-year follow-up study, 99 further ventricular enlargement was observed, and, surprisingly, the increased size of ventricles was associated with better outcome (see below).”
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    Premisecitation

    In DeLisi et al. initial follow-up studies to 5 years, progressive changes were reported in ventricular enlargement, decreased volume of both cerebral hemispheres, the cerebellum, and the corpus callosum, but smaller brain regions such as the amygdalo-hippocampal complex, the caudate nuclei, and the temporal lobes showed no change.

    “In their initial follow-up studies to 5 years, progressive changes were reported in a number of brain regions, including ventricular enlargement, as well as decreased volume of both cerebral hemispheres, the cerebellum, and the corpus callosum, but smaller brain regions such as the amygdalo-hippocampal complex, the caudate nuclei, and the temporal lobes showed no change.”
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    • cites [93][94][95][96][97][98][99][100]

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    Premisecitation

    Schizophrenia is associated with structural brain abnormalities, with the most consistent findings being enlarged lateral ventricles and reduced medial temporal and prefrontal lobe volumes.

    “It is now generally accepted that schizophrenia is associated with structural brain abnormalities, with the most consistent findings being enlarged lateral ventricles and reduced medial temporal and prefrontal lobe volumes.[1][2][3]”
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  • Classified as probably not a substantial claim.

    Premisecitation

    Cerebral volume is influenced by a number of factors throughout life.

    “cerebral volume (which is often used to derive measures of anatomical brain asymmetry) is influenced by a number of factors throughout life, 55”
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    Premisecitation

    Expansion of ventricles is reported consistently in more recent longitudinal MRI studies, though such changes may be more relevant to subgroups of patients or relevant to their clinical state.

    “Several other longitudinal MRI studies (see table 1) have also focused on the ventricular system, and expansion of ventricles is reported consistently in the more recent work, 16,86,[101][102][103][104][105][106] though such changes may be more relevant to subgroups of patients 16,101,107 or relevant to their clinical state.102”
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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    It remains possible that inverse correlations between progressive structural changes and better outcome are explained by effects of medication in reducing symptoms as well as being causative in producing brain structural abnormalities.

    “However, though studies have attempted to control for the effects of medication statistically, it remains possible that these inverse correlations are explained by the effects of medication in reducing symptoms as well as being causative in producing brain structural abnormalities, as demonstrated recently (e.g., [114][115][116] ).”
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    Premisecitation

    Mathalon et al. found similar findings in frontal lobe regions but additional change in temporal lobes of patients in their 4-year follow-up comparing 24 male patients with chronic schizophrenia with 25 controls.

    “Mathalon et al. have identified similar findings in frontal lobe regions but found additional change in the temporal lobes of patients in their 4-year follow-up study comparing 24 male patients with chronic schizophrenia with 25 controls.103”
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    Premisecitation

    Reductions in frontal and temporal volumes were associated with improvement in some symptoms, including delusions and thought disorder, with temporal lobe reduction being the main unique predictor of clinical improvement.

    “The relationship with symptoms was more complex but showed parallels with the findings above, in which reductions in frontal and temporal volumes were associated with improvement in some symptoms, including delusions and thought disorder, with temporal lobe reduction being the main unique predictor of clinical improvement.”
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    Interpretationreasoning

    Variability in longitudinal MRI findings probably relates to relatively small samples (especially for controls), differences in stages of illness (with very few studies at the very earliest phase), and important differences in age that may mask changes related to brain maturation.

    “The studies also demonstrate variability in findings, which probably relates to relatively small samples, especially for controls; differences in stages of illness, with very few studies at the very earliest phase of schizophrenia; and important differences in age, which may mask changes related to brain maturation in patients and controls.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Patients showed faster volume decrease in right frontal gray matter and bilateral posterior superior temporal gray matter and faster CSF volume increases in the right frontal sulci, left lateral ventricle, and bilateral prefrontal and posterior superior temporal sulci.

    “Patients showed faster volume decrease in right frontal gray matter and bilateral posterior superior temporal gray matter and faster CSF volume increases in the right frontal sulci, left lateral ventricle, and bilateral prefrontal and posterior superior temporal sulci.”
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    Study design and conductcitation

    Studies have not taken account of the high rate of alcohol or substance use in schizophrenia, though abuse of these substances is usually an exclusion criterion.

    “Studies have also not taken account of the high rate of alcohol or substance use in schizophrenia, [117][118] though abuse of these substances is usually an exclusion criterion.”
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    Interpretationreasoning

    The subvoxel-level methodology allowed subtle changes to be detected, which may explain the lack of significant findings in some follow-up studies using region of interest or other methods.

    “However, it should be noted that the methodology allowed examination at a subvoxel level, thereby allowing subtle changes to be detected, which may explain the lack of significant findings in some follow-up studies using region of interest or other methods (e.g., 127,131 ).”
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    Premisecitation

    Cahn et al. report reductions in total brain volume and cerebral gray matter and ventricular enlargement in 34 first-episode schizophrenic patients and 36 healthy comparison participants over a 1-year follow-up.

    “Similar to our study, Cahn et al. report reductions in total brain volume and cerebral gray matter and ventricular enlargement in their study of 34 firstepisode schizophrenic patients and 36 healthy comparison participants over a 1-year follow-up.105”
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  • May combine two claims.

    Interpretationreasoning

    Taken together, longitudinal MRI studies consistently demonstrate ventricular volume increases and brain volume reductions in schizophrenia, with evidence for cortical gray matter loss, possibly involving specific brain regions, particularly the prefrontal and temporal lobe cortices.

    “Taken together these longitudinal MRI studies are consistent in demonstrating ventricular volume increases and brain volume reductions in schizophrenia, with evidence for cortical gray matter loss, possibly involving specific brain regions, particularly the prefrontal and temporal lobe cortices.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Clinical outcome was correlated with the brain changes identified, and cerebral gray matter reduction correlated with cumulative dose of antipsychotics between scans.

    “Clinical outcome was correlated with the brain changes identified, and, importantly, cerebral gray matter reduction correlated with cumulative dose of antipsychotics between scans.”
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    Premisecitation

    Longitudinal studies examining global changes provide consistent evidence for progressive changes, with enlargement of CSF spaces over at least the first 10 years of illness and brain volume loss.

    “While longitudinal studies examining global changes provide consistent evidence for progressive changes, with enlargement of CSF spaces over at least the first 10 years of illness 99,104 and brain volume loss, increasingly, studies are focusing on specific brain regions in more detail.”
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    Premisecitation

    Some studies show an inverse relationship indicating that progressive structural changes are associated with better outcome, while Garver et al. identified clinical state-related changes in ventricles and brain volume.

    “The possibility of a relationship to clinical symptoms or outcome is intriguing, though this relationship seems complex, with some studies showing an inverse relationship indicating that progressive structural changes are associated with better outcome, 99,108 while Garver et al. 102 have identified clinical state-related changes in ventricles and brain volume.”
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    Premisecitation

    Whole brain volume was smaller in patients; however, there were no progressive changes identified for whole brain or CSF volumes.

    “Whole brain volume was smaller in patients; however, there were no progressive changes identified for whole brain or CSF volumes.”
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    Premisecitation

    Higher dose of medication was associated with greater volume reduction in the frontal and temporal lobes in first-episode but not previously treated patients.

    “Higher dose of medication was associated with greater volume reduction in the frontal and temporal lobes in first-episode but not previously treated patients.”
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    Premisecitation

    In Gur et al. longitudinal MRI study, both patient groups had smaller volumes of frontal and temporal lobes at intake, more pronounced on the left.

    “In their longitudinal MRI study of 20 first-episode and 20 previously treated patients with schizophrenia compared with 17 control subjects, Gur and colleagues have found that both patient groups had smaller volumes of frontal and temporal lobes at intake, more pronounced on the left.108”
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    Premisecitation

    In a 3-year follow-up study, Ho and colleagues found increases in cortical sulcal CSF and frontal sulcal CSF as well as shrinkage of frontal lobe tissue in patients with recent-onset schizophrenia compared with normal controls.

    “They have found increases in cortical sulcal CSF and frontal sulcal CSF as well as shrinkage of frontal lobe tissue.”
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    Premisecitation

    In Ho and colleagues' study, patients with poor outcome had greater lateral ventricular expansion, while negative symptom severity and poorer executive functions were related to frontal measures of reduced volume.

    “Patients with poor outcome had greater lateral ventricular expansion, while negative symptom severity and poorer executive functions were related to frontal measures of reduced volume.”
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    Premisecitation

    Temporal lobe reduction was greater in first-episode than previously treated patients, but reduction in temporal lobes was more pronounced in controls than in patients.

    “Temporal lobe reduction was greater in first-episode than previously treated patients, but, surprisingly, the reduction in temporal lobes was more pronounced in controls than in patients, a finding that requires further study.”
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    Interpretationcitation

    The findings of a similar but accelerated pattern of brain volume loss in early schizophrenia are in accord with emerging evidence of normal gray matter volume changes during adolescence and early adulthood and of greater changes in young patients with childhood-onset schizophrenia.

    “Our findings, demonstrating a similar but accelerated pattern of brain volume loss in early schizophrenia, are in accord with the emerging evidence of normal gray matter volume changes occurring during adolescence and early adulthood 91,[132][133][134][135][136] and of greater changes in young patients with childhood-onset schizophrenia.137”
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    Premisecitation

    Lieberman et al. 12-month follow-up found larger ventricles and smaller hippocampi at illness onset, and further ventricular enlargement longitudinally in poor outcome patients.

    “Consistent with findings in other studies, larger ventricles and smaller hippocampi were identified at illness onset, and further ventricular enlargement was observed longitudinally in poor outcome patients.”
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    Interpretationown data

    Prior to psychosis onset and in recently developed schizophreniform psychosis, hippocampal volumes are normal, while with greater illness duration smaller volumes are found, initially on the left and later bilaterally.

    “The important finding here is that prior to psychosis onset and in recently developed schizophreniform psychosis, the hippocampal volumes are normal, while with greater illness duration smaller volumes are found, initially on the left and later bilaterally.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Initial results from the Edinburgh MRI studies include reduced volume of the amygdala-hippocampal complex in presymptomatic cases compared with controls (though not as small as in first-episode schizophrenia) and smaller thalamus compared with controls.

    “Initial results from the MRI studies during various stages of recruitment include findings of reduced volume of the amygdala-hippocampal complex in presymptomatic cases compared with controls, though not as small as in FES, and smaller thalamus compared with controls.146”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146]

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  • May combine two claims.

    Interpretationown data

    Findings of smaller hippocampi in schizophrenia were confirmed and are consistent with other studies including meta-analyses.

    “Thus, findings of smaller hippocampi in schizophrenia were confirmed, and these results are consistent with those of other studies including meta-analyses.1,[109][110]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1]

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    • cites [109]

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    • cites [110]

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  • The quote only partly states this claim.

    Premisecitation

    The pattern of gray matter loss in childhood-onset schizophrenia was associated with expected patterns of psychotic symptoms and cognitive deficits.

    “This pattern of loss was associated with expected patterns of psychotic symptoms and cognitive deficits.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Active brain changes may be occurring throughout the early years of psychosis, and the nature and location of brain change may depend on the interaction between the disease process and normal brain development.

    “Thus, active brain changes may be occurring throughout the early years of psychosis, and the nature and location of brain change may depend on the interaction between the disease process and normal brain development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The findings of an accelerated process of gray matter loss over the first few years of onset of schizophrenia may be understood as reflecting aberrant maturation during adolescence or an interaction of early neurodevelopmental insult with the processes of maturation around the time of illness onset in adolescence and early adulthood.

    “In this context, our findings of an accelerated process of gray matter loss over the first few years of onset of schizophrenia may be understood as reflecting aberrant maturation during adolescence or an interaction of early neurodevelopmental insult with the processes of maturation around the time of illness onset in adolescence and early adulthood.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    VBM studies of these groups confirmed the findings and also identified reductions in anterior cingulate, medial prefrontal, and parahippocampal gray matter volumes, with greater reductions observed in the first-episode schizophrenia group.

    “Voxel-based morphometry (VBM) studies of these groups have confirmed these findings and also identified reductions in anterior cingulate, medial prefrontal, and parahippocampal gray matter volumes, with greater reductions observed in the FES group.[147][148]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [147]

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    • cites [148]

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  • May combine two claims.

    Interpretationreasoning

    The findings challenge the traditional early neurodevelopmental insult theory and raise questions about the possible relationship of progressive changes during late neurodevelopment to any such proposed early neurodevelopmental insult affecting medial temporal structures.

    “Our findings challenge the traditional early neurodevelopmental insult theory and raise questions about the possible relationship of progressive changes during late neurodevelopment (in adolescence) to any such proposed early neurodevelopmental insult affecting medial temporal structures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The available evidence suggests that neuropsychological functions are not progressive after illness onset and may improve.

    “The available evidence suggests that neuropsychological functions are not progressive after illness onset and may improve.[185][186][187][188][189]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [185]

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    • cites [186]

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    • cites [187]

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  • May combine two claims.

    Study design and conductcitation

    In the Edinburgh high-risk study, subjects were all neuroleptic naive, indicating that medication does not explain the changes.

    “Importantly, their subjects were all neuroleptic naı ¨ve, indicating that medication does not explain these changes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18]

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    Premisecitation

    In a Finnish birth cohort study, Cannon and colleagues found that fetal hypoxia is associated with gray matter changes and extracerebral CSF enlargement in patients and siblings but not in control subjects, while only patients showed this relationship with ventricular enlargement.

    “For example, in their study of patients, unaffected siblings, and controls, derived from a Finnish birth cohort, Cannon and colleagues have found that fetal hypoxia is associated with gray matter changes and extracerebral CSF enlargement in patients and siblings but not in control subjects, while only patients showed this relationship with ventricular enlargement.202”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202]

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    Premisecitation

    In 26/27 first-episode schizophrenia patients compared with 10 controls, left lateral ventricle changed over years 1-10 and years 5-10; years 1-5 ventricular change correlated with age at familial high risk, years 5-10 ventricular change correlated with hospitalization time, greater ventricular change correlated with better outcome, right temporal reduction correlated with age at familial high

    “years 1-5 ventricular change correlated with age at FH”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites DeLisi et al., 2004

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  • May combine two claims.

    Interpretationcitation

    These changes are broadly similar to those observed in the Melbourne group's data, identify changes in hippocampus as well as other temporal lobe regions, and suggest that these changes may be occurring up to 2 years before onset of illness.

    “These changes are broadly similar to those observed in the Melbourne group's data; however, these findings identify changes in hippocampus as well as other temporal lobe regions and, further, suggest that these changes may be occurring up to 2 years before onset of illness.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18]

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  • May combine two claims.

    Interpretationcitation

    There is evidence for accelerated loss of gray matter and aberrant connectivity particularly in prefrontal regions.

    “as indicated by evidence for accelerated loss of gray matter and aberrant connectivity particularly in prefrontal regions”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In 14 first-episode schizophrenia/schizoaffective/schizophreniform patients (no controls for longitudinal comparisons), frontal lobe increased by 2.3% per year and temporal lobe increased by 3.3% per year, and correlations were not found.

    “frontal lobe temporal lobe CSF”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bachmann et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These genes include genes important for brain development, apoptosis, myelination, regulation of synaptic plasticity, G-protein-coupled neurotransmission, and other factors.

    “These include genes important for brain development, apoptosis, myelination, regulation of synaptic plasticity, G-protein-coupled neurotransmission, and other factors.[22][23]204”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22]

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    Premisecitation

    Recent molecular biological findings suggest that multiple genes influence brain maturational processes at different stages of brain development and may act as modulators in the emergence and progression of psychosis.

    “For example, recent molecular biological findings suggest that multiple genes influence brain maturational processes at different stages of brain development and may act as modulators in the emergence and progression of psychosis.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22]

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    • cites [23]

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    • cites [204]

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  • May combine two claims.

    Interpretationreasoning

    While an early neurodevelopmental lesion may be acting in a proportion of patients subsequently developing schizophrenia, it does not fully explain the active changes occurring during the earliest stages of the illness.

    “The implications of these findings are that, while an early neurodevelopmental lesion may be acting in a proportion of patients subsequently developing schizophrenia, it does not fully explain the active changes occurring during the earliest stages of the illness.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These interacting processes together have neuroprogressive sequelae that may be neurodegenerative, involving medial temporal and orbital prefrontal regions.

    “which together have neuroprogressive sequelae that may be neurodegenerative, involving medial temporal and orbital prefrontal regions, as suggested by imaging studies around transition to active illness.”
    Quote in the paperSubstantial claim
62 of 62

  • The paper relies on this without support.

    Brain and skull growth are complete early in life before the onset of schizophrenia.

    “as brain and skull growth are complete early in life before the onset of schizophrenia.”

  • The paper relies on this without support.

    The patterns of sulci and gyri are essentially fixed early in life.

    “Given that the patterns of sulci and gyri are essentially fixed early in life”
2 of 2

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Cites

Part of this paper’s reference list could not be split into single entries.

Flagged first, then by citations

Research works printed but not linked: 7

  1. Lawrie SM, Abukmeil SS. Brain abnormality in schizophre- nia: a systematic and quantitative review of volumetric mag- netic resonance imaging studies. Brit J Psychiat 1998; 172:110-120.
  2. Weinberger DR. From neuropathology to neurodevelop- ment. Lancet 1995;346:552-557.
  3. McCarley RW, Hirayasu Y, Salisbury DF, et al. Left poste- rior superior temporal gyrus: progressive gray matter vol- ume reduction in schizophrenia. Schizophr Res 1999; 36:204-205.
  4. Oppenheimer DR. Diseases of the basal ganglia, cerebellum, and motor neurons. In: Adams JH, Corsellis JAN, Duchen LW, eds. Greenfield's Neuropathology. 4th ed. New York: John Wiley and Sons; 1984:699-747.
  5. Welker W. Why does the cerebral cortex fissure and fold? a review of determinants of gyri and sulci. In: Jones EG, Peters A, eds. Cerebral Cortex: Comparative Structure and Evolution of Cerebral Cortex. New York: Plenum Press; 1990:3-126.
  6. Worthen NJ, Gilbertson V, Lau C. Cortical sulcal develop- ment seen on sonography: relationship to gestational param- eters. J Ultras Med 1986;5(3):153-156.
  7. Weinberger DR, McClure RK. In reply: neurotoxicity, neu- roplasticity, and magnetic resonance imaging morphometry. Arch Gen Psychiat 2003;60(8):848-849.

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Related

Authors
Pantelis, C.
Affiliations
The Royal Melbourne Hospital (AU)
Corresponding author
Pantelis, C.
ORCID
Pantelis, C.
Venue
Schizophrenia Bulletin
Publisher
Oxford University Press (OUP)
Published
2005-07-27
Volume
31
Issue
3
Pages
672-696
ISSN
  • 0586-7614 (ISSN-L)
  • 1745-1707
DOI
10.1093/schbul/sbi034
OpenAlex
W2106970452
Semantic Scholar
0962d3a84337e875b96fa30efbed91c4c1e19922
Cited by
573
References
215
Citations by year
2026: 4 · 2025: 12 · 2024: 12 · 2023: 12 · 2022: 20 · 2021: 24 · 2020: 17 · 2019: 14 · 2018: 13 · 2017: 27 · 2016: 31 · 2015: 32 · 2014: 33 · 2013: 26 · 2012: 36
FWCI
4.67
Type
journal article
Language
en
Open access
Locations
  • Schizophrenia Bulletin (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • Deakin Research Online (Deakin University) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Science Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • David and Elaine Potter Foundation
  • Australian Agency for International Development
  • Ian Potter Foundation
  • Australasian Society for Psychiatric Research
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (145627)
  • University of Melbourne
  • Medical Research Council
  • National Health and Medical Research Council (252777, 209062, 350241, 970391, 145627, 981112, 145737, 236175, 299966, 970598)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords
schizophrenia, brain development
MeSH terms
Brain, Humans, Magnetic Resonance Imaging, Puberty, Radiography, Risk Factors, Schizophrenia, Disease Progression, Fetal Development

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