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Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia
Open accessAbstract
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.
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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.
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Claims the paper makes
107 Not checked yet · 23 Own interpretation · 1 Own method · 1 No basis given
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
What the sources say
- Not checked yetcites [70]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
What the sources say
- Not checked yetcites [70]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“These differences were over and above differences in cortical folding across the entire left hemisphere.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
What the sources say
- Not checked yetcites [61]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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]”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [16]
- Not checked yetcites [99]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“There was no difference in the rate of change between the chronic schizophrenia and control groups”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [113]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Following the first episode of schizophrenia, there was a subtle but highly significant degree of surface contraction in frontal (particularly dorsolateral prefrontal) and parietal regions of the cortex in both cerebral hemispheres relative to the changes seen in healthy controls.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [113]
plaincorrelationaln = 16 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Further, the rate of gray matter retraction was significantly associated with proximity to the transition point to psychosis.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [173]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“However, first-episode schizophreniform patients and the UHR groups had normal hippocampal size.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [160]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Some support from our own data in our UHR sample is that, regardless of subsequent diagnosis, there was a smaller volume of hippocampus in those with a negative family history of psychosis and schizophrenia, suggesting that an early nongenetic insult may be relevant in making this region vulnerable.78”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [78]
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“In contrast, all the schizophrenia patients had normal amygdala size.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [160]
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- It may state two separate claims as one. 59
- Probably not a substantial claim. 4
- The quote only partly states this claim. 3
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
What the sources say
- Not checked yetcites [61]
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
What the sources say
- Not checked yetcites [78]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
What the sources say
- Not checked yetcites [70]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [113]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [113]
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [17]
- Not checked yetcites [154]
plainn = 75- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [153]
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [173]
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [160]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“As before, patients with chronic schizophrenia had bilaterally smaller hippocampi, while first-episode schizophrenia patients had smaller left hippocampi.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [160]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [159]
plaincorrelationaln = 31- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [177]
plainn = 24- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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]”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
What the sources say
- Not checked yetcites [17][18]
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [92]
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [13]
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
- Rests on an assumption: Brain and skull growth are complete early in life before the onset of schizophrenia.
None of the sources cited for this claim have been checked yet.
In the paper
“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]”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [83][84][85][86][87]
- Not checked yetcites [88][89]
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
What the sources say
- Not checked yetcites [73]
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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).”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [99]
plaincorrelationaln = 27- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [93][94][95][96][97][98][99][100]
plainn = 50- Asserted: passes — The authors put it forward as true.
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In the paper
“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]”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Introduction
What the sources say
- Not checked yetcites [1][2][3]
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“cerebral volume (which is often used to derive measures of anatomical brain asymmetry) is influenced by a number of factors throughout life, 55”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Neuroimaging Markers of an Early Neurodevelopmental Insult
What the sources say
- Not checked yetcites [55]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites 16,86,[101][102][103][104][105][106]
- Not checked yetcites [16]
- Not checked yetcites [101]
- Not checked yetcites [107]
- Not checked yetcites [102]
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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] ).”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [114][115][116]
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“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”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [103]
plainn = 24- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [108]
plaincorrelationaln = 20- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [103]
plaindirectn = 24- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [117][118]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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 ).”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [127]
- Not checked yetcites [131]
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [105]
plaindirectn = 34- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Clinical outcome was correlated with the brain changes identified, and, importantly, cerebral gray matter reduction correlated with cumulative dose of antipsychotics between scans.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [105]
plaincorrelationaln = 34- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [99]
- Not checked yetcites [104]
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [99]
- Not checked yetcites [108]
- Not checked yetcites [102]
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Whole brain volume was smaller in patients; however, there were no progressive changes identified for whole brain or CSF volumes.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [108]
plainn = 20- Asserted: passes — The authors put it forward as true.
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In the paper
“Higher dose of medication was associated with greater volume reduction in the frontal and temporal lobes in first-episode but not previously treated patients.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [108]
plaincorrelationaln = 20- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [108]
plainn = 20- Asserted: passes — The authors put it forward as true.
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In the paper
“They have found increases in cortical sulcal CSF and frontal sulcal CSF as well as shrinkage of frontal lobe tissue.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [106]
plaindirectn = 73- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [106]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [108]
plainn = 20- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [91]
- Not checked yetcites [132]
- Not checked yetcites [137]
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [16]
plaincorrelationaln = 107- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [146]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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]”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [1]
- Not checked yetcites [109]
- Not checked yetcites [110]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“This pattern of loss was associated with expected patterns of psychotic symptoms and cognitive deficits.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
What the sources say
- Not checked yetcites [142]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in First-Episode Psychosis and Established Schizophrenia
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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]”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [147]
- Not checked yetcites [148]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The available evidence suggests that neuropsychological functions are not progressive after illness onset and may improve.[185][186][187][188][189]”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Conclusions and Future Directions
What the sources say
- Not checked yetcites [185]
- Not checked yetcites [186]
- Not checked yetcites [187]
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Importantly, their subjects were all neuroleptic naı ¨ve, indicating that medication does not explain these changes.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [18]
hedgedn = 65- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Conclusions and Future Directions
What the sources say
- Not checked yetcites [202]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“years 1-5 ventricular change correlated with age at FH”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Conclusions and Future Directions
What the sources say
- Not checked yetcites DeLisi et al., 2004
plaincorrelationaln = 27- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Structural Imaging Studies in Prodromal/High-Risk Individuals
What the sources say
- Not checked yetcites [18]
hedgedconditionaln = 8- Asserted: passes — The authors put it forward as true.
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In the paper
“as indicated by evidence for accelerated loss of gray matter and aberrant connectivity particularly in prefrontal regions”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Conclusions and Future Directions
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“frontal lobe temporal lobe CSF”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Conclusions and Future Directions
What the sources say
- Not checked yetcites Bachmann et al., 2004
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“These include genes important for brain development, apoptosis, myelination, regulation of synaptic plasticity, G-protein-coupled neurotransmission, and other factors.[22][23]204”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Conclusions and Future Directions
What the sources say
- Not checked yetcites [22]
- Not checked yetcites [23]
- Not checked yetcites [204]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Conclusions and Future Directions
What the sources say
- Not checked yetcites [22]
- Not checked yetcites [23]
- Not checked yetcites [204]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Conclusions and Future Directions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structural Brain Imaging Evidence for Multiple Pathological Processes at Different Stages of Brain Development in Schizophrenia > Conclusions and Future Directions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Moreover, some of the schizophreniarelated changes in gray 8,9 and white matter 10 are progressive in nature.”
From Physical exercise keeps the brain connected: biking increases white matter integrity in patients with schizophrenia and healthy controls. (2015) · cites this paper as [8]
Citations
Cites
Part of this paper’s reference list could not be split into single entries.
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Metadata
- 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
- 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
- bronze
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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