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

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.”

What the sources say

• Not checked yetcites [61]

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.”

What the sources say

• Not checked yetcites [78]

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.”

What the sources say

• Not checked yetcites [70]

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.”

What the sources say

• Not checked yetcites [113]

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.”

What the sources say

• Not checked yetcites [113]

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).”

What the sources say

• Not checked yetcites [17]
• Not checked yetcites [154]

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.”

What the sources say

• Not checked yetcites [153]

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.”

What the sources say

• Not checked yetcites [173]

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.”

What the sources say

• Not checked yetcites [160]

In the paper

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

What the sources say

• Not checked yetcites [160]

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).”

What the sources say

• Not checked yetcites [159]

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”

What the sources say

• Not checked yetcites [177]

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.”

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]”

What the sources say

• Not checked yetcites [17][18]

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.”

What the sources say

• Not checked yetcites [92]

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.”

What the sources say

• Not checked yetcites [13]

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]”

What the sources say

• Not checked yetcites [83][84][85][86][87]
• Not checked yetcites [88][89]

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”

What the sources say

• Not checked yetcites [73]

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).”

What the sources say

• Not checked yetcites [99]

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.”

What the sources say

• Not checked yetcites [93][94][95][96][97][98][99][100]

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]”

What the sources say

• Not checked yetcites [1][2][3]

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”

What the sources say

• Not checked yetcites [55]

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”

What the sources say

• Not checked yetcites 16,86,[101][102][103][104][105][106]
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• Not checked yetcites [101]
• Not checked yetcites [107]
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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] ).”

What the sources say

• Not checked yetcites [114][115][116]

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”

What the sources say

• Not checked yetcites [103]

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.”

What the sources say

• Not checked yetcites [108]

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.”

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.”

What the sources say

• Not checked yetcites [103]

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.”

What the sources say

• Not checked yetcites [117][118]

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 ).”

What the sources say

• Not checked yetcites [127]
• Not checked yetcites [131]

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”

What the sources say

• Not checked yetcites [105]

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.”

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.”

What the sources say

• Not checked yetcites [105]

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.”

What the sources say

• Not checked yetcites [99]
• Not checked yetcites [104]

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.”

What the sources say

• Not checked yetcites [99]
• Not checked yetcites [108]
• Not checked yetcites [102]

In the paper

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

What the sources say

• Not checked yetcites [108]

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.”

What the sources say

• Not checked yetcites [108]

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”

What the sources say

• Not checked yetcites [108]

In the paper

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

What the sources say

• Not checked yetcites [106]

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.”

What the sources say

• Not checked yetcites [106]

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.”

What the sources say

• Not checked yetcites [108]

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”

What the sources say

• Not checked yetcites [91]
• Not checked yetcites [132]
• Not checked yetcites [137]

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.”

What the sources say

• Not checked yetcites [16]

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.”

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”

What the sources say

• Not checked yetcites [146]

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]”

What the sources say

• Not checked yetcites [1]
• Not checked yetcites [109]
• Not checked yetcites [110]

In the paper

“This pattern of loss was associated with expected patterns of psychotic symptoms and cognitive deficits.”

What the sources say

• Not checked yetcites [142]

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.”

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.”

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]”

What the sources say

• Not checked yetcites [147]
• Not checked yetcites [148]

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.”

In the paper

“The available evidence suggests that neuropsychological functions are not progressive after illness onset and may improve.[185][186][187][188][189]”

What the sources say

• Not checked yetcites [185]
• Not checked yetcites [186]
• Not checked yetcites [187]

In the paper

“Importantly, their subjects were all neuroleptic naı ¨ve, indicating that medication does not explain these changes.”

What the sources say

• Not checked yetcites [18]

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”

What the sources say

• Not checked yetcites [202]

In the paper

“years 1-5 ventricular change correlated with age at FH”

What the sources say

• Not checked yetcites DeLisi et al., 2004

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.”

What the sources say

• Not checked yetcites [18]

In the paper

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

In the paper

“frontal lobe temporal lobe CSF”

What the sources say

• Not checked yetcites Bachmann et al., 2004

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”

What the sources say

• Not checked yetcites [22]
• Not checked yetcites [23]
• Not checked yetcites [204]

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.”

What the sources say

• Not checked yetcites [22]
• Not checked yetcites [23]
• Not checked yetcites [204]

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.”

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.”