Abnormal cortical folding in high-risk individuals: a predictor of the development of schizophrenia?

doi:10.1016/j.biopsych.2004.04.007

Biological Psychiatry

Volume 56, Issue 3, 1 August 2004, Pages 182-189

https://doi.org/10.1016/j.biopsych.2004.04.007 Get rights and content

Abstract

Background

A number of studies have found localized differences in the appearance and extent of cortical folding between the brains of schizophrenic patients and healthy control subjects. This study aimed to determine whether, within individuals at genetic high risk for schizophrenia, there are pre-existing differences in gyral folding between those who subsequently develop the disease and those who remain unaffected.

Methods

Assessment was conducted on baseline magnetic resonance imaging scans of 30 young adults grouped into 14 who remained unaffected and 16 who subsequently developed schizophrenia. The gyrification index (GI), the ratio of the inner and outer cortical surface contours, was measured bilaterally on every second 1.88-mm image slice in four specifically defined lobar regions. Independent t tests and volume and genetic liability correlations were conducted for each region, followed by a post hoc examination.

Results

Right prefrontal lobe GI values were significantly increased in individuals who subsequently developed schizophrenia. Post hoc examination suggested that the areas of greatest increase lay anteriorly and laterally in Brodmann areas 9 and 10. Correlations with volume and analysis of covariance suggested some overlap between GI and volume measures.

Conclusions

Differences in frontal lobe GI might reflect disturbed or abnormal connectivity predictive of subsequent schizophrenia.

Section snippets

Participants

The study participants were all individuals taking part in the Edinburgh High Risk Study, a prospective, longitudinal study of young people with at least two first- or second-degree relatives affected with schizophrenia. Participants were initially recruited at age 16–25 years so that they would pass through the age of greatest risk of schizophrenia in the following 5–10 years. Details of the recruitment process have been described previously (Hodges et al., 1999, Johnstone et al., 2000). In

Results

Table 2 shows the mean GI values for both groups in all examined regions. Gyrification index measures in each group were normally distributed in each region. Mean GI was significantly increased in the right prefrontal lobe of the high-risk group who developed schizophrenia [t(28) = −2.9, p < .01]. This significant difference was maintained [t(26) = −2.68, p = .013] on group comparison of the 14 matched pairs. No other between-group lobar differences approached significance. Figure 2 shows the

Discussion

Our main finding, of significantly increased right prefrontal GI, is consistent with other studies using the same technique to assess this region in schizophrenic groups (Sallet et al., 2003, Vogeley et al., 2000, Vogeley et al., 2001). In particular, the study of Sallet et al (2003) mirrored our findings with almost exactly the same slice divisions: the first five slices of frontal lobe were markedly higher in the schizophrenic subjects. These studies involved schizophrenic subjects of

Acknowledgements

This study was made possible by a Medical Research Council Program Grant but was specifically funded by The Stanley Medical Research Institute, grant R81133, and the Schizophrenia Research Fund.

References (52)

E Armstrong et al.
Cortical folding and the evolution of the human brain
J Hum Evol
(1993)
R.E Blanton et al.
Mapping cortical asymmetry and complexity patterns in normal children
Psychiatry Res
(2001)
L.E Delisi
Is schizophrenia a lifetime disorder of brain plasticity, growth and aging?
Schizophr Res
(1997)
I Feinberg
SchizophreniaCaused by a fault in programmed synaptic elimination during adolescence?
J Psychiatr Res
(1982–1983)
J.R Highley et al.
Temporal-lobe length is reduced, and gyral folding is increased in schizophreniaA post-mortem study
Schizophr Res
(1998)
P.R Huttenlocher
Morphometric study of human cerebral cortex development
Neuropsychologia
(1990)
D.E Job et al.
Voxel-based morphometry of grey matter densities in subjects at high risk of schizophrenia
Schizophr Res
(2003)
E.C Johnstone et al.
Edinburgh High Risk Study—findings after four yearsDemographic, attainment and psychopathological issues
Schizophr Res
(2000)
R Kikinis et al.
Temporal lobe sulco-gyral pattern anomalies in schizophreniaAn in vivo MR three-dimensional surface rendering study
Neurosci Lett
(1994)
J.J Kulynych et al.
Cortical abnormality in schizophreniaAn in vivo application of the gyrification index
Biol Psychiatry
(1997)

C.J Bruton et al.

Schizophrenia and the brainA prospective clinico-neuropathological study

Psychol Med

(1990)

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Increased parietal and occipital lobe gyrification predicts conversion to syndromal psychosis in a clinical high-risk cohort
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Local gyrification index (lGI), indicative of the degree of cortical folding is a proxy marker for early cortical neurodevelopmental abnormalities. We studied the difference in lGI between those who do and do not convert to psychosis (non-converters) in a clinical high-risk (CHR) cohort, and whether lGI predicts conversion to psychosis.
Seventy-two CHR participants with attenuated positive symptom syndrome were followed up for two years. The difference in baseline whole-brain lGI was examined on the T1-weighted MRIs between, i)CHR (N = 72) and healthy controls (N = 19), ii)Converters to psychosis (N = 24) and non-converters (N = 48), adjusting for age and sex, on Freesurfer-6.0. The significant cluster obtained in the converters versus non-converters comparison was registered as a region of interest to individual images of all 72 participants and lGI values were extracted from this region. A cox proportional hazards model was applied with these values to study whether lGI predicts conversion to psychosis.
lGI was not different between CHR and healthy controls. lGI was increased in converters in the right-sided inferior parietal and lateral occipital areas (corrected cluster-wise-p-value = 0.009, cohen's f = 0.42) compared to non-converters, which significantly increased the risk of onset of psychosis (p = 0.029, hazard ratio = 1.471).
Increased gyrification in the right-sided inferior parietal and lateral occipital area differentiates converters to psychosis in CHR, significantly increasing the risk of conversion to psychosis. This measure may reflect underlying traits in parts of the brain that develop earliest in-utero (parietal and occipital), conferring a heightened vulnerability to convert to syndromal psychosis subsequently.
NAS-optimized topology-preserving transfer learning for differentiating cortical folding patterns
2022, Medical Image Analysis
Increasing evidence suggests that cortical folding patterns of human cerebral cortex manifest overt structural and functional differences. However, for interpretability, few studies leverage advanced techniques (e.g., deep learning) to investigate the difference among cortical folds, resulting in more differences yet to be extensively explored. To this end, we proposed an effective topology-preserving transfer learning framework to differentiate cortical fMRI time series extracted from cortical folds. Our framework consists of three main parts: (1) Neural architecture search (NAS), which is used to devise a well-performing network structure based on an initialized hand-designed super-graph in an image dataset; (2) Topology-preserving transfer, which takes the model searched by NAS as the source network, keeping the topological connectivity in the network unchanged, while transforming all 2D operations including convolution and pooling into 1D, therefore resulting in a topology-preserving network, named TPNAS-Net; (3) Classification and correlation analysis, which involves using the TPNAS-Net to classify 1D cortical fMRI time series for each individual brain, and performing a group difference analysis between autism spectrum disorder (ASD) and healthy control (HC) and correlation analysis with clinical information (i.e., age). Extensive experiments on two ASD datasets obtain consistent results, demonstrating that the TPNAS-Net not only discriminates cortical folding patterns at high classification accuracy, but also captures subtle differences between ASD and HC (p-value = 0.042). In addition, we discover that there is a positive correlation between the classification accuracy and age in ASD (r = 0.39, p-value = 0.04). These findings together suggest that structural and functional differences in cortical folding patterns between ASD and HC may provide a potentially useful biomarker for the diagnosis of ASD.
Familial high risk and high-risk studies
2020, Risk Factors for Psychosis: Paradigms, Mechanisms, and Prevention
A prominent risk factor for psychosis is its high heritability. This offers us a means to identify potential biomarkers of risk and resilience by focusing on people who are at familial high risk, but are currently free of both illness and medication. The genetic underpinnings of this risk allow us to gain a more mechanistic understanding, which may better guide therapeutic development and prevention strategies. Here, we summarize two prospective longitudinal familial high-risk studies: the Edinburgh High Risk Study of schizophrenia and the Bipolar Family Study. This work highlights the complex interactions between molecular mechanisms and environmental circumstances in the generation and perpetuation of psychosis.
Neuroimaging studies in people at clinical high risk for psychosis
2020, Risk Factors for Psychosis: Paradigms, Mechanisms, and Prevention
In neuroimaging studies of people at clinical high risk (CHR) for psychosis, it is possible to assess the structure, function, connectivity, and chemistry of the brain before, during, and after the onset of a psychotic disorder. This chapter describes the range of neuroimaging techniques that have been applied to CHR populations and discusses current limitations and future directions. We highlight the need for both multicenter collaboration in recruitment of CHR participants and for standardized methods to allow the aggregation of data from separate CHR cohorts. Of particular interest in neuroimaging of psychosis risk is the application of machine learning–based classifiers, which could be used in providing individualized treatment.
Adolescents at clinical high risk for psychosis show qualitatively altered patterns of activation during rule learning
2020, NeuroImage: Clinical
The ability to flexibly apply rules to novel situations is a critical aspect of adaptive human behavior. While executive function deficits are known to appear early in the course of psychosis, it is unclear which specific facets are affected. Identifying whether rule learning is impacted at the early stages of psychosis is necessary for truly understanding the etiology of psychosis and may be critical for designing novel treatments. Therefore, we examined rule learning in healthy adolescents and those meeting criteria for clinical high risk (CHR) for psychosis.
24 control and 22 CHR adolescents underwent rapid, high-resolution fMRI while performing a paradigm which required them to apply novel or practiced task rules.
Previous work has suggested that practiced rules rely on rostrolateral prefrontal cortex (RLPFC) during rule encoding and dorsolateral prefrontal cortex (DLPFC) during task performance, while novel rules show the opposite pattern. We failed to replicate this finding, with greater activity for novel rules during performance. Comparing the HC and CHR group, there were no statistically significant effects, but an effect size analysis found that the CHR group showed less activation during encoding and greater activation during performance. This suggests the CHR group may use less efficient reactive control to retrieve task rules at the time of task performance, rather than proactively during rule encoding.
These findings suggest that flexibility is qualitatively altered in the clinical high risk state, however, more data is needed to determine whether these deficits predict disease progression.
Cortical Morphometry in the Psychosis Risk Period: A Comprehensive Perspective of Surface Features
2019, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Gyrification features reflect brain development in the early prenatal environment. Clarifying the nature of these features in psychosis can help shed light on the role of early developmental insult. However, the literature is currently widely discrepant, which may reflect confounds related to formally psychotic patient populations or overreliance on a single feature of cortical surface morphometry (CSM).
This study compares CSM features of gyrification in clinical high-risk (n = 43) youths during the prodromal risk period to typically developing control subjects over two time points across three metrics: local gyrification index, mean curvature index, and sulcal depth (improving resolution and examination of change over 1 year).
Gyrification was stable over time, supporting the idea that gyrification reflects early insult rather than abnormal development or reorganization associated with the disease state. Each of the indices highlighted unique, aberrant features in the clinical high-risk group with respect to control subjects. Specifically, the local gyrification index reflected hypogyrification in the lateral orbitofrontal cortex, superior bank of the superior temporal sulcus, anterior isthmus of the cingulate gyrus, and temporal poles; the mean curvature index indicated sharper gyral and flatter or wider sulcal peaks in the cingulate, postcentral, and lingual gyrus; sulcal depth identified shallow features in the parietal, superior temporal sulcus, and cingulate regions. Further, both the mean curvature index and sulcal depth converged on abnormal features in the parietal cortex.
Gyrification metrics suggest early developmental insult and provide support for neurodevelopmental hypotheses. Observations of stable CSM features across time provide context for interpreting extant studies and speak to CSM as a promising stable marker and/or endophenotype. Collectively, findings support the importance of considering multiple CSM features.

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Original articleAbnormal cortical folding in high-risk individuals: a predictor of the development of schizophrenia?

Abstract

Background

Methods

Results

Conclusions

Section snippets

Participants

Results

Discussion

Acknowledgements

J Hum Evol

Psychiatry Res

Schizophr Res

J Psychiatr Res

Schizophr Res

Neuropsychologia

Schizophr Res

Schizophr Res

Neurosci Lett

Biol Psychiatry

Lancet

Biol Psychiatry

Biol Psychiatry

Schizophr Res

Biol Psychiatry

Biol Psychiatry

Schizophr Res

Schizophr Res

Psychiatry Res

Biol Psychiatry

Neuroimage

The ontogeny of human gyrification

Cereb Cortex

Genetic variability of human brain size and cortical gyral patterns

Brain

Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients

Arch Gen Psychiatry

Synaptic development of the cerebral cortexImplications for learning, memory and mental illness

Prog Brain Res

Schizophrenia and the brainA prospective clinico-neuropathological study

Psychol Med

Original article
Abnormal cortical folding in high-risk individuals: a predictor of the development of schizophrenia?