Skip to main content Accessibility help

Structural covariance and cortical reorganisation in schizophrenia: a MRI-based morphometric study

  • Lena Palaniyappan (a1) (a2) (a3), Olha Hodgson (a4), Vijender Balain (a4), Sarina Iwabuchi (a4), Penny Gowland (a5) and Peter Liddle (a4)...



In patients with schizophrenia, distributed abnormalities are observed in grey matter volume. A recent hypothesis posits that these distributed changes are indicative of a plastic reorganisation process occurring in response to a functional defect in neuronal information transmission. We investigated the structural covariance across various brain regions in early-stage schizophrenia to determine if indeed the observed patterns of volumetric loss conform to a coordinated pattern of structural reorganisation.


Structural magnetic resonance imaging scans were obtained from 40 healthy adults and 41 age, gender and parental socioeconomic status matched patients with schizophrenia. Volumes of grey matter tissue were estimated at the regional level across 90 atlas-based parcellations. Group-level structural covariance was studied using a graph theoretical framework.


Patients had distributed reduction in grey matter volume, with high degree of localised covariance (clustering) compared with controls. Patients with schizophrenia had reduced centrality of anterior cingulate and insula but increased centrality of the fusiform cortex, compared with controls. Simulating targeted removal of highly central nodes resulted in significant loss of the overall covariance patterns in patients compared with controls.


Regional volumetric deficits in schizophrenia are not a result of random, mutually independent processes. Our observations support the occurrence of a spatially interconnected reorganisation with the systematic de-escalation of conventional ‘hub’ regions. This raises the question of whether the morphological architecture in schizophrenia is primed for compensatory functions, albeit with a high risk of inefficiency.


Corresponding author

Author for correspondence: Lena Palaniyappan, E-mail:


Hide All
Achard, S, et al. (2006) A resilient, low-frequency, small-world human brain functional network with highly connected association cortical hubs. Journal of neuroscience: the Official Journal of the Society for Neuroscience 26, 6372.
Alexander-Bloch, A, Giedd, JN and Bullmore, E (2013) Imaging structural co-variance between human brain regions. Nature Reviews. Neuroscience 14, 322336.
Alexander-Bloch, AF, et al. (2010) Disrupted modularity and local connectivity of brain functional networks in childhood-onset schizophrenia. Frontiers in Systems Neuroscience 4, 147.
Ammons, RB and Ammons, CH (1962) The quick test (QT): provisional manual. Psychological Reports 11, 111161.
Ashburner, J (2007) A fast diffeomorphic image registration algorithm. NeuroImage 38, 95113.
Barabasi, AL (2009) Scale-free networks: a decade and beyond. Science 325, 412413.
Bassett, DS, et al. (2008) Hierarchical organization of human cortical networks in health and schizophrenia. Journal of Neuroscience 28, 92399248.
Bullmore, E and Sporns, O (2009) Complex brain networks: graph theoretical analysis of structural and functional systems. Nature Reviews Neuroscience 10, 186198.
Bullmore, E, et al. (2009) Generic aspects of complexity in brain imaging data and other biological systems. NeuroImage 47, 11251134.
Chan, RCK, et al. (2011) Brain anatomical abnormalities in high-risk individuals, first-episode, and chronic schizophrenia: an activation likelihood estimation meta-analysis of illness progression. Schizophrenia Bulletin 37, 177188.
Chen, Z, et al. (2014) Extensive brain structural network abnormality in first-episode treatment-naive patients with schizophrenia: morphometrical and covariation study. Psychological Medicine 44, 24892501.
Crossley, NA, et al. (2014) The hubs of the human connectome are generally implicated in the anatomy of brain disorders. Brain: a Journal of Neurology 137, 23822395.
Eack, SM, et al. (2010) Neuroprotective effects of cognitive enhancement therapy against gray matter loss in early schizophrenia: results from a 2-year randomized controlled trial. Archives of General Psychiatry 67, 674682.
Ellison-Wright, I, et al. (2008) The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. American Journal of Psychiatry 165, 10151023.
Evans, AC (2013) Networks of anatomical covariance. NeuroImage 80, 489504.
Fornito, A, Zalesky, A and Breakspear, M (2013) Graph analysis of the human connectome: promise, progress, and pitfalls. NeuroImage 80C, 426444.
Fornito, A, et al. (2012) Schizophrenia, neuroimaging and connectomics. NeuroImage 62, 22962314.
Fusar-Poli, P and Meyer-Lindenberg, A (2016) Forty years of structural imaging in psychosis: promises and truth. Acta Psychiatrica Scandinavica 134, 207224.
Glahn, DC, et al. (2008) Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis. Biological Psychiatry 64, 774781.
Griffa, A, et al. (2013) Structural connectomics in brain diseases. NeuroImage 80, 515526.
Griffa, A, et al. (2015) Characterizing the connectome in schizophrenia with diffusion spectrum imaging. Human Brain Mapping 36, 354366.
Ho, BC, et al. (2011) Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Archives of General Psychiatry 68, 128137.
Hoekzema, E, et al. (2011) Training-induced neuroanatomical plasticity in ADHD: a tensor-based morphometric study. Human Brain Mapping 32, 17411749.
Hosseini, SMH, Hoeft, F and Kesler, SR (2012) GAT: a graph-theoretical analysis toolbox for analyzing between-group differences in large-scale structural and functional brain networks. PLoS ONE 7, e40709.
Hosseini, SMH, et al. (2013) Topological properties of large-scale structural brain networks in children with familial risk for reading difficulties. NeuroImage 71, 260274.
Humphries, MD and Gurney, K (2008) Network “small-world-ness”: a quantitative method for determining canonical network equivalence. PLoS ONE 3, e0002051.
Leckman, JF, et al. (1982) Best estimate of lifetime psychiatric diagnosis: a methodological study. Archives of General Psychiatry 39, 879883.
Leung, M, et al. (2009) Gray matter in first-episode schizophrenia before and after antipsychotic drug treatment. Anatomical likelihood estimation meta-analyses with sample size weighting. Schizophrenia Bulletin 37, 199211.
Li, X, et al. (2013) Age-related changes in brain structural covariance networks. Frontiers in Human Neuroscience 7, 98.
Liddle, PF, et al. (2002) Signs and symptoms of psychotic illness (SSPI): a rating scale. The British Journal of Psychiatry 180, 4550.
Lo, CYZ, et al. (2015) Randomization and resilience of brain functional networks as systems-level endophenotypes of schizophrenia. Proceedings of the National Academy of Sciences of the United States of America 112, 91239128.
Luders, E, et al. (2012) The unique brain anatomy of meditation practitioners: alterations in cortical gyrification. Frontiers in Human Neuroscience 6, 34.
Lynall, ME, et al. (2010) Functional connectivity and brain networks in schizophrenia. Journal of Neuroscience 30, 94779487.
May, A, et al. (2007) Structural brain alterations following 5 days of intervention: dynamic aspects of neuroplasticity. Cerebral Cortex 17, 205210.
Mechelli, A, et al. (2005) Structural covariance in the human cortex. Journal of Neuroscience 25, 83038310.
Modinos, G, et al. (2009) Structural covariance in the hallucinating brain: a voxel-based morphometry study. Journal of Psychiatry & Neuroscience 34, 465469.
Montembeault, M, et al. (2012) The impact of aging on gray matter structural covariance networks. NeuroImage 63, 754759.
Newman, MEJ (2006) Finding community structure in networks using the eigenvectors of matrices. Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics 74, 36104.
Pajonk, FG, et al. (2010) Hippocampal plasticity in response to exercise in schizophrenia. Archives of General Psychiatry 67, 133143.
Palaniyappan, L (2017) Progressive cortical reorganisation: a framework for investigating structural changes in schizophrenia. Neuroscience & Biobehavioral Reviews 79, 113.
Palaniyappan, L and Liddle, PF (2012) Differential effects of surface area, gyrification and cortical thickness on voxel based morphometric deficits in schizophrenia. NeuroImage 60, 693699.
Palaniyappan, L and Liddle, PF (2013) Diagnostic discontinuity in psychosis: a combined study of cortical gyrification and functional connectivity. Schizophrenia Bulletin 40, 675684.
Palaniyappan, L, et al. (2014) Abnormalities in structural covariance of cortical gyrification in schizophrenia. Brain Structure & Function 220, 20592071.
Palaniyappan, L, et al. (2016) Globally efficient brain organization and treatment response in psychosis: a connectomic study of gyrification. Schizophrenia Bulletin 42, 14461456.
Ramsay, JO and Dalzell, CJ (1991) Some tools for functional data analysis. Journal of the Royal Statistical Society. Series B. Methodological 53, 539572.
Rapp, C, et al. (2012) Effects of Cannabis use on human brain structure in psychosis: a systematic review combining In vivo structural neuroimaging and post mortem studies. Current Pharmaceutical Design 18, 50705080.
Rose, D and Pevalin, DJ (2003) A Researcher's Guide to the National Statistics Socio-Economic Classification. London: Sage Publications.
Rubinov, M and Sporns, O (2010) Complex network measures of brain connectivity: uses and interpretations. NeuroImage 52, 10591069.
Singh, MK, et al. (2013) Anomalous gray matter structural networks in major depressive disorder. Biological Psychiatry 74, 777785.
Stam, C and Reijneveld, J (2007) Graph theoretical analysis of complex networks in the brain. Nonlinear Biomedical Physics 1, 3.
Tandon, R, Keshavan, MS and Nasrallah, HA (2008) Schizophrenia, ‘Just the Facts’: what we know in 2008 part 1: overview. Schizophrenia Research 100, 419.
van den Heuvel, MP and Sporns, O (2011) Rich-club organization of the human connectome. Journal of Neuroscience: the Official Journal of the Society for Neuroscience 31, 1577515786.
van den Heuvel, MP, et al. (2010) Aberrant frontal and temporal complex network structure in schizophrenia: a graph theoretical analysis. Journal of Neuroscience: the Official Journal of the Society for Neuroscience 30, 1591515926.
Wang, Q, et al. (2012) Anatomical insights into disrupted small-world networks in schizophrenia. NeuroImage 59, 10851093.
WHO Collaborating Centre for Drug Statistics and Methodology (2003) Guidelines for ATC Classification and DDD Assignment. WHO Collaborating Centre for Drug Statistics and Methodology.
Xia, M, Wang, J and He, Y (2013) Brainnet viewer: a network visualization tool for human brain connectomics. PLoS ONE 8, e68910.
Zalesky, A, et al. (n.d.) Whole-brain anatomical networks: does the choice of nodesmatter? NeuroImage 50, 970983.
Zhang, Y, et al. (2012) Abnormal topological organization of structural brain networks in schizophrenia. Schizophrenia Research 141, 109118.


Type Description Title
Supplementary materials

Palaniyappan et al. supplementary material
Palaniyappan et al. supplementary material 1

 Word (2.7 MB)
2.7 MB


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed