Increased white matter radial diffusivity is associated with prefrontal cortical folding deficits in schizophrenia

https://doi.org/10.1016/j.pscychresns.2017.01.011Get rights and content

Highlights

  • Combined DTI and cortical folding analysis in patients with schizophrenia.

  • Higher radial diffusivity of the SLF is associated with reduced prefrontal cortical folding.

  • Findings support tension based models of gyrification.

Abstract

The neuronal underpinnings of cortical folding alterations in schizophrenia remain unclear. Theories on the physiological development of cortical folds stress the importance of white matter fibers for this process and disturbances of fiber tracts might be relevant for cortical folding alterations in schizophrenia. Nine-teen patients with schizophrenia and 19 healthy subjects underwent T1-weighted MRI and DTI. Cortical folding was computed using a surface based approach. DTI was analyzed using FSL and SPM 5. Radial diffusivity and cortical folding were correlated covering the entire cortex in schizophrenia. Significantly increased radial diffusivity of the superior longitudinal fasciculus (SLF) in the left superior temporal region was negatively correlated with cortical folding of the left dorsolateral prefrontal cortex (DLPFC) in patients, i.e. higher radial diffusivity, as an indicator for disturbed white matter fiber myelination, was associated with lower cortical folding of the left DLPFC. Patients with pronounced alterations of the SLF showed significantly reduced cortical folding in the left DLPFC. Our study provides novel evidence for a linkage between prefrontal cortical folding alterations and deficits in connecting white matter fiber tracts in schizophrenia and supports the notion that the integrity of white matter tracts is crucial for intact morphogenesis of the cortical folds.

Introduction

The highly folded cerebral cortex is a unique feature of the primates` brain. Gross alterations of cortical folding such as lissencephaly leading to intellectual disability and motor retardation demonstrate the relevance of the intact formation of the cortical folds. The process of cortical folding takes place in utero and is, to a large extent, completed at the time of birth (Zilles et al., 2013). Moreover, the pattern of the cortical folds is usually largely stable over the life-span (Armstrong et al., 1995). Hence, deviations of cortical folding might be regarded as an indicator of altered brain maturational processes. Schizophrenia is conceptualized as neurodevelopmental disorder (Rapoport et al., 2005) and the investigation of cortical folding is thus a promising approach to increase our understanding of the neurobiology of the disorder. A growing number of MRI studies explored cortical folding in schizophrenia in vivo and demonstrated cortical folding alterations in terms of both hypo- and hypergyrification in several cortical areas (s. for review (White and Hilgetag, 2011) and overview for more recent studies in (Nanda et al., 2014)). Increased cortical folding in mainly occipito-temporal areas has been shown in first episode patients (Harris et al., 2004b, Schultz et al., 2010a) whereas predominantly decreased folding in terms of a lower local gyrification index in mainly prefrontal, middle temporal and parietal regions (i.e., precuneus) has been found in chronic patients (Nesvag et al., 2014, Palaniyappan et al., 2011). In high risk states increased prefrontal folding as indicated by a higher local gyrification index seems to be a risk factor for the conversion to psychosis (Harris et al., 2007, Harris et al., 2004a). Moreover, cortical folding alterations seem to be genetically driven as both increased cortical folding in frontal regions as well as slightly decreased cortical folding (as assessed by calculation of the regional local gyrification index) in anterior and posterior cingulate regions has been detected in non-affected first degree relatives (Falkai et al., 2007, Nanda et al., 2014). Finally, cortical folding defects also seem to be of major clinical relevance as reduced cortical folding in terms of a smaller local gyrification index in bilateral insular, frontal, and temporal regions has been shown to predict poor treatment response (Palaniyappan et al., 2013) and an alteration in the structural covariance of specific folding patterns has been shown to be linked to illness severity (Palaniyappan et al., 2015). In the overall view findings on altered cortical folding in schizophrenia are still rather heterogeneous with previous studies providing evidence for both decreased and increased cortical folding. On a closer inspection there seems to be a tendency towards increased cortical folding in high-risk and first episode patients and decreased cortical folding in chronic patients or patients at a later stage of the illness. Predominantly the decreased folding in more chronic patients seems to be psychopathologically relevant. Despite this relevance the pathomechanism underlying cortical folding deficits in schizophrenia is poorly understood. In line with theories which consider cortical shape as a product of underlying patterns of connectivity first evidence (Schaer et al., 2013) showed alterations in cortical folding to be directly associated with altered white matter structural connectivity. Although this association was found in patients with autism it can be assumed that similar mechanisms underlie folding alterations in schizophrenia considering that disrupted white matter connectivity is a frequent finding in schizophrenia (Tamnes and Agartz, 2016).

To investigate this presumed relationship and its relevance for the disorder of schizophrenia we explored a potential association between a previously reported disruption in white matter fiber tract diffusivity and cortical folding in patients with schizophrenia.

More specifically, we performed a correlational analysis between a DTI derived indirect measure of myelination (“radial diffusivity”) and fine grained cortical folding covering the entire cortex in a well characterized sample of patients with schizophrenia and healthy controls. In this sample we demonstrated in two previous studies significantly increased radial diffusivity – as an indirect indicator of disturbed myelination - in the superior temporal cortex confined to parts of the superior and inferior longitudinal fasciculus (Koch et al., 2013, Koch et al., 2011). For our current analysis we extracted the radial diffusivity values from these voxels in order to perform a node-by-node correlational analysis with cortical folding. We hypothesized a negative correlation between radial diffusivity and cortical folding, i.e., we expected higher radial diffusivity to be associated with stronger alterations in cortical folding.

Section snippets

Participants

We studied 19 patients with schizophrenia and 19 healthy controls. All participants were right-handed (Annett, 1967). Diagnoses were established by a clinical psychiatrist (C. Chr. S.) based on the Structured Clinical Interview for DSM-IV and were confirmed by an independent psychiatrist (R. G. M. S.). All patients met DSM-IV criteria for schizophrenia and had no second psychiatric diagnosis. They were on stable medication, mostly with second-generation antipsychotics.

Healthy volunteers were

Relationship between radial diffusivity and cortical folding

In patients we found a significant negative correlation between radial diffusivity and cortical folding in the left dorsolateral prefrontal cortex (DLPFC) (s. Fig. 1), i.e., increased radial diffusivity of fibers corresponding to the superior and inferior longitudinal fasciculus was associated with reduced cortical folding of the DLPFC. The R2 value was 0.621, i.e., 62% of the variation of cortical folding in the DLPFC cluster could be explained by the radial diffusivity values. Table 2

Discussion

Our study which is the first one to investigate the relationship between white matter alterations and cortical folding in schizophrenia has three main findings:

  • 1.

    We provide novel evidence for an association of increased radial diffusivity and cortical folding of the DLPFC in schizophrenia.

  • 2.

    Our study revealed that the relationship between white matter diffusivity and DLPFC cortical folding was not evident in healthy controls, implicating a pathological relationship in patients.

  • 3.

    We demonstrate that

Disclosure statement

All of the authors reported no financial, personal or other relationships with other people or organizations that could inappropriately influence, or be perceived to influence, their work.

Acknowledgments

This work was supported by the Bundesministerium für Bildung und Forschung, BMBF Grant 01GW0740 (to G.W. and K.K.) and an IZKF Young Scientist Grant (to C.C.C.). The sponsor served no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

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