Corpus callosum size and shape alterations in individuals with bipolar disorder and their first-degree relatives

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Abstract

Reductions in the size of the corpus callosum (CC) have been described in patients with bipolar disorder (BD), although the contribution of genetic factors to these changes is unclear. We previously showed a global thinning of the CC in BD patients, and found those with a family history of affective disorders had a larger CC than those without. In this study, we compared callosal size and shape in 180 individuals: 70 with BD, 45 of their first-degree relatives, and 75 healthy controls. The callosum was extracted from a mid-sagittal slice from T1-weighted magnetic resonance images, and its total area, length and curvature were compared across groups. A non-parametric permutation method was used to examine for alterations in width of the callosum along 39 points.

Validating our previous findings, a significant global reduction in callosal thickness was seen in BD patients, with a disproportionate thinning in the anterior body. First-degree relatives did not differ in callosal size or shape from controls. In BD patients, duration of illness and age were associated with thinning in the anterior body; BD patients on lithium treatment showed a thicker anterior mid-body than those on other psychotropics.

Global and regional thinning of the callosum is seen in BD but not in their first-degree relatives. This suggests that CC abnormalities are linked to disease expression in BD and may not represent a marker of familial predisposition.

Introduction

The corpus callosum (CC) is the most prominent white matter tract in the brain. It connects the two hemispheres and has a prolonged sequence of maturation through childhood, adolescence and early adulthood. It serves to integrate cognitive and behavioural function across the two cerebral hemispheres to facilitate language, affective and sensorimotor information processing (Clarke and Zaidel, 1994, Hoptman and Davidson, 1994). Impaired information transfer between hemispheres has been implicated in bipolar disorder (Soares and Mann, 1997), and may be mediated by altered callosal structure. Two recent meta-analyses of published studies of mid-sagittal callosal area in bipolar disorder demonstrated a significant reduction in BD patients compared to controls, with an effect size of diagnosis of 0.52 (Arnone et al., 2008) and 0.43 (Kempton et al., 2008), suggesting that widespread disruptions to connectivity affecting the callosum may relate to or reflect functional impairments in the prefrontal and cingulate cortex, the hippocampus and amygdala seen in BD (Soares and Mann, 1997). As the callosum is topographically organized, a differential effect on callosal shape may be seen in areas connecting brain regions disproportionately functionally affected; regional reductions in size and signal intensity have been shown in anterior and posterior callosal regions in both first-episode and established adult BD patients both in our lab (Walterfang et al., 2008a) and by other colleagues (Atmaca et al., 2007, Brambilla et al., 2004, Brambilla et al., 2003).

In addition, we (Walterfang et al., 2008a) reported that patients with a family history of affective disorder showed increased total callosal area, suggesting that familial factors may moderate callosal structure in BD. We sought to validate and explore further these results, through examination of a larger dataset which included first-degree relatives of BD patients to examine genetic influences on changes to callosal structure, and thus inter-hemispheric connectivity, in BD.

Section snippets

Subjects

The entire sample was recruited at the Institute of Psychiatry, London, UK. Patients (n = 70) were identified by clinicians' referrals and were included if they (a) were aged between 17 and 65 years (b) fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised (DSM-IV) criteria for Bipolar Disorder, type I (BDI), (c) had no family history (up to second degree) of schizophrenia or schizophrenia spectrum disorders. Siblings and offspring (n = 45) were invited to

Demographic and symptom data

Demographic and symptom data is presented in Table 1. The patient group was significantly older than the control or relative groups (F[2,189] = 9.03, p < 0.0001). There were no group differences in gender (χ2 = 0.35, p = 0.840), or full-scale IQ (F[2,189] = 0.18, p = 0.837).

In the patient group, the mean age of BD onset was 25.14 ±8.89 years; thirty patients presented with depression at onset and 40 with a manic or mixed episode. Mean duration of illness prior to scanning of 18.24 ± 1.12 years and the mean

Discussion

We corroborated our previous findings (Walterfang et al., 2008a) showing a global thinning of the CC in patients with BD compared to healthy controls, and further regional reductions in the anterior mid-body of the CC in BD patients only. These reductions were affected by both age and duration of illness. Notably patients treated with lithium showed a thicker callosum in this region than those patients not treated with lithium. There was no difference between relatives – either siblings or

Conclusion

We have validated previous findings suggesting callosal size and shape changes in BD, and demonstrated that both illness duration and lithium treatment affect mid-callosal areas. Longitudinal studies are required from an early illness phase to determine whether these changes are progressive, and whether changes seen in lithium-treated patients represent a true neuroprotective effect. That no findings of significant size or shape change were shown in unaffected first-degree relatives suggests

Acknowledgements

Dr Walterfang was supported by a Stanley Research Centre Grant. Dr Wood was supported by an NH&MRC Fellowship (fellowship ID 251755). Dr Kempton was funded in part by the NIHR Biomedical Research Centre for Mental Health at King's College London, Institute of Psychiatry, and South London and Maudsley NHS Foundation Trust. Dr Walterfang takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors wish to acknowledge the assistance of Dr Christopher

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