Midline brain structures in patients with current and remitted major depression

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Abstract

Brain morphologic changes of limbic-cortical regions have been reported in major depressive disorder (MDD). However, it remains largely unknown whether MDD is associated with abnormalities in midline brain structures, which play a critical role in limbic-cortical connectivity, and whether such changes reflect state or trait markers of the disorder. We used magnetic resonance imaging to investigate the length of the adhesio interthalamica (AI) and cavum septum pellucidum (CSP) in 29 currently depressed patients, 27 remitted depressed patients, and 33 age- and gender-matched healthy control subjects. The currently depressed patients had a significantly shorter AI compared with controls, but there was no difference in the AI length between the remitted patients and controls. The AI length in the overall patient group was negatively correlated with the severity of symptoms of “loss of interest” at the time of scanning. Furthermore, the patients with co-morbid anxiety disorders tended to have a shorter AI compared with those without. The CSP length and prevalence of a large CSP (≥ 6 mm) did not differ between the groups. Although a comprehensive investigation of medication effects was not possible due to incomplete medication data, these findings suggest that a shorter length of the AI may be associated with state-related brain changes in major depression rather than a stable marker of illness vulnerability. Whether the AI length exhibits ongoing changes across the course of the illness remains to be determined in longitudinal studies.

Introduction

Magnetic resonance imaging (MRI) studies of major depressive disorder (MDD) have demonstrated neuroanatomical alterations predominantly in the amygdala, hippocampus, basal ganglia, orbitofrontal and anterior cingulate cortices (Konarski et al., 2008, Lorenzetti et al., in press), consistent with a limbic-cortical dysregulation model of unipolar depression (Mayberg, 2003). The precise nature of these morphologic changes is unclear, but illness stage (e.g., acutely depressed versus remitted) may affect these findings in a regionally specific manner (Caetano et al., 2004, Caetano et al., 2006, Lorenzetti et al., in press). While some brain abnormalities (e.g., volume reduction of subgenual cingulate region) appear to be a trait marker of MDD (Lorenzetti et al., in press), regional expansion of the corpus callosum has been observed in currently depressed patients, but not in remitted patients (Walterfang et al., 2009), implicating state-related impairments of interhemispheric connectivity in the neurobiology of MDD. However, it remains unknown whether other midline brain abnormalities are present in MDD, and whether they also show specific state-related changes.

The adhesio interthalamica (AI), a midline structure connecting the medial surfaces of the thalami, is variable in size among individuals and absent in about 20% of human brains (Kretschmann and Weinrich, 1992, Percheron, 2004). While a smaller AI in schizophrenia spectrum disorders (Shimizu et al., 2008, Takahashi et al., 2008a, Takahashi et al., 2008b) has been implicated in early neurodevelopmental insult (O'Rahilly and Muller, 1990, Rosales et al., 1968), the fact that acceleration of the age-related AI atrophy has been observed in schizophrenia suggests state-dependent dynamic changes of the AI (Rosales et al., 1968, Takahashi et al., 2008c). Given that AI abnormalities have also been reported in affective psychosis and borderline personality disorder (Takahashi et al., 2008c, Takahashi et al., 2009), it is important to examine whether other neuropsychiatric disorders also exhibit abnormalities of the AI. Although the functional significance of the AI in humans is unclear, the midline nuclei of the thalamus, including the AI, has efferent connections with the amygdala and anterior cingulate cortex (Graff-Radford, 1997, Percheron, 2004), suggestive of a role for the AI in functional disconnectivity of the limbic–thalamic-cortical circuitry that mediates depressive symptoms (state effects) in MDD (Anand et al., 2005a, Anand et al., 2005b). To our knowledge, however, no MRI studies have examined the size of the AI in MDD.

The cavum septum pellucidum (CSP), which is formed by the incomplete fusion of the septum pellucidi, is thought to be a normal anatomical variant, but an unusually large CSP might reflect abnormalities in the fetal neurodevelopment of midline and limbic system structures (Rakic and Yakovlev, 1968). While several MRI studies have reported increased prevalence of a large CSP in schizophrenia and affective psychosis (e.g., de Souza Crippa et al., 2006, Kasai et al., 2004, Kwon et al., 1998, Nopoulos et al., 1997), further studies in larger samples did not replicate these findings (Hagino et al., 2001, Rajarethinam et al., 2008, Takahashi et al., 2007, Takahashi et al., 2008d). On the other hand, the prevalence of a large CSP in non-psychotic affective disorders has not been adequately investigated; negative CSP findings in small numbers of affective disorder patients (Brisch et al., 2007, Kwon et al., 1998) or in MDD patients (Shioiri et al., 1996) warrant further replication as they have important implications for potential neurodevelopmental models of these disorders (Sanches et al., 2008).

This MRI study investigated the size of the AI and CSP in currently depressed patients (cMDD), individuals with a history of major depression but who were currently in remission (rMDD), and healthy comparison subjects. This approach potentially enabled us to examine whether abnormalities in these midline structures in MDD, if present, reflect state or trait influences. On the basis of putative state-related limbic-cortical abnormalities in MDD (Anand et al., 2005a, Anand et al., 2005b) and AI abnormalities in various neuropsychiatric disorders (Takahashi et al., 2008a, Takahashi et al., 2008b, Takahashi et al., 2008c), we predicted that only cMDD patients would have shorter length of the AI compared with controls, and that the AI length in the MDD patients would be associated with their symptoms. We also predicted negative CSP findings based on previous studies in mood disorders.

Section snippets

Participants

Eighty-nine subjects were recruited in the study, of which 29 received a current diagnosis of major depressive disorder (cMDD), 27 were currently medically and psychiatrically well individuals with a previous history of major depressive disorder (rMDD), and 33 were healthy control subjects (Table 1). Seven rMDD patients had a total Beck Depression Inventory (BDI; Beck and Steer, 1987) score > 18 at the study, but they did not fulfill the criteria of MDD by the Structured Clinical Interview for

Demographic and clinical data

Comparison of the groups revealed no significant difference in age, gender, and intelligence but, as expected, measures of depressive and anxiety symptoms were significantly different between groups (Table 1). The cMDD patients, as compared to rMDD patients, had an earlier age of onset, a higher proportion of participants on medication in the previous 6 months, and a higher rate of co-morbid anxiety disorder.

AI and CSP measurements

There was no significant group difference in the prevalence of an absent AI (Table 2).

Discussion

To our knowledge, this is the first MRI study to report the size of both AI and CSP in patients with current and remitted MDD. As predicted, the currently depressed patients had a significantly shorter AI compared with controls, but AI length in remitted patients was not different from healthy controls. The AI length in the MDD patients was negatively correlated with the degree of loss of interest at the time of scanning. On the other hand, we did not identify any differences in the prevalence

Conclusion

In conclusion, our findings of a shorter AI in currently depressed but not in remitted MDD patients suggest that the AI abnormalities are state-dependent. A significant negative correlation between the AI length and severity of depressive symptoms at scanning further supports this hypothesis. Further studies are needed to confirm these putative state-related AI changes during the course of illness using longitudinal designs.

Acknowledgements

This research was supported by a grant from the Australian Research Council (I.D. DP0557663) awarded to A/Prof. Allen and A/Prof. Yücel. Neuroimaging analysis was facilitated by the Neuropsychiatry Imaging Laboratory managed by Ms. Bridget Soulsby at the Melbourne Neuropsychiatry Centre and supported by Neurosciences Victoria. The authors thank Ms. Orli Schwartz and Ms. Diana Maud for recruitment and assessment of the participants. A/Prof. Yücel is supported by an NHMRC Clinical Career

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