Preliminary communication
Fronto-limbic volumetric changes in major depressive disorder

https://doi.org/10.1016/j.jad.2011.10.038Get rights and content

Abstract

Background

Fronto-limbic dysregulation in major depressive disorder (MDD) may be influenced by early life stress and antidepressant treatment. The present structural MRI study aimed to determine the relationship between amygdala, cingulate and subgenual prefrontal cortex volumes in MDD and their associations with child abuse and antidepressants.

Methods

Right-handed subjects (21–50 years), meeting DSM-IV criteria for MDD, either with (n = 19) or without (n = 20) childhood sexual or physical abuse. Healthy controls (n = 34) were matched for age, sex, education and smoking. 3D-MPRAGE images with a spatial resolution of 1.5 mm × 1.0 mm × 1.0 mm were acquired with a Siemens Sonata 1.5T system. Volumes of subgenual prefrontal cortex, amygdala and affective, cognitive, superior and posterior divisions of cingulate cortex were analyzed using DISPLAY software using reliable volumetric protocols. Groups were compared using ANCOVA, with intracranial volume as a covariate.

Results

MDD subjects had low cingulate (cognitive division) and high amygdala volumes. Low cingulate volume was related to abuse and treatment history. Amygdala volume was predicted by subgenual prefrontal and cingulate (cognitive division) volumes and the presence of paracingulate cortex. Limitations: This study was cross sectional and the sample size was limited for subgroup and correlational analyses.

Summary

Our data suggest that MDD may be associated with alterations in anterior cingulate cortex and amygdala. Morphological variation, early stress and stress-protective factors may contribute to differences in fronto-limbic structures in MDD.

Introduction

Major depressive disorder (MDD) is associated with fronto-limbic dysregulation as evidenced by alterations in amygdala activation and prefrontal-amygdala connectivity (Savitz and Drevets, 2009). Supragenual cingulate, subgenual cingulate and orbitofrontal cortices have strong structural and functional connections with amygdala (Ghashghaei et al., 2007, Stein et al., 2007). Prior volumetric Magnetic Resonance Imaging (MRI) studies in MDD have examined these structures independently. In meta-analytic studies, amygdala volume findings have been heterogeneous and anterior cingulate and orbitofrontal cortex volumes have been lower in MDD patients (Hajek et al., 2008, Hajek et al., 2009, Koolschijn et al., 2009). However, cingulate studies did not account for inter-individual variation of the paracingulate cortex (Fornito et al., 2008) or the impact of early life stress (Cohen et al., 2006), factors that influence anterior cingulate volume in normative samples. Furthermore, most studies of cingulate cortex in MDD have focused on subgenual portions of anterior cingulate (Drevets et al., 2008, Hajek et al., 2008). Amygdala changes in MDD have not previously been investigated in association with cingulate or ventromedial prefrontal volumes.

The present structural MRI study aimed to determine the relationship between cingulate, subgenual prefrontal and amygdala volumes in MDD patients with or without childhood maltreatment and healthy matched controls. We hypothesized that regional volume differences in MDD would be associated with childhood trauma and that amygdala volume would also be related to variation in anterior cingulate and subgenual prefrontal cortex volumes.

Section snippets

Subjects

A total of 39 patients with MDD (males = 10, females = 29; all right-handed, 21–50 years of age) meeting DSM-IV criteria for moderate or severe episodes of MDD, on the basis of full clinical assessment and the Structured Clinical Interview for Diagnosis for DSM-IV (SCID, First et al., 1997), either with (n = 19) or without (n = 20) childhood sexual or physical abuse (≥ moderate severity on Childhood Trauma Questionnaire, (CTQ) (Bernstein and Fink, 1998)) and 34 healthy controls (males = 7, females = 27)

Clinical characteristics

Controls and MDD participants were prospectively matched for demographic variables, but MDD participants had higher abuse scores (Table 1). High abuse MDD participants had lower education and higher smoking rates, episode recurrence, anxiety, adult trauma and suicide attempts than low abuse MDD, but did not differ in current mood symptoms, treatment history, or other abuse ratings (Table 1).

Structural brain changes

A PaCG was more often left-sided and was associated with smaller affective, cognitive and superior

Discussion

The results of present study suggest that MDD is associated with increased volume of amygdala and reduced volume of cognitive anterior cingulate gyrus. Second, low cognitive cingulate volume could not be clearly ascribed to MDD diagnosis versus childhood trauma. Third, subgenual prefrontal cortex, cognitive cingulate and amygdala were inter-related at the volumetric level. Fourth, antidepressant treatment history was associated with higher cognitive cingulate volume. To our knowledge this is

Limitations

This study was cross sectional and the sample size was limited for subgroup and correlational analyses. Additional longitudinal studies are needed to determine effects of antidepressant treatment on anterior cingulate structure. We did not acquire data on cognition in medicated subjects to link with the structural findings.

Role of the funding source

Canadian Institutes of Health Research (CIHR) operating grant 64413 (PI — Nicholas Coupland) was the source of salary (part only) for research nurse Rawle Carter and MRI technician Peter Seres, payment for MRI services and subject reimbursement.

Nikolai Malykhin and Nicholas Coupland received personal support (postdoctoral fellowship award to NM and salary award to NC) from Alberta Heritage Foundation for Medical Research (AHFMR).

Nikolai Malykhin also received postdoctoral CIHR/Wyeth Fellowship

Conflict of interest

All authors reported no conflict of interest.

Acknowledgments

This study was supported by the Canadian Institutes of Health Research (CIHR) operating grant 64413 to Nicholas Coupland. Personnel support: CIHR/Wyeth Fellowship (Nikolai Malykhin), Alberta Heritage Foundation for Medical Research (Nicholas Coupland, Nikolai Malykhin).

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