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. Author manuscript; available in PMC: 2015 Jul 9.
Published in final edited form as: Am J Geriatr Psychiatry. 2013 Feb 6;22(5):459–464. doi: 10.1016/j.jagp.2012.12.010

Cortical thinning in patients with late-life minor depression

Anand Kumar 1, Olusola Ajilore 1, Aifeng Zhang 1, Daniel Pham, Virginia Elderkin-Thompson 2
PMCID: PMC4497565  NIHMSID: NIHMS353245  PMID: 24636843

Abstract

Objectives

Clinically significant minor depression is among the most common mental disorders in the elderly and is associated with considerable medical and psychosocial morbidity. Despite its clinical impact, the biological basis of minor depression in the elderly remains poorly understood. The purpose of our current study was to examine cortical thickness in a sample of patients with late-life minor depression and non-depressed comparison subjects using magnetic resonance imaging (MRI).

Design

Cross-sectional analysis.

Setting

Community

Participants

Patients (n=16; mean age=76.2+7.5) met modified DSM criteria for minor depression and were free of other brain diseases. Healthy comparison subjects (HC; n=16) were of comparable age and gender distribution.

Measurements

All subjects were scanned on a 1.5 Tesla GE scanner and brain regions were outlined using Freesurfer Image Analysis.

Results

Results show that patients with minor depression have cortical thinning in the right cingulate cortex compared to HC.

Conclusions

These findings indicate that abnormalities in specific structures and associated neural circuitry may underlie minor and major depression in the elderly and the pathophysiological abnormalities are comparable in major and less severe forms of the disorder.

Keywords: minor depression, MRI, Freesurfer

OBJECTIVE

Clinically significant minor depression is a common psychiatric disturbance in late-life with prevalence estimates ranging from 5 to 10 percent (1). Minor forms of depression are associated with considerable medical and psychosocial morbidity comparable to those observed in patients with major depressive disorder (MDD) – the more widely recognized and clinically severe form of the disorder (2-5). Like individuals with MDD, older adults diagnosed with minor depression show increased suicide attempts, emergency room visits and tranquilizer use (1;2;4). Clinical and health services studies have elaborated on the economic and psychosocial consequences of minor depression in the elderly (2;4;6;7). The prognosis of “subthreshold” disorders is unfavorable and these minor forms of depression are often chronic in nature (8). Not only is minor depression deemed risk factor for MDD, studies suggest there may be a genetic basis to minor depression (9). Despite these clinical observations, the biological basis of minor depression in late life, unlike MDD, has received scant attention (1;6).

The neuroanatomical basis of MDD has been relatively well characterized using magnetic resonance imaging (MRI). Principal findings suggest that MDD in late life is associated with a combination of smaller brain volumes in specific regions with an increase in high intensity lesion volumes – areas that appear bright on conventional T2-weighted FLAIR MRI (10). Volumetric reductions and white matter hyperintensities have been identified in prefrontal subregions, the hippocampus and subcortical nuclei in older adults diagnosed with MDD (11-14). Volume decreases associated with late-life MDD have been correlated with duration of illness and age of disease onset, particularly measures of parahippocampal and inferior parietal regions (15).

Furthermore, smaller brain volumes and high intensity lesions appear to be autonomous pathways to MDD in the elderly (10).

As previously stated, there is little work investigating the biological basis of minor depression. In an earlier study of minor depression in late life, we reported that the volume of the prefrontal lobe was significantly smaller in patients when compared with healthy comparison subjects (16;17). More specifically, patients with late life minor depression had frontal lobe volumes that were in between those of healthy comparison subjects and patients with late life MDD (17). The purpose of our current study was to expand on our earlier observation and determine if cortical thickness, a reliable in vivo marker of gray matter structure, was lower in the prefrontal regions in patients diagnosed with late-life minor depression when compared with comparison subjects (18). The thickness of the cortical mantle ranges from 1.5 to 3.4 mm in humans and extends from the pial surface of the brain to the boundary between the gray and white (19). Cortical thickness, due to decreased variability in gray matter cytoarchitecture, is a sensitive measure of the structural integrity of the brain, comparable to such measures as gray matter density (18;20). Cortical thinning has been observed in patients diagnosed with schizophrenia, Alzheimer’s disease and mild cognitive impairment, a condition widely considered to be a precursor of AD (21-23). Thinning of the cortical mantle, more marked in the right hemisphere, has also been identified in patients at increased familial risk for major depression (24) and correlated with measures of attention and emotional memory.

The focus of this study was on prefrontal lobes and its subregions including the anterior cingulate cortex, areas that are consistently implicated in the pathophysiology of mood disorders and formed the basis of the earlier report of minor depression from our laboratory (11).

METHODS

Clinical

Sixteen patients diagnosed with minor depression (7 men, 9 women, mean age =76.25, SD=7.54) using modified DSM criteria (25) and 16 non-depressed comparison subjects (7 men and 9 women, mean age=75.06, SD=5.42) were recruited from the community using identical outreach mechanisms described in detail elsewhere (11). Data from the subjects recruited for this study have not been previously reported. Patients and comparison subjects had comparable medical comorbidities and were free of all neurological brain disorders including dementia. Minor depression was operationally defined as presence of low mood and/or loss of interest in activities and at least one additional symptom from the DSM checklist of one month duration (26). All patients had 17 item Hamilton Depression Scale Scores of between 8 and 14 inclusive (27). Twelve of the 16 patients diagnosed with minor depression reported duration of illness greater than 2 years thereby meeting criteria for dysthymic disorder (chronic clinical depression that does not meet criteria for MDD); however, none of the patients had a prior episode of MDD. The study was performed in accordance with UCLA’s policies of the Human Subject Protection Committees, and written informed consent was obtained from all subjects after the procedures had been fully explained.

MRI

All subjects were scanned on a 1.5 Tesla GE Signa scanner using a coronal T1 weighted spoiled gradient/recall (SPGR) acquisition with the following parameters; TR=42 msec, TE=7 msec, field of view (FOV) =220mm, number of slices=124 and NEX=1. Slices were 1.5 mm contiguous, flip angle of 35 degrees and a matrix of 256 × 192 mm. After acquisition, cortical reconstruction and volumetric segmentation were processed using the Freesurfer Image Analysis Suite (http://surfer.nmr.mgh.harvard.edu). The technical details of these procedures are described in prior publications (28;29). This method uses both intensity and continuity information from the entire three dimensional MR volume in segmentation and deformation procedures to produce representations of cortical thickness, calculated as the closest distance from the gray/white boundary to the gray/CSF boundary at each vertex on the tessellated surface (28). The maps are created using spatial intensity gradients across tissue classes and are therefore not simply reliant on absolute signal intensity. The maps produced are not restricted to the voxel resolution of the original data thus are capable of detecting submillimeter differences between groups. Procedures for the measurement of cortical thickness have been validated against histological analysis (30) and manual measurements (31;32). Freesurfer morphometric procedures have been demonstrated to show good test-retest reliability across scanner manufacturers and across field strengths (33).

Statistics

Groups were comparable across measures of age (HC, 75.1+5.4; Minor, 76.2+7.5, p=.61, t=-.513, df=30) and sex distribution. We performed separate between-group analyses of covariance (ANCOVA) on the neuroimaging measures controlling for age, gender and overall global thickness. Significance tests were adjusted for multiple comparisons using a permutation test for each hemisphere with 2000 iterations each and corrected p-values are reported (34). The regions of interest used in the permutation analyses were based on the a priori hypothesis that cortical thickness differences would occur bilaterally in the prefrontal cortex.

RESULTS

Uncorrected significance maps demonstrated multiple regions of cortical changes between minor depressed subjects and comparison subjects (Figure 1). However, in examining regions that survived permutation testing, older adults with minor depression had significant cortical thinning in the right isthmus cingulate (p = .0037, F = 10.03, df = 1,28; Talairach coordinates: [1, −26, 45]; surface area: 107±20 mm2) compared to healthy comparison subjects (Figure 2). Cortical thickness in this region did not correlate with depression severity or age. It should be noted that overall global cortical thickness did not significantly differ (left hemisphere (LH), p = .9, t=.127, df=30; right hemisphere (RH), p = .746, t=-.327,df=30) between healthy comparison subjects (LH, mean thickness = 2.28+.14mm; RH, mean thickness = 2.26+.14mm) and subjects with minor depression (LH, mean thickness = 2.26+.10mm; RH, mean thickness = 2.28+.09mm).

Figure 1.

Figure 1

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Uncorrected voxel-wise thickness difference maps between healthy comparison and minor depression groups, with general linear model controlled for age and global thickness by hemisphere: (A) left lateral view (B) left medial view (C) right lateral view (D) right medial view. Areas of significant cortical thinning are indicated in blue while significant cortical thickening is indicated in red. The significance scale at the bottom of each view is represented as-log(p). Light gray band indicates a gyrus and dark gray sulcus. Cortical parcellation (color band) is overlaid on top of the surface with transparency on. The area of significant cortical thinning that survived permutation testing was the right isthmus cingulate cortex (white circle).

Figure 2.

Figure 2

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Scatterplot demonstrating significant cortical thinning in the right isthmus cingulate (p = .0037, F=10.03, df=1,28, adjusted p = .046)

CONCLUSIONS

Our results demonstrate, for the first time, that the cortical mantle of subregions of the cingulate is thinner in older adults diagnosed with clinically significant minor depression when compared with non-depressed older adults. The cingulate has been consistently identified as a region that is smaller in MDD when compared with comparison subjects both in our work (11) and others (35;36). Our current findings in late life minor depression expand these observations and demonstrate that cortical thinning in the cingulate region may be a specific structural abnormality relevant in the pathophysiology of minor depression in the elderly. This finding, using automated parcellation methods, indicates that there may be common biological substrates to the spectrum of clinically significant mood disturbances involving depression in the elderly; biological substrates in regions that have well-established roles in both cognitive and emotional processing in humans and animals.

The structural and functional affiliations of the cingulate region are wide-ranging. The cingulate has extensive connections with the hippocampus and the amygdala, with the amygdaloid projection being directed to its anterior part (37-39). Thus, the behavioral implications of the cingulate and its associated neural circuitry include attention, memory, learning, motivation and emotion. Anatomical and physiological abnormalities in this region have been demonstrated in late life depression and in non-geriatric adults with MDD (40-42). For example, lower volumes in the subgenual gray matter have been reported in adults with MDD (41). Furthermore, positron emission tomography studies and studies utilizing functional MRI have shown lower blood flow and blunted hemodynamic response (activation) in response to specific cognitive challenges in elderly patients with MDD (40). Thus, alterations in the structure of the anterior cingulate has broad consequences for emotional, cognitive, and memory processing.

The precise cellular and neurobiological changes that underlie the cortical thinning in patients with mood disorders remain unclear. Changes in brain-derived neurotrophic factor, cortisol and excitatory amino acids have all been invoked as plausible explanations for smaller volumes in circumscribed brain regions in patients with mood disorders (43;44). It is plausible that these neurobiological mechanisms also play a role in cortical thinning as well. Future studies addressing these mechanisms may involve measurement of these biomarkers and correlating them with cortical thickness in this patient population. In addition, post-mortem analyses together with concurrent histological approaches are needed to ascertain and validate the precise relationship of neuroimaging findings to underlying cellular and other neurobiological changes.

The primary limitation of our current study is the relatively small sample sizes of our groups. In addition, the majority of patients in our study sample reported illness duration that exceeded 2 years and consequently met criteria for dysthymic disorder - minor depression two years or longer. Despite this technical distinction between minor depression and dysthymia, based entirely on a subjective history of the duration of current illness, our findings support the fundamental assertion that there are neurobiological correlates to clinically significant minor depression in late life that are comparable to those reported in the literature for more severe forms of depression in older adults including MDD (6;45).

In conclusion, our findings demonstrate that there are cortical thickness reductions in the anterior cingulate regions in elderly patients with minor depression that are comparable to those reported in the literature for patients with MDD. These regions are part of the mesial frontal circuit that has an important role in the regulation of emotions and behavior. These findings support the thesis that milder forms of major depression have neurobiological substrates that may be critical in the pathophysiology of mood disorders. While the term minor depression has crept into psychiatric nosology, it is a misnomer that both miscommunicates the seriousness of these disorders and creates artificial boundaries between this heterogeneous group of disorders and the more readily recognized classical psychiatric illnesses. Our findings provide a converging line of evidence in support of the thesis that there are substantial similarities, both in clinical correlates and neurobiological substrates, between MDD and less severe, but clinically significant forms of depression in the elderly.

Acknowledgements

Supported by research grants from NIMH to Anand Kumar, MD (MH-55115, MH-61567, MH-02043);

Footnotes

the authors of this manuscript have no conflicts of interest to disclose.

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