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Dec 2012, Vol 69, No. 12 >

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Original Article | Dec 2012

Prefrontal Cortical Deficits in Type 1 Diabetes Mellitus:  Brain Correlates of Comorbid Depression

In Kyoon Lyoo, MD, PhD, MMS; Sujung Yoon, MD, PhD; Alan M. Jacobson, MD; Jaeuk Hwang, MD, PhD; Gail Musen, PhD; Jieun E. Kim, MD, PhD; Donald C. Simonson, MD, MPH, ScD; Sujin Bae, PhD; Nicolas Bolo, PhD; Dajung J. Kim, PhD; Katie Weinger, EdD; Junghyun H. Lee, MD, MS; Christopher M. Ryan, PhD; Perry F. Renshaw, MD, PhD
Arch Gen Psychiatry. 2012;69(12):1267-1276. doi:10.1001/archgenpsychiatry.2012.543.
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Context  Neural substrates that may be responsible for the high prevalence of depression in type 1 diabetes mellitus (T1DM) have not yet been elucidated.

Objective  To investigate neuroanatomic correlates of depression in T1DM.

Design  Case-control study using high-resolution brain magnetic resonance images.

Settings  Joslin Diabetes Center and McLean Hospital, Massachusetts, and Seoul National University Hospital, South Korea.

Participants  A total of 125 patients with T1DM (44 subjects with ≥1 previous depressive episodes [T1DM-depression group] and 81 subjects who had never experienced depressive episodes [T1DM-only group]), 23 subjects without T1DM but with 1 or more previous depressive episodes (depression group), and 38 healthy subjects (control group).

Main Outcome Measures  Spatial distributions of cortical thickness for each diagnostic group were compared with the control group using a surface-based approach. Among patients with T1DM, associations between metabolic control measures and cortical thickness deficits were examined.

Results  Thickness reduction in the bilateral superior prefrontal cortical regions was observed in the T1DM-depression, T1DM-only, and depression groups relative to the control group at corrected P < .01. Conjunction analyses demonstrated that thickness reductions related to the influence of T1DM and those related to past depressive episode influence were observed primarily in the superior prefrontal cortical region. Long-term glycemic control levels were associated with superior prefrontal cortical deficits in patients with T1DM (β = −0.19, P = .02).

Conclusions  This study provides evidence that thickness reduction of prefrontal cortical regions in patients with T1DM, as modified by long-term glycemic control, could contribute to the increased risk for comorbid depression.
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Figure 1. Mean cortical thickness maps for the type 1 diabetes mellitus (T1DM)–only (n = 81), depression (n = 23), T1DM-depression (n = 44), and control (n = 38) groups and statistical maps showing differences in cortical thickness between groups. Patients with T1DM who have never experienced depressive episodes are defined as the T1DM-only group. Subjects who had 1 or more previous depressive episodes but were not currently depressed are defined as the depression group. Patients with T1DM who had 1 or more previous depressive episodes but were not currently depressed are defined as the T1DM-depression group. Healthy individuals who have not had either T1DM or past depressive episodes are defined as the control group. Brain regions in orange and light yellow of the brain template indicate clusters of significant group differences, thinner than control subjects, adjusting for age and sex at initial cluster-forming thresholds of P < .01 and P < .05, respectively, corrected for multiple comparisons. There were no regions of increased cortical thickness in the T1DM-only, T1DM-depression, or depression groups relative to the control group. L indicates left; R, right.

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Figure 2. Conjunction analyses for the brain regions of jointly significant cortical thickness differences between the type 1 diabetes mellitus (T1DM)–only and T1DM-depression vs control groups (A) and between the depression and T1DM-depression vs control groups (B). There were no regions of significantly greater cortical thickness in the T1DM-only, T1DM-depression, and depression groups relative to the control group. L indicates left; R, right.

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Figure 3. Regression slopes for lifetime glycemic control levels and prefrontal cortical deficits in the type 1 diabetes mellitus (T1DM)–only and T1DM–depression groups. The superior prefrontal cortical (sPFC) cluster is defined from the conjunction analysis for T1DM influence shown in Figure 2A. The gray and orange lines correspond to the regression lines (lines of best fit) of associations between lifetime average hemoglobin A1C (HbA1C) and thickness of the sPFC cluster for the T1DM-only (β = −0.13, P = .23) and the T1DM-depression (β = −0.29, P = .03) groups, respectively. Age and sex were included into the regression model as covariates. Gray and orange arrows on the y-axis represent the mean age-adjusted and sex-adjusted thickness of the sPFC cluster of the T1DM-only and the T1DM-depression groups, respectively, and there was a significant difference in the mean thickness of the sPFC region of interest between groups (t = 2.11, P = .03). Gray and orange arrows on the x-axis represent the mean values of lifetime average HbA1C of the T1DM-only and the T1DM-depression groups, respectively. Although the T1DM-depression group shows numerically higher lifetime average HbA1C levels than the T1DM-only group, there is no significant difference in lifetime average HbA1C levels between groups (t = 1.23, P = .22).

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Response to: Prefrontal cortical deficits in type 1 diabetes mellitus: brain correlates of comorbid depression
Posted on January 10, 2013
Eelco van Duinkerken, Frederik Barkhof, Martin Klein, Michaela Diamant, Frank J. Snoek
VU University Medical Center
Conflict of Interest: None Declared

We read with great interest the article by Lyoo, et al. in the December 2012 issue of Archives of General Psychiatry (1). The authors studied cortical thickness in type 1 diabetes (T1DM) patients with and without a history of depression, non-T1DM participants with a history of depression and healthy controls. None met DSM-IV-TR criteria for current depression, with HDRS within normal range. Compared with controls all other groups showed reduced cortical thickness, while no differences between T1DM- and non-T1DM depression groups were observed. The superior prefrontal cortex (sPFC) was identified as a possible neuronal substrate of co-morbid depression in T1DM (1). The authors demonstrated a stepwise reduction in sPFC thickness, executive and memory functioning from controls, T1DM without, to T1DM with previous depression (Lyoo, et al. eFigure 4-5) (1). Cognitive functioning was 0.4 standard deviations lower in T1DM with versus without previous depression, whereas sPFC thickness was only slightly lower in T1DM with versus without previous depression (1).

This trend-analysis could indicate that cognition may be permanently affected by depression, whereas brain structure could recuperate after remission (neuronal plasticity). Data from studies in depression support this differential effect on the brain (2, 3). The prolonged impact of depression on cognition, even after remission may be of clinical importance as it might compromise individuals’ quality of life and interfere with their daily functioning, including diabetes (self)care. The hypothesis forwarded here needs to be further studied.

Moreover, the trend-analysis could imply that permanent effects of depression on cognition cannot be explained by temporary loss of brain volume or thickness. Functional connectivity, communications between and within neuronal networks, is an important underlying mechanism of cognition (4), and could be a key factor in explaining depression-related cognitive dysfunction. Additionally, structural connectivity (i.e. white matter tract integrity) between brain regions is a ‘hardware’ prerequisite for functional connectivity and therefore may also have a key role in depression-related cognitive decrements. Indeed in T1DM without depression, functional connectivity, measured using resting-state functional MRI and magnetoencephalography, is altered compared with non-T1DM controls (5, 6). Structural connectivity, measured by MR-Diffusion Tensor Imaging, was found lower in these T1DM patients relative to controls (7). These changes were found diffusely distributed throughout the brain (5-7). It was also shown that higher degrees of functional and structural connectivity are related to better cognitive performance on domains commonly affected in T1DM, including processing speed and attention (5-7).

Lyoo, et al. provide first evidence of cortical and cognitive alterations in T1DM patients with remitted depression (1). Similar findings were reported in type 2 diabetes patients with current depression (8). This underscores the need for further research in the field, both in type 1 and type 2 diabetes--more so when we realize that an estimated 10% of the worlds adult population will suffer from diabetes by 2030 (9), and approximately 20% of those patients will suffer from clinically relevant depressive symptoms (10). To further our understanding of the debilitating effects of depression on cognition we suggest using state-of-the-art imaging techniques to assess functional and structural connectivity in diabetes patients with and without depression.

References:

1. Lyoo IK, Yoon S, Jacobson AM, et al. Prefrontal cortical deficits in type 1 diabetes mellitus: Brain correlates of comorbid depression. Arch Gen Psychiatry. 2012;69(12):1267-1276.

2. Paelecke-Habermann Y, Pohl J, Leplow B. Attention and executive functions in remitted major depression patients. J Affect Disord. 2005;89:125-135.

3. Phillips JL, Batten LA, Aldosary F, Tremblay P, Blier P. Brain-volume increase with sustained remission in patients with treatment-resistant unipolar depression. J Clin Psychiatry. 2012;73:625-631.

4. Bressler SL. Understanding cognition through large-scale cortical networks. Curr Dir Psychol Sci. 2002;11:58-61.

5. van Duinkerken E, Klein M, Schoonenboom NS, et al. Functional Brain Connectivity and Neurocognitive Functioning in Patients with Longstanding Type 1 Diabetes Mellitus with and without Microvascular Complications: a Magnetoencephalography Study. Diabetes. 2009;58(10):2335-2343.

6. van Duinkerken E, Schoonheim MM, Sanz-Arigita EJ, et al. Resting-state brain networks in type 1 diabetes patients with and without microangiopathy and their relation with cognitive functions and disease variables. Diabetes. 2012;61:1814-1821.

7. van Duinkerken E, Schoonheim MM, IJzerman RG, et al. Diffusion tensor imaging in type 1 diabetes: decreased white matter integrity relates to cognitive functions. Diabetologia. 2012;55:1218-1220.

8. Ajilore O, Narr K, Rosenthal J, et al. Regional cortical gray matter thickness differences associated with type 2 diabetes and major depression. Psychiatry Res. 2010;184(2):63-70.

9. International Diabetes Federation. Diabetes Atlas, 5th edition; 2012.10. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The Prevalence of Comorbid Depression in Adults With Diabetes: A meta-analysis. Diabetes Care. June 1, 2001 2001;24(6):1069-1078.

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