Elsevier

Journal of Affective Disorders

Volume 213, 15 April 2017, Pages 191-198
Journal of Affective Disorders

Research paper
Depressive disorder may be associated with raphe nuclei lesions in patients with brainstem infarction

https://doi.org/10.1016/j.jad.2017.02.005Get rights and content

Highlights

  • Depressive disorder was more frequent in the raphe-nuclei-damaged patients with brainstem infarction.

  • Montgomery Åsberg Depression Rating Scale scores were higher in the damaged patients.

  • Diffusion tensor imaging and proton density-weighted images were used to identify the damage in the dorsal and median raphe nucleus.

  • Findings suggest that the disruption of the ascending serotonergic system is a key mechanism underlying depressive disorder due to stroke.

Abstract

Background

Depression is a common symptom after stroke, but its neural substrates remain unclear. The ascending serotonergic system originates from the raphe nuclei in the brainstem. We hypothesized that depressive disorder due to brainstem infarction is associated with damage to the raphe nuclei.

Methods

We prospectively enrolled 19 patients who had the first-ever acute isolated brainstem infarction in an observational cross-sectional study. All patients were evaluated by using the Montgomery Åsberg Depression Rating Scale (MADRS), the clinician-rated version of Apathy Evaluation Scale (AES-C) and Mini-Mental State Examination (MMSE). Depressive disorder was diagnosed according to DSM-5 and MADRS score of 12 or greater. Diffusion tensor imaging and proton density-weighted images were used to identify damage in the raphe nuclei. Accordingly, patients were classified into either the raphe-nuclei–damaged or intact group. Prevalence of depressive disorder and the MADRS, AES-C, and MMSE scores were compared between the two groups.

Results

Depressive disorder was more frequent in the damaged group (n=6) than in the intact group (n=13) (83% vs. 15%; P=0.01). MADRS scores were higher in the damaged group than in the intact group (mean±1 SD, 17.5±7.9 vs. 7.0±4.4; P=0.002), whereas the AES-C and MMSE scores did not differ between groups.

Limitations

We did not assess the damage to the ascending projection fibers from the raphe nuclei.

Conclusions

Our results suggest that damage to the raphe nuclei underlies depressive disorder due to brainstem infarction, possibly via serotonergic denervation.

Introduction

Depressive disorder is a common and important affective problem after stroke (Pohjasvaara et al., 1998, Robinson and Jorge, 2016). The most recent meta-analysis of 61 cohorts, comprising a total of 25,488 patients, reported that 31% of patients developed depression within 5 years after stroke (Hackett and Pickles, 2014). Depressive disorder can influence the prognosis of rehabilitation (Matsuzaki et al., 2015), and severity of depression is an independent predictor of severity of impairment in activities of daily living (Robinson, 2006).

Although depression is a critically disabling symptom for patients, the pathogenesis of depressive disorder due to stroke remains to be elucidated. Five meta-analyses failed to reveal a clear relationship between depressive disorder due to stroke and stroke lesions in the cerebral hemispheres (Ayerbe et al., 2013, Carson et al., 2000, Kutlubaev and Hackett, 2014, Wei et al., 2015, Yu et al., 2004). However, other studies assessing clinical populations proposed possible pathogeneses for depressive disorder due to stroke. For example, levels of the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA) in cerebrospinal fluid were decreased in patients with depressive disorder due to cerebral infarction (Bryer et al., 1992). Because serotonin-containing neural fibers are thought to run through the limbic system and prefrontal cortex via the medial forebrain bundle, projecting to broad areas in the cerebral hemisphere; this finding suggests that such fibers are damaged in depressive disorder due to stroke (Hornung, 2003). Serotonin may thus play an important role in the development of depressive disorder due to stroke, as in other types of depression (Loubinoux et al., 2012).

Serotonin is produced by neurons in the raphe nuclei that lie near the midline tegmentum along the rostrocaudal axis in the brainstem (Hornung, 2003). The rostral group of raphe nuclei consists of the dorsal raphe nucleus (DRN), located in the midbrain, and the median raphe nucleus (MRN), in the upper pons. The DRN and MRN are the main origins of the ascending serotonergic projections to the cerebral hemispheres (Hornung, 2003). The association between depressive disorder due to stroke and damage to the DRN and MRN has not yet been investigated. Although the internal structures of the brainstem are difficult to visualize in vivo by using routine clinical magnetic resonance imaging (MRI) sequences, some complex anatomical structures, including the raphe nuclei, can be discriminated by using advanced neuroimaging techniques, such as diffusion tensor imaging (DTI) (Aggarwal et al., 2013) and proton density-weighted imaging (PDWI) (Sasaki et al., 2008).

Another common affective symptom after stroke is apathy, of which loss of interest or pleasure is a major factor. Depressive disorder often coexists with or is misdiagnosed as post-stroke apathy because these conditions share several features (Hama et al., 2011). Therefore, we assessed apathy as well as depressive disorder in patients with brainstem infarction.

To our best knowledge, no previous study has demonstrated the frequency and etiology of depressive disorder due to brainstem infarction. We hypothesized that damage to the raphe nuclei due to brainstem infarction is associated with depressive disorder. Here, we used DTI and PDWI to identify the damage to the DRN and MRN, and tested the association between depressive disorder and the damage to the DRN, MRN, or both nuclei.

Section snippets

Ethics statement

The Institutional Review Boards of Tokyo Medical and Dental University and the three participating hospitals approved this study. All procedures followed were in accordance with institutional guidelines. All patients gave prior written informed consent to participate in this study.

Study design

This study was an observational cross-sectional study.

Patients

We prospectively enrolled patients who suffered a brainstem infarction and were admitted to three hospitals with stroke units: Musashino Red Cross Hospital

Results

We enrolled 19 patients (9 at Musashino Red Cross Hospital, 8 at JA Toride Medical Center, and 2 at Tsuchiura Kyodo General Hospital) from October 2013 through December 2015; 6 patients were classified into the damaged group, and 13 into the intact group. Patients’ demographic data are summarized in Table 1; there was no significant intergroup difference in any demographic parameter other than lesion volume (P=0.02). The number of FLAIR high intensity lesions were as follows (number of lesions

Discussion

This study is the first to demonstrate an association between depressive disorder due to acute isolated brainstem infarction and the primary damage to the DRN or MRN. Depressive disorder was significantly more frequent in patients with damaged raphe nuclei (83%) than in those whose nuclei were intact (15%). The DRN and MRN are distributed near the midline tegmentum along the rostrocaudal axis in the brainstem (Hornung, 2003); these nuclei can be damaged when an infarct lesion reaches the

Limitations

The current study has several limitations. First, technical difficulties prevented us from assessing the damage to ascending projection fibers from the raphe nuclei. In color map, blue color area contains not only serotonergic fibers but also other ascending and descending fibers according to the anatomical knowledge. Thus, we couldn’t discriminate the ascending serotonergic fibers from other structures in the brainstem. Consequently, patients who had serotonergic denervation due to damage to

Conclusion

Damage to the DRN and MRN is associated with depressive disorder after brainstem infarction. This suggests that disruption of the ascending serotonergic system is a key mechanism underlying depressive disorder due to stroke.

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