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