Brain Imaging and Behavior DOI 10.1007/s11682-016-9605-7
ORIGINAL RESEARCH
Depression and anxiety symptoms are associated to disruption of default mode network in subacute ischemic stroke Jéssica Elias Vicentini 1,2 & Marina Weiler, PhD 1,2 & Sara Regina Meira Almeida 1,2 & Brunno Machado de Campos 1,2 & Lenise Valler 1,2 & Li Min Li 1,2
# Springer Science+Business Media New York 2016
Abstract Depression and anxiety symptoms are common after stroke and associated to reduction in quality of life and poor physical and social outcomes. The Default Mode Network (DMN) plays an important role in the emotional processing. We investigated whether these symptoms are associated to a disruption of DMN functional connectivity in the first month after stroke. Thirty-four subacute ischemic stroke patients were submitted to: 1) behavioral assessment through Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Structured Clinical Interview for DSM Disorders; 2) neuropsychological assessment using Mini Mental State Examination and Montreal Cognitive Assessment; 3) resting state functional magnetic resonance imaging acquisition using a 3 T scanner (Philips Achieva). Patients with depression and/ or anxiety symptoms showed an increased DMN functional connectivity in left inferior parietal gyrus and left basal nuclei, when compared to stroke controls. Specific correlation between BDI/BAI scores and DMN functional connectivity indicated that depression symptoms are correlated with increased functional connectivity in left inferior parietal gyrus, while anxiety symptoms are correlated with increased functional connectivity in cerebellum, brainstem and right middle frontal gyrus. Our study provides new insights into the underlying mechanisms of post stroke depression and anxiety, suggesting an alternate explanation other than regional structural
* Li Min Li
[email protected] 1
Brazilian Institute of Neuroscience and Neurotechnology, Brainn, Campinas, SP, Brazil
2
Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Vital Brasil, 251, Zeferino Vaz, Campinas, SP 13083-888, Brazil
damage following ischemic event, that these psychiatric symptoms are related to brain network dysfunction. Keywords Ischemic stroke . Depression . Anxiety . Default mode network . Functional magnetic resonance imaging
Background Post stroke depression and anxiety are common in stroke survivors. Previous meta-analysis studies estimated that post stroke depression (PSD) symptoms occurs in 33 % of subjects, ranging from 19 % to 44 % (Hackett et al. 2005) and post stroke anxiety (PSA) symptoms assessed by rating scales affects 25 % of patients (Burton et al. 2013), ranging from 21 % to 28 %. Variations of reported PSD and PSA frequencies probably reflect differences in patient selection or time of assessment and diagnostic criteria (Andersen 1997; Robinson 2006). Both depression and anxiety are associated to reduction in quality of life and poor physical and social outcomes (Astrom 1996; Shimoda and Robinson 1998; Chemerinski and Robinson 2000; Chemerinski et al. 2001; Pan et al. 2008). Despite their high prevalence and negative consequences on recovery, these psychiatric disorders are relatively neglected in comparison to research carried out regarding the physical disabilities after stroke. Mechanisms involved in PSD and PSA are still unclear. Available clinical data about the relationship between these psychiatric symptoms and lesion location have been contradictory. Carson et al. (2000) in a meta-analysis found no support for the hypothesis of brain lesion location and risk of development of PSD. In a recent systematic review, Wei et al. (2015) reported a significant association between right hemisphere stroke and incidence of depression within 1– 6 months post stroke. However, the research had limitations
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such as no standardized measures of depression, different cutoff points on scales, variable interval between stroke and depression assessment and different methods of reporting results (Wei et al. 2015). Exclusion criteria of aphasic patients may also have accounted as a confounding variable to associate increased risk of depression and right-sided lesions (Yu et al. 2004). The same is true for PSA, where few studies explored the relationship between anxiety symptoms and lesion location, and the results are also conflicting (Astrom 1996; Sharpe et al. 1990). Functional neuronal network disruption has been suggested to be more critical than lesion location to explain PSD and PSA (Fornito et al. 2015). fMRI allows assessment of neuronal functional connectivity based on temporal correlation between the low-frequency fluctuations in the blood oxygen level dependent signal from different brain areas (Friston et al. 1993; Biswal et al. 1995). One of the most studied networks is the Default Mode Network (DMN), which mediates self-referential processing during resting-state (Raichle et al. 2001). DMN also seems to play an important role in emotional processing (Greicius et al. 2003), especially in depression and anxiety (Greicius et al. 2007; Grimm et al. 2009a, 2009b; Sheline et al. 2009). In stroke patients, only one study (Lassalle-Lagadec et al. 2012) has explored DMN in association with PSD and PSA despite its potential involvement as the underlying mechanism of these symptoms. In this study, Lassalle-Lagadec et al. (2012) in addition to show that the disruption of functional connectivity predicted depressive symptoms three months after a stroke, they suggested a correlation between altered functional connectivity of DMN with anxiety severity, but not with depression, ten days after stroke. These results allow us to hypothesize that depression and anxiety symptoms after stroke are associated with changes in DMN functional connectivity and in different ways. Therefore, we seek as primary aim to assess whether patients with symptoms of depression and/or anxiety have a disruption of DMN in the first month after stroke. In addition, our secondary aim is to investigate patterns of DMN disruption in PSD and PSA symptoms and to correlate regions of DMN disruption to the severity of anxiety and depression symptoms.
Methods Participants In this study, 37 right-handed patients aged 45–80 years who had experienced their first unilateral ischemic stroke were recruit between February 2014 and June 2015 through an emergency unit of the Clinics Hospital of the University of Campinas (UNICAMP). We decided to exclude stroke affecting young age ( 0.25 or r < −0.25. Second level imaging analysis was performed with SPM12, following the parameters of p < 0.001 uncorrected and cluster size with at least 50 voxels. In order to investigate the primary aim, we performed a two-sample t-test adjusting for NIHSS and modified Rankin Scale scores. To assess the secondary aim of the study, we carried out correlation analysis between BDI/BAI scores and DMN functional connectivity. At this stage, to increase the statistical power, all 34 individuals were combined into a single group. Using Spearman correlation test, the following variables correlated with BDI: age, MoCA, NIHSS, modified Rankin scale and BAI. Gender, age, years of education, in-hospital length stay and BDI correlated with BAI. For this reason, we included them as adjustment in the functional connectivity analysis.
Results Regarding the correlation between PSD/PSA symptoms and demographic and clinical characteristics, BDI scores were associated with NIHSS, modified Rankin scale, age, MoCA and BAI scores. The correlation between BAI scores and other variables was found for gender, age, years of schooling, inhospital length and BDI scores (Table 1). Frequency of PSD and PSA symptoms was 20.6 % (7/34) and 11.8 % (4/34), respectively. Although they are different entities, we grouped PSD and PSA symptoms due to number of PSD group and PSA group did not allow us to conduct a separated statistical analysis. We grouped PSD and PSA based on the assumption that both depression and anxiety are stressrelated disorders, since depression has been conceptualized as a dysregulated activation of the generalized stress response (Chrousos 1998; Raison and Miller 2003) and anxiety can be a result of chronic activation of stress response and
Brain Imaging and Behavior Table 1 Statistical analysis of Spearman correlation between BDI/BAI scores and different variables (n = 34) Variables
BDI scores
BAI scores
Gender
-0.167
-0.356*
Age
0.308*
BAI scores positively correlated with DMN functional connectivity in right and left cerebellum, left and right brainstem and right middle frontal gyrus, as demonstrated in letter C of Fig. 1. Coordinates and cluster sizes are shown in Table 6.
-0.406*
Years of schooling MEEM
0.006 -0.204
0.325* 0.177
Discussion
MoCA
-0.335*
0.136
modified Rankin Scale NIHSS
0.519* 0.463*
-0.178 -0.081
Time of post-stroke In-hospital length stay
0.112 0.014
-0.234 -0.324*
Stroke hemisphere
-0.153
-0.052
Stroke localization
Our study showed that patients with PSDA symptoms have disruption of DMN in the first month after stroke. The demographic and clinical characteristics of patients showed that both PSD and PSA symptoms are frequent in the first month. These results are consistent to literature (Hackett et al. 2005; Burton et al. 2013) and emphasize the importance of understanding its mechanisms. We observed that group of patients with PSDA had more severe functional impairment than group PSCon. Specifically, functional impairment correlated with BDI scores, but not with BAI scores (Table 1). Astrom et al. (1993) reported association between previous dependence in activities of daily living (ADL) and depression at three months post-stroke. Ramasubbu et al. (1998) found that depressed stroke patients evidenced greater physical impairment than non depressed patients at 7–10 days post stroke. In a review, Robinson (2006) found 83 % of studies reported that depression impairs recovery in activities of daily life. Narushima and Robinson (2003) showed an improvement in ADL in a prospective study which patients with or without depression were treated with selective serotonin reuptake inhibitors in first month after a stroke. Although the association between anxiety and dependency in activities of daily living has been reported in literature (Astrom 1996), our results corroborate other studies that did not find association between functional impairment and anxiety symptoms (Shimoda and Robinson 1998; BarkerCollo 2007; Menlove et al. 2015). The fMRI study disclosed an increased DMN functional connectivity in left inferior parietal gyrus and left basal nuclei of PSDA in comparison to PSCon. Our finding indicates that abnormalities in this network are involved in the symptomatology of post stroke depression and/or anxiety. Although we faced a lack of studies exploring the neural mechanisms underlying the functional impairment of the DMN in stroke patients with symptoms of depression and anxiety, a relative large number of population studies corroborate our results. Greicius et al. (2007) in a seminal study described increased subgenual cingulate and thalamic functional connectivity in subjects with depression. Subsequent publications have shown functional abnormalities for a range of brain regions for both depression (for a review, see Wang et al. 2012) and anxiety disorders (for a review, see Peterson et al. 2014). Therefore, it was demonstrated that depressed subjects with high comorbid anxiety had increased connectivity in the posterior regions of the DMN, suggesting
-0.241
0.163
Stroke arterial territory Fazekas scale BDI
0.186 0.168 1
0.218 -0.157 0.251*
BAI
0.251*
1
NIHSS: National Institute of Health Stroke Scale; MMSE: Mini-Mental State Examination; MoCA: Montreal Cognitive assessment; BDI: Beck Depression Inventory; BAI: Beck Anxiety Inventory; *r > 0.25 or r < −0.25 were considered as significant for inclusion as adjustment variable in statistical analysis between BDI/BAI scores and DMN functional connectivity performed in SPM12
consequent long-term biological damage (Chrousos 1998; McEwen 2003). There were no statistical differences between post stroke patients with depression and/or anxiety symptoms group (PSDA) and post stroke patients without depression and/or anxiety symptoms group (PSCon) for gender, age, years of schooling, time of post stroke imaging acquisition, inhospital length stay, use of thrombolysis, stroke hemisphere, stroke localization, stroke arterial territory, MMSE and MoCA. As expected, groups differed for BDI scores (p < 0.001). However, for BAI scores, there was only a trend to significant difference (p = 0.081). NIHSS and modified Rankin scale were significantly different between groups (p = 0.048 and p = 0.007, respectively). Demographic and clinical characteristics of patients are shown in Table 2. Stroke lesions were found in frontal, parietal and insular lobes, basal nuclei, corona radiata and brainstem (Table 3). Regarding the results of DMN, we found increased functional connectivity in left inferior parietal gyrus and left basal nuclei of PSDA group in comparison to PSCon, as shown in Table 4. The functional connectivity differences within the DMN of the two groups are illustrated in letter A of Fig. 1. We found a positive correlation between BDI scores and DMN functional connectivity in left inferior parietal gyrus (see letter B in Fig. 1). Coordinates and cluster sizes are represented in Table 5.
Brain Imaging and Behavior Table 2 Demographic and clinical characteristics of stroke patients with and without symptoms of anxiety and depression
Patient Characteristics
PSDA
PSCon
Level of significance
N Age (years)
10 63.8 ± 10.2
24 61.9 ± 9.6
p = 0.621
Gender (female)
4
8
p = 0.711
Years of schooling (years) Time after stroke (days)
7.1 ± 6.7 24.4 ± 7.9
5.2 ± 3.23 26.2 ± 7.3
p = 0.548 p = 0.536
In-hospital length stay
2.70 ± 3.34
2.71 ± 2.46
p = 0.380
7 (70)
13 (54.2)
p = 0.393
3 (30)
11 (45.8)
Stroke Hemisphere (%) Right Left Stroke localization (%) Cortical
6 (60)
12 (50)
Subcortical
4 (40)
12 (50)
9 (90) 1 (10)
23 (95.8) 1 (4.2)
Use of thrombolysis (%)
0 (0)
3 (8)
p = 0.542
Fazekas scale NIHSS modified Rankin Scale 0
1.60 ± 0.96 4.60 ± 4.22
1.46 ± 1.10 1.83 ± 2.60
p = 0.739 p = 0.048*
Stroke arterial territory (%) Anterior Posterior
p = 0.594
p = 0.508
0 (0.0)
8 (33.3 %)
1 2 3
2 (20 %) 4 (40 %) 1 (10 %)
10 (41.7 %) 1 (4.2 %) 3 (12.5 %)
4 MMSE MoCA
3 (30 %) 22.4 ± 9.0 15.2 ± 8.1
2 (8.3 %) 24.1 ± 3.4 17.0 ± 4.3
p = 0.732 p = 0.412
BDI BAI
13.0 ± 4.3 4.3 ± 2.2
4.3 ± 2.7 8.8 ± 6.7
p < 0.001* p = 0.081
p = 0.007*
Data presented as average ± standard deviation. PSDA: post stroke depression and/or anxiety symptoms group; PSCon: post stroke control group; NIHSS: National Institute of Health Stroke Scale; MMSE: mini-mental status examination; MoCA: Montreal Cognitive assessment; BDI: Beck Depression Inventory; BAI: Beck Anxiety Inventory. *significant difference
an effort to detect external or internal potential sources of threat (Andreescu et al. 2011).
Table 3
Description of patients’ cerebrovascular lesion
Stroke localization
PSDA group (n = 10)
PSCon group (n = 24)
Cortical region (%) Frontal lobe Parietal lobe Insular lobe Subcortical region (%) Basal nuclei Corona radiata Brainstem
6 (60) 4 (40) 2 (20) 0 (0) 4 (40) 1 (10) 2 (20) 1 (10)
12 (50) 9 (37.5) 2 (8.3) 1 (4.2) 12 (50) 6 (25) 5 (20.8) 1 (4.2)
Coutinho et al. (2015) found anterior portions of DMN including medial prefrontal, anterior cingulate and orbitofrontal cortex to be correlated with anxiety and depression scores in healthy individuals, whereas posterior regions of DMN such as posterior cingulate cortex, precuneus, angular gyrus and inferior parietal cortex were negatively correlated with anxiety and depression scores. These findings could be interpreted as functional specialization of DMN, in which anterior regions would be associated with self-referential and emotional processes and posterior areas would be involved in episodic memory and perceptual processing (Zhu et al. 2012). Yet, our results showed posterior areas of DMN positively correlated with depression and anxiety symptoms adjusted for MoCA score. Moreover, the MMSE and MoCA yielded no differences between groups for general cognition, suggesting that DMN functional connectivity in posterior areas may also be related to depression and anxiety symptoms.
Brain Imaging and Behavior Table 4 Anatomical regions of increased DMN functional connectivity of PSDA patients vs PSCon (p < 0.001, uncorrected)
Stereotaxic coordinates (mm) Cluster size
Region
X
Y
Z
T value
Z value
157
Left inferior parietal gyrus
-32
-84
42
4.66
4.01
78
Left basal nuclei
-16
-22
-8
4.43
3.86
In this regard, Lassalle-Lagadec et al. (2012) also showed the recruitment of posterior regions of DMN in post stroke depression and anxiety symptoms. Similar to our results, in
which we showed a positive correlation between DMN functional connectivity in bilateral cerebellum, bilateral brainstem and right middle frontal gyrus with anxiety scores of BAI,
Fig. 1 Group comparison of DMN functional connectivity (a) and correlation results between depression/anxiety symptoms and DMN functional connectivity (b and c, respectively) Letters represent each statistical analysis. a independent t-test adjusted for NIHSS and modified Rankin Scale showed that PSDA group presented increased DMN functional connectivity in left inferior parietal gyrus and left basal nuclei when compared to PSCon. b positive correlation between BDI scores and
DMN functional connectivity in left parietal gyrus. Statistical analysis was adjusted for NIHSS, modified Rankin Scale, age, MoCA and BAI scores. c positive correlation between BAI scores and DMN functional connectivity in bilateral cerebellum, bilateral brainstem and right middle frontal gyrus. Statistical analysis was corrected for gender, age, years of schooling, in-hospital length and BDI scores. Colored bar denotes t values, p < 0.001 uncorrected, cluster size ≥50 voxels
Brain Imaging and Behavior Table 5 Coordinates and cluster size of positively correlated area between BDI scores and DMN functional connectivity (p < 0.001, uncorrected) Stereotaxic coordinates (mm) Cluster size
Region
X
Y
Z
T value
Z value
225
Left inferior parietal gyrus
-46
-56
52
4.64
3.94
they also found increased DMN functional network correlated with a scoring scale of anxiety symptoms in the subacute phase, but in middle temporal cortex. Additionally, they reported a negative correlation between anterior midcingulate cortex and left insula with anxiety symptoms. Variation regarding their reported results and ours may be justified by different scoring scale and time of assessment. Even so, regardless the different regions that can turn more or less activated, both studies showed that anxiety symptoms are correlated to DMN disruption. Nevertheless, they did not find a correlation between the depression scoring scale and DMN functional connectivity ten days post stroke. Thus, our study was the first to report the involvement of DMN functional connectivity in depression symptoms in the subacute phase of stroke. In addition, we also showed distinct patterns within DMN disruption for PSD and PSA symptoms. In relation to depression symptoms, the inferior parietal lobule, especially the posterior portion, showed increased connection. Along with the posterior cingulate cortex/precuneus and the medial prefrontal cortex, this is a DMN core area, suggesting that depression could be directly related to this network. The DMN is an anatomical-functional unit engaged in the processing of selfreferential stimuli and is a fundamental component in generating a model of the ‘self’, an aspect known to be affected in depressed patients (Northoff et al. 2006). Because the role of the DMN during resting periods is to properly make selfreferential processing, miscommunications between the DMN regions might cause the self-related problems faced by depressed patients (Northoff 2013; Grimm et al. 2009a, 2009b). Moreover, inferior parietal lobule is described in literature as contributing to the attentional control directed at internal and mnemonic representations (Shomstein 2012; Wagner et al. 2005). It was suggested that increased functional Table 6 Coordinates and cluster size of positively correlated areas between BAI scores and DMN functional connectivity (p < 0.001, uncorrected)
connectivity in regions related to attentional and memory processes in depression can be a result from previous negative emotional experiences, which can persist even in the absence of current external events or a representation of prediction in consequence of the overall negative expectations (Zhou et al. 2010). In agreement, a previous review found that patients with Major Depression Disorder exhibited enhanced attention and memory for negative emotional material, but they showed an attentional bias away from positive emotional cues (Leppänen 2006), suggesting an association between negative emotion and attention/memory processes. So, we assumed that despite posterior regions of the DMN are described as more related to episodic memory and perceptual processing (Zhu et al. 2012), they could directly influence emotional processing of depression and anxiety symptoms through an intrinsic functional organization. Anxiety symptoms have also been related to DMN functional disconnectivity either during resting periods (Modi et al. 2015) or during reward processing tasks in previous work (Maresh et al. 2014), suggesting functional impairment of the perception of socially relevant emotional state and selfrelated mental representations (Qiu et al. 2011). Thus, increased connectivity of DMN in anxiety may represent a greater effort to remain on alert (Andreescu et al. 2011). Increased connectivity in brainstem and cerebellum showed in the correlation with anxiety allows us to hypothesize that the DMN disruption may be also affected by abnormalities of other networks. It has been reported that the Salience Network, which it is composed by an extensive subcortical connectivity, is involved in anxiety, since it is activated in subjective salient stimulus as in acute stress (Hermans et al. 2014). A previous study with depression showed increased interconnectivity between the Salience Network and DMN, suggesting inter-network aberration in mood disorders (Manoliu et al. 2014). Therefore, intrinsic activity of cerebellum was described as correlated to Executive Network and Salience Network in anxiety vulnerability (Caulfield et al. 2015). The interconnection between posterior cerebellum and associative cortices such as prefrontal and posterior parietal cortex has been shown (Habas 2012; Bostan et al. 2013), suggesting that due to the involvement of cerebellum into cognitive and emotional networks, it may contribute to regulation of cognitive and affective functions. It opens the hypothesis that cerebellum is recruited in face of potential
Stereotaxic coordinates (mm) Cluster size
Region
X
Y
Z
T value
Z value
387 106 63
Left and right cerebellum Left and right brainstem Right middle frontal gyrus
-26 4 40
-92 -30 36
-46 -8 56
5.02 4.66 5.65
4.18 3.95 4.55
Brain Imaging and Behavior
relevant information to subsequent actions or motor planning, which can be integrated into internal models (Stoodley 2012). Affective network may also have an important role in emotional processing. As suggested by Zhang et al. (2014), disruption of Affective Network is present in PSD patients compared to stroke patients and healthy controls. Multiple functional networks in the brain are connected and continuously cooperating with each other (van den Heuvel and Hulshoff Pol 2010) and regions we found disrupted in DMN can be functionally interconnected to other networks. However, our study has been limited to describe DMN, highlighting need for further research exploring the role of other brain networks involved in post stroke depression and anxiety. We recognize limitations in our cross sectional study as of usage of scoring scale of symptoms severity (BDI and BAI) instead of clinical diagnosis, small number of subset of patients with depression and anxiety symptoms to conduct a separated detailed analysis, which lead to drawback in the statistical analysis precluding corrected multiple comparisons. Although we have found a correlation between NIHSS at admission (n = 30) and inclusion (n = 34), this score can strongly change from baseline to first month evaluation depending on the type of acute stroke treatment used and it is a limitation of our study. We felt that future studies combining analysis of structural connectivity of white matter tracts and functional brain regions could deepen the understanding of types of network disruption. In summary, we found a relationship between increased DMN functional connectivity and depression and anxiety symptoms in the first month after stroke. Regarding the patterns of functional connectivity alterations, both PSD and PSA symptoms seem to be distinct and correlated with disruption of the DMN. Our study provides new insights into the underlying mechanisms of post stroke depression and anxiety, suggesting an alternate explanation other than regional structural damage following ischemic event, that these psychiatric symptoms are related to brain network dysfunction. Acknowledgments This study is funded by Cepid-Brainn-Fapesp 2013/07559-3. Jéssica Elias Vicentini was recipient of Fapesp scholarship 2013/23183-3 and Marina Weiler is recipient of Fapesp scholarship 2015/06163-4. Compliance with ethical standards Conflict of interest Jéssica Elias Vicentini, Marina Weiler, Sara Regina Meira Almeida, Brunno Machado de Campos, Lenise Valler and Li Min Li declare that they have no conflict of interest. Informed consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, and the applicable revisions at the time of the investigation. Informed consent was obtained from all patients for being included in the study. The study was approved by Ethics Committee number: 483.401.
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