RETRACTED ARTICLE: Factors associated with post-stroke depression and fatigue: lesion location and coping styles

Post-stroke depression (PSD) and post-stroke fatigue (PSF) are frequent and persistent problems among stroke survivors. Therefore, awareness of signs and symptoms of PSD and PSF is important for their treatment and recovery from stroke. Additionally, since sudden serious illness can result in disequilibrium, early institution of a coping process is essential to restoring stability. The brain damage of stroke leaves patients with unique physical and mental dysfunctions for which coping maybe a key resource while rebuilding lives. We evaluated 368 consecutive patients with acute ischemic stroke for post-stroke emotional disorders at admission and 3 months later. PSD was evaluated by using the Beck Depression Inventory, and PSF was scored with the Fatigue Severity Scale. The Social Support Rating Scale and Medical Coping Modes Questionnaire were also used as measurement tools. Locations of lesions were based on MRI. Those scans revealed infarcts located in the basal ganglia, corona radiate and internal capsule and constituted the independent factors associated with PSF 3 months after stroke occurrence. Conversely, PSD was not related to lesion location. Acceptance-resignation related to PSD and PSF both at admission and 3 months after stroke. Avoidance was the independent factor most closely related to PSD, whereas confrontation was the independent factor best related to PSF at 3 months after stroke onset.


Introduction
Each year, of the approximately 15 million human stroke victims worldwide, at least five million die, and one-third remain disabled [1]. Overwhelming feelings of fatigue, that is, tiredness and lack of energy, is the chief complaint in more than half of the 10 million survivors [2]. Fatigue as a common post-stroke emotional disturbance always impairs patients' ability to regain lost functions [3] and leads to negative long-term outcomes. Similarly, post-stroke depression (PSD) mainly manifested as sadness, reduction of interest and pleasure, and multiple psychological and vegetative symptoms [4] afflicts 20-65 % of these patients, depending on the population studied, the assessment measures, and the definition of depression applied [5]. As the most common psychological sequel of stroke, patients who had PSD experienced the least benefit from rehabilitation, the poorest quality of life and a substantially increased risk of suicide [6].
Several cross-sectional papers have linked fatigue with depression after stroke [7]. In a Swedish study, 49 % of patients with fatigue 1 year after stroke were diagnosed with depression compared with 39 % in the total sample [8]. Similarly, in a Korean study, 34 % of patients diagnosed as depressed were among those with fatigue approximately 15 months after stroke [7]. Fatigue was considered an essential component of PSD [9], and depression-related symptoms such as insomnia or appetite loss resulted in fatigue [10]. In contrast, PSF accompanying PSD is often relieved when the depression is adequately treated [11]. An association between these two syndromes at a particular time point does not necessarily mean that one causes the other or exclude the possibility that a third factor causes both. Nevertheless, among all these attempts to make sense of PSD and PSF, identifying predictors and early signs is crucial for taking preventive measures, promoting early diagnosis, implementing early and adequate treatment, and improving quality of life, both for patients with stroke and for their caregivers.
Some studies invoke more physiologic than behavioral causes for PSD and PSF by suggesting that the extent of stroke-induced functional residual impairment is the major risk factor. Others suggest a possible biological relationship between the occurrence of emotional disturbances and structural brain damage [5]. However, the effect of lesion location has remained the most controversial purported cause of PSD and PSF. With, social support and coping styles also prominent considerations. Coping refers to the person's cognitive and behavioral efforts to manage (reduce, minimize, master, or tolerate) the internal and external demands of his/her environment that seem too taxing or exceed personal resources [12]. Moos and Tsu [13] proposed that sudden serious illness often results in disequilibrium, which triggers adaptive processes to restore equilibrium. The coping process, initiated to restore equilibrium (adaptation), includes cognitive appraisal of the illness, identification of adaptive tasks and coping skills. Contextual factors (background, patient illness and socialenvironmental variables) shape these coping factors. Emotional disturbance and physical health are designated as adaptation outcomes. Since stroke is considered a special physical illness with neurological dysfunction and brain damage, coping may be the key psychological resource involved in rebuilding the lives of patients. Studies assessing coping strategies in patients after stroke have produced inconsistent results [14]. In this context, we evaluated PSD and PSF at different stages after cerebral infarction and attempted to correlate patients' symptoms with lesion location, coping styles and other variables. The goal of this research is to provide new insight into the rehabilitation and management of stroke.

Participants
This descriptive, cohort study was conducted with stroke patients upon admission and at 3 months afterward. Our study was approved by the ethics committees of Tianjin Medical University General Hospital. All participants provided written informed consent. We evaluated 989 consecutive patients who were admitted to Tianjin Medical University General Hospital (Tianjin, China) with a diagnosis of acute stroke, between Jan 2012 and Jun 2014. The diagnosis was confirmed based on CT or MRI findings within 7 days after stroke onset. Exclusion criteria applied to patients with hemorrhagic stroke (n = 83); those with unusual causes such as dissection, venous infarction, or moyamoya disease (n = 77); those with transient ischemic attack without progression to stroke (n = 120); those with communication problems (decreased consciousness, confusion, aphasia, dementia, or dysarthria) severe enough to preclude a reliable interview (n = 142); and those with very severe neurologic or medical conditions (such as metastatic cancer) (n = 54). We also excluded patients who scored B23 on the Mini-Mental State Examination (n = 31), patients diagnosed with depression or other psychiatric illnesses or treated with selective serotonin reuptake inhibitors before the onset of stroke (n = 16), patients who lived alone (because no information was available from relatives) (n = 9), patients who did not undergo a complete follow-up (n = 37), and patients who did not sign an informed consent (n = 52). Finally, 368 patients were enrolled into the study.
Before the project began officially, all interviewers/ raters completed and passed a consistency-training examination. Two researchers (L.C. and F. Z.) recorded all clinical and socio-demographic information. The neuropsychological evaluations were recorded by one of the authors (C. W.) and supervised by a psychiatrist (L. L.). An experienced stroke neurologist (N. Z.) documented patients' neurologic findings during the 3-month follow-up, and one of the authors with experience in neuroimaging (F. Z.) analyzed MRI and Fazeka's scale scores. Questions arising during subsequent interviews were brought to a research team meeting for group consensus on the appropriate answer.

Testing instruments
Depression was assessed with the Beck Depression Inventory (BDI) [15], which was self-recorded. Fatigue was measured on the fatigue severity scale [16,17]. To calculate cognitive functioning we applied the Mini-Mental State Examination (MMSE) [18], a measure of global cognitive decline that encompasses basic cognitive domains. The Social Support Rating Scale (SSRS) [19] was adopted to evaluate social support, which consisted of three dimensions: objective support, subjective support and the degree of social utilization. Coping styles were measured with the Medical Coping Modes Questionnaire (MCMQ) [20,21], which is a 19-item instrument that addresses three forms of coping: confrontation, avoidance and acceptanceresignation.
MRI studies were performed on a 3.0T clinical scanner (HDx, General Electric, USA) with an 8-channel phase-array coil. Locations of lesions based on MRI were characterized as anterior cortical when identified in the anterior cerebral artery territory, the frontal and parietal areas of the middle cerebral artery, or predominantly in the temporal lobe of the middle cerebral artery territory. Posterior cortical referred to the lesions at the following occipital area or medial temporal area of the posterior cerebral artery territory; internal capsule/corona radiata/basal ganglia of the lenticulostriate artery territory; thalamus; pons, including pure midbrain lesions; medulla; and cerebellum [19]. White matter intensity (leukoaraiosis) derived from fluid-attenuated inversion recovery (FLAIR) imaging was graded from 0 to 3 on Fazeka's scale of deep white matter changes, with scores of 2 and 3 indicating significant leukoaraiosis [20].

Procedure
Each first interview was completed at approximately 14 days after the onset of stroke to ensure that the patients were stable. We tried our best to avoid conducting the interviews under conditions of acute neurologic progression or any other condition that could affect the emotions of patients or assessments made by our team. To ensure that each evaluation was reliable, patients were asked to take the interview accompanied by the caregiver who lived with him/her. The caregiver was present to verify the information and to assist the patient, but could not take part in the assessment. Neurologic and psychological assessments (including BDI, FSS, SSRS, MCMQ, Fazeka's scale and symptom observation) were completed by doctors assigned specifically for that purpose. MMSE was used for cognition screening, excluding dementia. The second patient interview was performed 3 months after the onset of stroke. Neurologic and psychological assessments were completed by the same doctors who conducted the first interview.

Diagnostic criteria
PSD was diagnosed in patients with a BDI score [13 or those who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [22,23]. The presence of PSF is defined as an FSS score of 4.0 or more, because fewer than 5 % of healthy controls rate their fatigue at that level. However, 60-90 % of patients with medical disorders experience fatigue at or above that score [3].

Statistical analyses
Ages, years of education, MCMQ and SSRS scores were compared using Mann-Whitney U tests, because they were not normally distributed. Variables of frequency were compared using Chi-square tests. Fisher's exact probability test was used in tests of dichotomous variables when small numbers were involved. Multiple logistic regression analysis was used to explore relationships among PSF/PSD variables. The level of significance was set at P \ 0.05. All data were analyzed by SPSS version 19.0 (IBM Corp., Armonk, NY).

Prevalence of PSD and PSF
A total of 368 participants was enrolled within 14 days after the onset of stroke and completed their second interview at 3 months after the stroke. PSD was diagnosed in 19.3 % of the patients at admission and in 23.6 % at 3 months. Of the 71 patients who developed PSD during the acute stage of stroke, 23 recovered but 48 still had PSD after 3 months. In comparison, 39 patients without PSD at admission had developed PSD at 3 months. PSF was present in 23.4 % of the patients at admission and in 29.6 % at 3 months. Of the 86 patients who developed PSF during the acute stage of stroke, 28 recovered and 58 still had PSF at 3 months, whereas 51 patients without PSF at admission developed PSF at 3 months. Further, 75.6 % (65/86) of the patients who had PSF at admission presented with PSD 3 months after stroke. More than half (38/71, 53.5 %) of the patients who had PSD at admission presented with PSF 3 months after stroke. In addition, 10.9 % (40/368) and 12.2 % (45/368) of the patients had PSD accompanied by PSF at admission and 3 months later, respectively.

Factors related to PSD and PSF
Both motor and sensory dysfunction at admission (P \ 0.01) compared with only motor or only sensory dysfunction was related to PSD at admission. Patients who prefer acceptance-resignation (MCMQ; P \ 0.01) were prone to PSD at admission. Three months later, none of the above risk factors for PSD changed significantly. Moreover, the patients who manifested a lower degree of social utilization (SSRS; P \ 0.05) and chose avoidance coping styles (MCMQ; P \ 0.01) were more prone to PSD. We also found that the patients who had only sensory dysfunction at admission (P \ 0.05) were not susceptible to PSD (Table 1).
As presented in tabular form (Table 3), multivariate logistic regression analysis indicated that initial presentation with PSD at admission was related to both motor and

Discussion
Here as we tracked likely predictors of PSD and PSF in stroke patients to promote early identification and prevention, both conditions changed constantly over time. Fatigue and depression often accompanied occurrence after stroke. Compared with previous studies in which PSF ranged from 36 to 77 % of stroke-afflicted subjects [24], the extent of morbidity documented here represented by was lower, that is, of 71 stroke patients we reviewed. PSF was present in 23.4 % at admission and 29.6 % at 3 months. However, throughout this more than 2-year study, we observed that PSD and PSF changed constantly as time passed. Dopamine and serotonin are considered responsible for fatigue in patients with Parkinson's disease (PD) [25]. With respect to localization of brain damage, basal ganglia, corona radiate or internal capsule infarctions were the independent factors associated with PSF 3 months after stroke occurrence, whereas cerebellum infarction was not susceptible to PSF. Previously, dopamine reward neurons localized in the ventral tegmental area were found projecting into the ventral striatum [26]. Animal experiments have shown that profuse serotonergic fibers from the brainstem raphe nuclei project to the basal ganglia and the cerebellum [27]. In accord, our results suggested that, PSF was related to derangement of dopaminergic system secondary to strokes occurring in strategic areas. Elsewhere, pharmacological studies yielded a reduction in fatigue following the administration of a dopamine agonist [28]. High, moderate and low concentrations of extracellular dopamine induced euphoric, seeking and aversive states, respectively. Still other findings identified circuit loops involving the cerebral cortex, basal ganglia, thalamus, epithalamus, and midbrain through which dopaminergic activity affected motivation [29]. In that study, lack of energy or motivation, boredom, adynamia and lassitude were the main symptoms of fatigue after stroke. Overall, in our hands, the relationship between PSF and lesion location was not significant during the acute stage indicating that the redistribution of neurotransmitters may take some time.
Moreover, there was no evidence that PSD was related to lesion location, despite the correlation between PSF and PSD. Quite possibly though, PSD is an emotional disturbance associated with social stress, premorbid personality or disability caused by stroke. In support, our study confirmed that types of neurologic dysfunction, social support and coping styles were closely associated with PSD. Since neurologic dysfunction was not an independent factor related to PSF, correct cognitive appraisal may be necessary to determine the pathogenesis of PSF. Although we recorded age, gender, extent of formal education and stroke history as background factors for the patients included here, no significant differences emerged, either at admission or at 3 months later. Although patients with 1-20 h weekly working time were not susceptible to PSF, this feature was not an independent factor involved in development of PSF as judged by multivariate analyses. Social support is often found to protect against the effects of stress, with most studies finding either a main effect or a buffering effect [30]. In our study, a low degree of social utilization as a cognitive appraisal variable was an independent risk factor associated with PSD at 3 months and PSF at both time points after stroke. So, regardless of how much social support was present, patients were routinely encouraged to seek and use those opportunities during the stroke recovery period. In addition, coping styles were associated with the ability to seek social support. Feifel [20] pointed out that acceptance-resignation indicated that the expression of negative affect, lack of focus, and gloomy expectations about the future always induced longer illness. Records of acceptance-resignation related to PSD and PSF both at admission and at 3 months later revealed that these patients focused on their limited power to influence the course of illness and lost confidence for recovery. High avoidance scores of PSD patients denoted less self-directed life orientation and negative self-perception [20]. Avoidance only associated PSD for individuals with subacute stroke indicated that this style may be effective for managing short-term threats, but for the long-term problem-solving activity was more effective [14]. Higher scores for confrontation by PSF patients indicated the presence of extroversion, negative self-perception, a view of their illness as serious, religiosity, concern about life direction, the situational variables of fearing death, and positive expectations about recovery and the future. So apart from effective cognitive ability, a confrontational coping style was more important for patients with stroke. The results of this study have potentially important implications for intervention. Possibly, a change in strategies for coping with stroke would reverse HPA-axis dysfunction, thereby avoiding the symptoms of emotional disturbances and the related pathogenic effects. Finally, the presence of a significant relationship between coping and cortisol has been noted in other studies [31]. With strategies for a new direction to predict and to treat PSD and PSF, and by engendering a greater willingness on the part of post-stroke patients to be participants in their own recovery, medical practitioners might improve outcomes.
The main limitations of our study are the size of our sample, the single medical center used as a source of patients and the short time period of only 3 months. Because this is the first study that combines the specific attributes measured here, caution dictated applying these limitations as a foundation before engaging in a larger, longer investigation. Further, we excluded patients with severe neurologic conditions, aphasia, and cognitive impairment and those who lived alone. The patients who dropped out of the study before 3 months were older and had more severe neurologic dysfunction at admission, suggesting that occurrence of emotional disturbances may have been underestimated.

Conclusion
Basal ganglia, corona radiate or internal capsule infarction were the independent factors associated with PSF 3 months after stroke occurrence. The appearance of PSD was not related to lesion location. Both motor and sensory dysfunction was independently associated with PSD at admission. A low degree of social utilization was the independent factor associated with PSD and PSF at 3 months after stroke. Acceptance-resignation independently related to PSD and PSF both at admission and 3 months after stroke. Avoidance was the independent factor related to PSD at 3 months, whereas confrontation was the independent factor related to PSF at 3 months after stroke onset.