Of 4502 identified articles, 167 articles were selected for full-text screening (see Fig. 1). Nine articles could not be retrieved from authors after several contact requests. Based on full-text evaluation of the remaining articles, 135 articles met inclusion criteria. Reasons for exclusion were: conference abstract (Akiashvili et al. 2013), research protocol (Toso et al. 2004), review article (Beckson and Cummings 1991; Robinson and Starkstein 1989), small sample size (Beblo et al. 1999; Grasso et al. 1994; Lassalle-Lagadec et al. 2012, 2013; Matsuoka et al. 2015; Mayberg et al. 1988; Paradiso et al. 2013; Ramasubbu et al. 1999), other outcome than depression or apathy (Astrom 1996; Downhill and Robinson 1994; Vataja et al. 2005), study population other than stroke or no separate results available for stroke subpopulation (Bella et al. 2010; Grool et al. 2013; O’Brien et al. 2006; Ojagbemi et al. 2013; Sachdev et al. 2007; Tanislav et al. 2015; Wu et al. 2014), and no evaluation of imaging markers (Eriksen et al. 2016). Fourteen additional studies found in reference lists and fulfilling eligibility criteria were included, resulting in a total of 149 studies.

Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart of study selection and review. PSA post-stroke apathy, PSD post-stroke depression Full size image

Characteristics of Included Studies

A detailed overview of study characteristics for PSD studies (n = 132) and PSA studies (n = 23) is presented in supplementary Online Resource 4 and 5. Of all PSD studies, 51 (39%) studies included only first-ever strokes. Thirty-nine cohorts (30%) were followed prospectively. Some studies used semi-structured psychiatric interviews like the Mini International Neuropsychiatric Interview (Sheehan et al. 1998), or the Structured Clinical Interview for DSM disorders (Spitzer et al. 1995), based on Diagnostic and Statistical Manual of Mental Disorders (DSM) version III (American Psychiatric Asociation 1980) or IV (American Psychiatric Asociation 1994), whereas others used clinician-rated or self-rated questionnaires (e.g. the Hamilton Depression Rating Scale (Hamilton 1960), Montgomery-Åsberg Depression Rating Scale (Montgomery and Asberg 1979), or the Geriatric Depression Scale (Yesavage et al. 1983) to evaluate the presence of PSD, and different cut-offs were applied.

Based on 107 (81%) studies that reported on PSD prevalence within the first year, a median prevalence of 30.4% was found (IQR 20.1–40.0). Of all PSA studies, nine (39%) studies included first-ever stroke patients. Four (17%) cohorts were studied prospectively. Most studies used the Apathy Scale (Starkstein et al. 1992) or Apathy Evaluation Scale (Marin et al. 1991) to evaluate the presence of PSA, and different cut-offs were applied. Based on 20 (87%) studies that reported on PSA prevalence within the first year, a median prevalence of 37.3% was found (IQR 22.1–42.5).

Lesion Laterality

Sixty (45%) studies presented data on PSD and lesion laterality. In the pooled analyses, no significant overall association between PSD and lesion side was found (Table 1). A subgroup analysis stratified by study phase showed a 26% higher odds of PSD after left-sided stroke in the acute phase, but this effect was not statistically significant (OR 1.26, 95% CI 0.95–1.67, I 2 = 60.1%, see Fig. 2). Neither in the post-acute stroke phase (OR 1.00, 95% CI 0.83–1.20, I 2 = 50.4%), nor in the chronic stroke phase (OR 1.12, CI 0.87–1.45, I 2 = 0.0%) a significant association was found with lesion side (see Fig. 3).

Table 1 Overall effect sizes and Egger’s bias coefficients Full size table

Fig. 2 Forest plot of the relationship between post-stroke depression and lesion laterality. Subanalyses on acute stroke phase are presented. CI confidence interval, OR odds ratio Full size image

Fig. 3 Forest plot of the relationship between post-stroke depression and lesion laterality. Subanalyses on post-acute stroke phase (upper panels) and chronic stroke phase (lower panels) are presented. CI confidence interval, OR odds ratio Full size image

Nine (39%) studies presented data on PSA and lesion laterality. In the pooled analyses, the overall odds of PSA were a bit higher after left-sided stroke (Table 1). A subgroup analysis stratified by study phase showed higher odds after left-sided stroke in the post-acute phase, although this effect was not statistically significant (OR 1.90, 95% CI 0.88–4.09, I 2 = 0.0%, see Fig. 4a). No significant association was found in the acute stroke phase (OR 0.95, 95% CI 0.42–2.16, I 2 = 72.0%, see Fig. 4a) and no studies reported on the association in the chronic phase.

Fig. 4 Forest plot of the relationship between post-stroke apathy and lesion laterality/type. In panel a, the results of the meta-analysis on lesion laterality are presented. In panel b, the results of the meta-analysis on lesion type are presented. Apart from the overall analysis, the subanalyses on acute stroke phase (upper panels) and post-acute stroke phase (lower panels) are presented. CI confidence interval, OR odds ratio Full size image

Lesion Type

Fourteen (11%) studies reported outcomes on lesion type associated with PSD. Overall, no significant association between PSD and lesion type was observed (Table 1). A subgroup analysis by study phase showed no significant association between lesion type and PSD in the acute (OR 0.95, 95% CI 0.59–1.53, I 2 = 14.0%), post-acute (OR 0.94, 95% CI 0.47–1.87, I 2 = 59.9%), or chronic stroke phase (OR 0.76, 95% CI 0.22–2.65, I 2 = 0.0%, see Fig. 5).

Fig. 5 Forest plot of the relationship between post-stroke depression and lesion type. Apart from the overall analysis, the subanalyses on acute stroke phase (upper panels), post-acute stroke phase (middle panels), and chronic stroke phase (lower panels) are presented. CI confidence interval, OR odds ratio Full size image

Four (17%) studies reported outcomes on lesion type associated with PSA. Overall, the odds of PSA after hemorrhagic stroke was not higher than after ischemic stroke (Table 1). A subgroup analysis by study phase showed higher odds after hemorrhagic stroke in the acute phase (OR 2.58, 95% CI 1.18–5.65, I 2 = 0.0%, see Fig. 4b), whereas higher odds after ischemic stroke were found in the post-acute phase (OR 0.20, 95% CI 0.06–0.69, I 2 = 0.0%, see Fig. 4b). Only two studies were included per phase.

Lesion Location

In Table 2, an overview is provided of lesion locations that were significantly associated with PSD. As frontal/anterior, subcortical, and basal ganglia lesions were frequently associated with PSD, meta-analyses were performed on these locations. Thirty (23%) studies reported outcomes on frontal lesion location associated with PSD. Overall, a 54% higher odds of PSD after frontal stroke was found (Table 1). Subgroup analysis suggested this association was limited to PSD in the post-acute stroke phase (OR 1.72, 95% CI 1.34–2.19, I 2 = 47.2%), as no significant association was found in the acute stroke phase (OR 1.21, 95% CI 0.90–1.63, I 2 = 21.1%), see Fig. 6.

Table 2 Lesion locations significantly associated with post-stroke depression and post-stroke apathy Full size table

Fig. 6 Forest plot of the relationship between post-stroke depression and frontal/anterior lesions. Apart from the overall analysis, the subanalyses on acute stroke phase (upper panels) and post-acute stroke phase (lower panels) are presented. CI confidence interval, OR odds ratio Full size image

Ten (8%) studies reported outcomes on subcortical lesion location associated with PSD. Pooled odds for PSD were not significantly higher after subcortical lesions (Table 1). A subgroup analysis by study phase showed no significant associations between subcortical lesions and PSD in the acute (OR 1.04, 95% CI 0.64–1.70), post-acute (OR 0.93, 95% CI 0.65–1.32), or chronic stroke phase (OR 1.88, 95% CI 0.92–3.84), see Fig. 7a), but the latter association consisted only of two studies. No significant heterogeneity was observed (each phase, I 2 = 0.0%). Twelve (9%) studies reported outcomes on basal ganglia lesion location associated with PSD. Overall, basal ganglia lesions were significantly associated with PSD (Table 1). A subgroup analysis by study phase showed that basal ganglia lesions were significantly associated with PSD in the post-acute phase (OR 2.25, 95% CI 1.33–3.84, I 2 = 71.2%), but not in the acute stroke phase (OR 1.26, 95% CI 0.74–2.14, I 2 = 41.4%), see Fig. 7b).

Fig. 7 Forest plot of the relationship between post-stroke depression and subcortical/basal ganglia lesions. In panel a, the results of the meta-analysis on subcortical lesion location are presented. Apart from the overall analysis, the subanalyses on acute stroke phase (upper panels), post-acute stroke phase (middle panels), and chronic stroke phase (lower panels) are presented. In panel b, the results of the meta-analysis on basal ganglia lesions are presented. Apart from the overall analysis, the subanalyses on acute stroke phase (upper panels) and post-acute stroke phase (lower panels) are presented. CI confidence interval, OR odds ratio Full size image

Five (22%) studies provided data on the association between PSA and frontal lesions. Overall, no significant association between PSA and frontal lesions was found (Table 1). Subgroup analyses showed different albeit no significant results per phase, with stronger associations with frontal lesions in the acute phase (OR 1.68, 95% CI 0.52–5.45, I 2 = 0.0%), and an inverse relation in the post-acute phase (OR 0.63, 95% CI 0.29–1.34, I 2 = 0.0%), see Fig. 8a. No significant association between PSA and subcortical lesions was found (Table 1), but this was only evaluated in two (9%) studies (OR 1.03, 95% CI 0.38–2.80, I 2 = 0.0%), see Fig. 8b. Four (17%) studies provided data on the association between PSA and basal ganglia lesions. Overall, no significant association between PSA and basal ganglia lesions was found (Table 1). Stratification by study phase showed similar results, with no significant heterogeneity (acute phase: OR 1.45, 95% CI 0.42–4.95, post-acute phase: OR 1.29, 95% CI 0.73–2.29), see Fig. 8c.

Fig. 8 Forest plot of the relationship between post-stroke apathy and lesion location. In panel a, the results of the meta-analysis on frontal lesion location are presented. In panel b, the results of the meta-analysis on subcortical lesion location are presented. In panel c, the results of the meta-analysis on basal ganglia lesions are presented. Apart from the overall analysis, the subanalyses on acute stroke phase (upper panels) and post-acute stroke phase (lower panels) are presented. CI confidence interval, OR odds ratio Full size image

Other Imaging Markers

Several studies examined imaging markers other than lesion location and type in association with PSD. These markers could not be evaluated in a meta-analysis. Therefore, the most important imaging markers are described qualitatively (see Table 3). PSD was associated with total (Chatterjee et al. 2010; Pavlovic et al. 2016), deep (Pavlovic et al. 2016), frontal (Chatterjee et al. 2010; Mok et al. 2010), and periventricular WMH (Pavlovic et al. 2016). Also, cerebral microbleeds are associated with PSD (Choi-Kwon et al. 2012; Tang et al. 2014a; Tang et al. 2011a, b, 2014b), and several studies showed that PSD is more prevalent in patients with a large lesion volume (Hama et al. 2007b; Ku et al. 2013; MacHale et al. 1998; Morris et al. 1992; Nys et al. 2005; Schwartz et al. 1993; Sharpe et al. 1990, 1994; Shimoda and Robinson 1999; Zhang et al. 2012) or large number of lesions (Bendsen et al. 1997; Chatterjee et al. 2010; Jiang et al. 2014; Pavlovic et al. 2016; Tang et al. 2014b; Zhang et al. 2012).

Table 3 Imaging markers associated with post-stroke depression and post-stroke apathy Full size table

More recently, advanced diffusion tensor imaging (DTI) techniques have been used to investigate the association between microstructural abnormalities in white matter (WM) and PSD. Yasuno et al. (2014) showed that a reduction in fractional anisotropy (FA) in the bilateral anterior limbs of the internal capsule was associated with an increased risk of PSD and Williamson et al. (2010) showed that decreased WM integrity in the frontal lobes was associated with mood deficits. This indicates that WM damage in certain brain regions is associated with the development of PSD. A resting-state functional MRI (fMRI) study showed that altered functional connectivity in regions involved in affect was associated with higher levels of depression (Zhang et al. 2014). Atrophy also seems to be an important predictor of PSD, as significant associations were found with frontal lobe atrophy (Tang et al. 2013b), subcortical atrophy (Astrom et al. 1993; Starkstein et al. 1988), and left inferior frontal gyrus atrophy (Fu et al. 2010). Interestingly, none of these studies reported on hippocampal atrophy. Recently, Chen et al. (2016) looked at medial temporal lobe atrophy, but found no association with PSD in the acute or post-acute stroke phase. According to proton magnetic resonance spectroscopy (1H–MRS) studies, biochemical changes in metabolite levels in frontal lobe (Glodzik-Sobanska et al. 2006; Wang et al. 2012; Xu et al. 2008), hippocampus (Huang et al. 2010), and left thalamus (Huang et al. 2010) seem to accompany the development of PSD.

Compared with PSD studies, only few studies evaluated imaging markers related to PSA (see Table 3). PSA was significantly associated with degree of right-hemisphere (Brodaty et al. 2005), right fronto-subcortical circuit (Brodaty et al. 2005), and periventricular WMH (Tang et al. 2013a). In addition, large lesion volume (Hama et al. 2007b), and large number of lesions (Tang et al. 2013a) were associated with PSA. A recent study by Mihalov et al. (2016) showed that frontal cortical atrophy was a strong predictor of PSA, and this relation increased with higher age. In two DTI studies reductions in FA in several brain areas were associated with an increased level of apathy (Yang et al. 2015c). In addition, PSA was associated with reductions in regional cerebral blood flow in the bilateral basal ganglia (Onoda et al. 2011), right dorsolateral frontal cortex, and left frontotemporal cortex (Okada et al. 1997) measured with single-photon emission computed tomography. An H1-MRS study suggested that lower N-acetylaspartate/creatine ratio in the right frontal lobe was related to PSA (Glodzik-Sobanska et al. 2005).

Meta-Regression Analyses

Egger’s regression tests showed no evidence for statistically significant small-study effects in above meta-analyses (see Table 1), although it was not possible to calculate Egger’s regression coefficients for the association with subcortical lesions in PSA as the pooled sample size was too small. Visual inspection of the shape of the funnel plots also did not reveal convincing evidence of obvious asymmetry (see supplementary Online Resource 6). However, some plots, especially for the PSA studies, only consisted of few studies.

Meta-regression analyses were performed to assess potential sources of heterogeneity between PSD studies reporting on lesion laterality (n = 60). None of the included variables appeared to be a significant cause of heterogeneity. In addition, meta-regression analyses were performed on PSD studies reporting on frontal (n = 30) and basal ganglia lesions (n = 12). Only study phase appeared to be a significant cause of heterogeneity in both analyses (frontal: p = 0.041, residual I 2 = 58.9%, Adj. R 2 = 25.7%; basal ganglia: p = 0.044, residual I 2 = 55.4%, Adj. R 2 = 50.7%). To assess potential sources of heterogeneity among PSA studies reporting on lesion laterality (n = 9), meta-regression analyses were performed showing that only imaging method appeared to be an important cause of heterogeneity (p = 0.052, residual I 2 = 31.2%, Adj. R 2 = 64.6%).