Neuropsychol Rev (2017) 27:202–219

DOI 10.1007/s11065-017-9356-2

REVIEW

Imaging Markers of Post-Stroke Depression and Apathy:

a Systematic Review and Meta-Analysis
Elles Douven 1 & Sebastian Köhler 1 & Maria M. F. Rodriguez 2 & Julie Staals 3 &
Frans R. J. Verhey 1 & Pauline Aalten 1

Received: 6 February 2017 / Accepted: 27 July 2017 / Published online: 22 August 2017
# The Author(s) 2017. This article is an open access publication

Abstract Several brain imaging markers have been studied in CI 1.33–3.84). Hemorrhagic stroke related to higher odds for
the development of post-stroke depression (PSD) and post- PSA in the acute phase (OR 2.58, 95% CI 1.18–5.65), where-
stroke apathy (PSA), but inconsistent associations have been as ischemic stroke related to higher odds for PSA in the post-
reported. This systematic review and meta-analysis aims to acute phase (OR 0.20, 95% CI 0.06–0.69). Frequency of PSD
provide a comprehensive and up-to-date evaluation of imag- and PSA is modestly associated with stroke type and location
ing markers associated with PSD and PSA. Databases and is dependent on stroke phase. These findings have to be
(Medline, Embase, PsycINFO, CINAHL, and Cochrane taken into consideration for stroke rehabilitation programs, as
Database of Systematic Reviews) were searched from incep- this could prevent stroke patients from developing PSD and
tion to July 21, 2016. Observational studies describing imag- PSA, resulting in better clinical outcome.
ing markers of PSD and PSA were included. Pooled odds
ratios (OR) and 95% confidence intervals (CI) were calculated Keywords Stroke . Depression . Apathy . Imaging .
to examine the association between PSD or PSA and stroke Systematic review . Meta-analysis
lesion laterality, type, and location, also stratified by study
phase (acute, post-acute, chronic). Other imaging markers
were reviewed qualitatively. The search retrieved 4502 stud- Introduction
ies, of which 149 studies were included in the review and 86
studies in the meta-analyses. PSD in the post-acute stroke Post-stroke depression (PSD) and post-stroke apathy (PSA) are
phase was significantly associated with frontal (OR 1.72, frequent neuropsychiatric symptoms after stroke, with estimat-
95% CI 1.34–2.19) and basal ganglia lesions (OR 2.25, 95% ed prevalence rates between 30 and 40%, respectively, in the
first few months after stroke (Hackett et al. 2014). Depression
can be defined as a feeling of low mood, loss of interest, and
Electronic supplementary material The online version of this article
(doi:10.1007/s11065-017-9356-2) contains supplementary material, lack of pleasure that persists for a time period of at least 2 weeks
which is available to authorized users. (Hackett et al. 2005). Apathy is generally defined as a disorder
of diminished motivation, characterized by loss of interest, di-
* Pauline Aalten minished emotional response, and loss of initiative (Marin
p.aalten@maastrichtuniversity.nl 1990), and can occur independently (Levy et al. 1998), or in
combination with symptoms of depression (Marin et al. 1993).
1
Department of Psychiatry and Neuropsychology, School for Mental According to a previous meta-analysis, approximately 40%
Health and Neuroscience (MHeNS), Alzheimer Center Limburg,
Maastricht University, Dr. Tanslaan 12, PO Box 616 (DRT 12), 6200
of patients with PSA also suffer from PSD (van Dalen et al.
MD Maastricht, The Netherlands 2013). Because depression and apathy share several features,
2
Hospital Alvaro Cunqueiro, Department of Psychiatry, Complexo
mainly loss of interest, patients with apathy after stroke are
Universitario de Vigo, Vigo, Spain frequently misdiagnosed as having PSD (Hama et al. 2011).
3
Department of Neurology, Cardiovascular Research Institute
However, despite the considerable overlap in symptoms be-
Maastricht (CARIM), Maastricht University Medical Center, tween PSD and PSA, there is evidence indicating that the two
Maastricht, The Netherlands syndromes seem to develop from different anatomical and
Neuropsychol Rev (2017) 27:202–219 203

neurobiological constructs (Andersson et al. 1999; Hama et al. Methods

2007b, 2016; Hollocks et al. 2015; Murakami et al. 2013).
Earlier studies have already attempted to disentangle the Search Strategy and Selection Criteria
relationship between PSD and PSA, which have shown incon-
clusive results. The Sydney Stroke Study showed evidence for This systematic review and meta-analysis was conducted ac-
independence of PSA and PSD when measuring 3 to 6 months cording to the Preferred Reporting Items for Systematic
post-stroke (Brodaty et al. 2005). However, at 1-year follow- Reviews and Meta-Analyses (PRISMA) statement (Liberati
up, a significant overlap between apathy and depression was et al. 2009) and by use of a predefined research protocol.
found (Withall et al. 2011). Contrastingly, Caeiro et al. (2013b) Databases (Medline, Embase, PsycINFO, CINAHL, and
did not find an association between PSA and PSD at 1-year Cochrane Database of Systematic Reviews) were searched
post-stroke. It is important to disentangle the relationship be- from inception to December 2015 and updated to July 21,
tween PSA and PSD, at least from a clinical perspective, since 2016. A full description of the search strategy is presented in
the two syndromes seem to benefit from different types of supplementary Online Resource 1. To be eligible for inclu-
medication (Withall et al. 2011). Both PSD and PSA are known sion, studies had to a) include patients with ischemic or hem-
to have a negative influence on clinical outcome (Hama et al. orrhagic stroke, b) assess the presence of depressive or apa-
2007a; Pohjasvaara et al. 2001) and quality of life (Carod-Artal thetic symptoms, c) examine the association between these
et al. 2000; Mayo et al. 2009). Early treatment and prevention symptoms and an imaging marker, d) the population had to
of PSD and PSA might have a positive effect on functional be human adults, e) sample size had to be larger than 25 to
outcome, thereby limiting the impact of stroke on patients’ avoid inclusion of spurious associations from underpowered
daily lives (Ramasubbu and Kennedy 1994). Identification of studies, and f) language had to be English, German, Dutch, or
associated risk factors is thus important for early detection and French. Studies were excluded if (a) the study population was
tailoring of rehabilitation programs. other than stroke or a combined population was studied with-
Several brain imaging markers have been studied in the out separate results available for stroke, (b) the population
development of PSD. Early studies suggested that PSD is consisted of only patients with cognitive impairment or de-
frequent in patients with left frontal lesions (Brodaty et al. mentia in which vascular damage (infarcts, WMH, atrophy)
2005; Hama et al. 2007b), but this hypothesis could not be was studied, or (c) no imaging data or lesion-related data (e.g.
supported by later studies (Carson et al. 2000). Previous sys- lesion location, type, laterality, WMH) were described.
tematic reviews primarily looked at the relationship with le- Records of research protocols, reviews, and abstracts from
sion laterality, while other potential imaging markers such as scientific meetings were excluded. If studies presented results
lesion location, lesion type, lesion volume, white matter from the same cohort on a certain outcome measure, data from
hyperintensities (WMH), and atrophy have been ignored the study that used the largest group of patients were used, or
(Carson et al. 2000; Kutlubaev and Hackett 2014; Wei et al. if they used an equal number of patients, data from the earliest
2015). In addition, imaging markers of PSA have been studied publication were used.
less frequently compared with PSD. Some studies provided Two reviewers (E.D. and P.A.) independently screened ti-
evidence that PSA is associated with right hemispheric and tles and abstracts manually for potential eligibility. Doubtful
subcortical lesions (Andersson et al. 1999; Caeiro et al. 2012; records were discussed (E.D. and P.A.) and an independent
Starkstein et al. 1993), though two recent systematic reviews third reviewer (S.K.) decided if doubtful cases were included
on lesion location in PSA reported inconclusive results or not for full-text scrutiny. For completeness, reference lists
(Caeiro et al. 2013a; van Dalen et al. 2013). Caeiro et al. were screened for additional articles. One reviewer (E.D.)
(2013a) only studied the association with lesion laterality assessed eligibility for inclusion based on full-text screening.
and were not able to find an association, whereas van Dalen
et al. provided a qualitative overview of associations with
lesion location and laterality, but no meta-analysis, and con- Data Collection and Extraction
cluded that no clear association with lesion side or location
could be found, though associations with the basal ganglia Data extraction was performed on selected articles for which
were most consistent. full texts were obtained. Two independent reviewers (E.D. and
A systematic review and meta-analysis was performed to M.R.) extracted data from each study according to a
evaluate the association between different brain imaging predefined data extraction form. The following information
markers and PSD and PSA, thereby updating and extending was extracted for each study included in the review: (1) first
previous meta-analyses just focusing on lesion location in author and year of publication, (2) demographic characteris-
association with PSD and PSA. The main aim of the present tics, (3) in- and exclusion criteria if specified, (4) imaging
study was to investigate differences and similarities in several method and imaging markers, (5) questionnaires and criteria
brain correlates associated with PSD and PSA. used to define PSD or PSA, (6) time of measurement after
204 Neuropsychol Rev (2017) 27:202–219

stroke, (7) statistical methods used and results needed for the To identify possible sources of heterogeneity, random-
meta-analysis, (8) main conclusion and limitations. effect meta-regression models were conducted including the
following covariates: study phase, mean age, PSD/PSA prev-
Statistical Analyses and Study Quality alence, percentage of females, imaging method (CT/MRI vs.
MRI), patient source, and first-ever stroke (yes/no).
Statistical analyses were performed using STATA 13.1 The study quality was assessed by a single investigator
(StataCorp, TX, USA). Statistical significance was defined (E.D.) with the Newcastle-Ottowa Scale (NOS) for case-
by p < .05 in two-sided tests. Pooled odds ratios (ORs) with control and cohort studies, and a modified NOS was applied
corresponding 95% confidence intervals (CIs) were calculated for cross-sectional studies (Wells et al. 2000). A maximum
to examine the association between PSD or PSA and stroke score of 9 can be obtained and studies with a score < 5 were
lesion laterality, type, and location, also stratified by study not included in the meta-analyses (see supplementary Online
phase (acute, post-acute, chronic), using a DerSimonian- Resource 3). Visual inspection of asymmetry in funnel plots,
Laird random-effects model to account for within- and in which the relation between sample size and effect size is
between-study variance (DerSimonian and Laird 1986). A full assessed, was used to test for possible publication bias.
description of the observations used in the meta-analyses is Egger’s regression tests were performed to test for significant
presented in supplementary Online Resource 2. Studies were asymmetry of funnel plots as a test for small-study effects
stratified according to phase in which they measured depres- (Egger et al. 1997).
sion or apathy after stroke: acute (< 15 days from stroke on-
set), post-acute (15 days–6 months), and chronic phase
(> 6 months). This stratification was based on the meta- Results
analysis by Caeiro et al. (2013a) and was chosen because
the acute stroke phase corresponds with the period of hospi- Of 4502 identified articles, 167 articles were selected for full-
talization and acute care (Buisman et al. 2015) and in this text screening (see Fig. 1). Nine articles could not be retrieved
period the risk of complications and recurrent stroke is highest from authors after several contact requests. Based on full-text
(Prasad et al. 2011). After this period of acute care, patients evaluation of the remaining articles, 135 articles met inclusion
usually start with rehabilitation and most recovery will take criteria. Reasons for exclusion were: conference abstract
place in the first 6 months (Aziz 2010). Therefore, we defined (Akiashvili et al. 2013), research protocol (Toso et al. 2004),
this period as the post-acute period, and > 6 months as the review article (Beckson and Cummings 1991; Robinson and
chronic stroke phase. Starkstein 1989), small sample size (Beblo et al. 1999; Grasso

Fig. 1 Preferred Reporting Items

for Systematic Reviews and
Meta-analyses (PRISMA) flow-
chart of study selection and re-
view. PSA post-stroke apathy,
PSD post-stroke depression
Neuropsychol Rev (2017) 27:202–219 205

et al. 1994; Lassalle-Lagadec et al. 2012, 2013; Matsuoka (Hamilton 1960), Montgomery-Åsberg Depression Rating
et al. 2015; Mayberg et al. 1988; Paradiso et al. 2013; Scale (Montgomery and Asberg 1979), or the Geriatric
Ramasubbu et al. 1999), other outcome than depression or Depression Scale (Yesavage et al. 1983) to evaluate the pres-
apathy (Astrom 1996; Downhill and Robinson 1994; Vataja ence of PSD, and different cut-offs were applied.
et al. 2005), study population other than stroke or no separate Based on 107 (81%) studies that reported on PSD preva-
results available for stroke subpopulation (Bella et al. 2010; lence within the first year, a median prevalence of 30.4% was
Grool et al. 2013; O’Brien et al. 2006; Ojagbemi et al. 2013; found (IQR 20.1–40.0). Of all PSA studies, nine (39%) stud-
Sachdev et al. 2007; Tanislav et al. 2015; Wu et al. 2014), and ies included first-ever stroke patients. Four (17%) cohorts
no evaluation of imaging markers (Eriksen et al. 2016). were studied prospectively. Most studies used the Apathy
Fourteen additional studies found in reference lists and fulfill- Scale (Starkstein et al. 1992) or Apathy Evaluation Scale
ing eligibility criteria were included, resulting in a total of 149 (Marin et al. 1991) to evaluate the presence of PSA, and dif-
studies. ferent cut-offs were applied. Based on 20 (87%) studies that
reported on PSA prevalence within the first year, a median
Characteristics of Included Studies prevalence of 37.3% was found (IQR 22.1–42.5).

A detailed overview of study characteristics for PSD studies

(n = 132) and PSA studies (n = 23) is presented in supplemen- Lesion Laterality
tary Online Resource 4 and 5. Of all PSD studies, 51 (39%)
studies included only first-ever strokes. Thirty-nine cohorts Sixty (45%) studies presented data on PSD and lesion
(30%) were followed prospectively. Some studies used semi- laterality. In the pooled analyses, no significant overall asso-
structured psychiatric interviews like the Mini International ciation between PSD and lesion side was found (Table 1). A
Neuropsychiatric Interview (Sheehan et al. 1998), or the subgroup analysis stratified by study phase showed a 26%
Structured Clinical Interview for DSM disorders (Spitzer higher odds of PSD after left-sided stroke in the acute phase,
et al. 1995), based on Diagnostic and Statistical Manual of but this effect was not statistically significant (OR 1.26, 95%
Mental Disorders (DSM) version III (American Psychiatric CI 0.95–1.67, I2 = 60.1%, see Fig. 2). Neither in the post-acute
Asociation 1980) or IV (American Psychiatric Asociation stroke phase (OR 1.00, 95% CI 0.83–1.20, I2 = 50.4%), nor in
1994), whereas others used clinician-rated or self-rated ques- the chronic stroke phase (OR 1.12, CI 0.87–1.45, I2 = 0.0%) a
tionnaires (e.g. the Hamilton Depression Rating Scale significant association was found with lesion side (see Fig. 3).

Table 1 Overall effect sizes and Egger’s bias coefficients

Marker Number of studies Effect size Heterogeneity Publication bias

included
Odd’s ratio 95% CI I2 (%) p-value Egger’s bias coefficient p-value

PSD
Laterality 60a 1.07 0.93–1.23 49.6 < .001 0.14 .743
Type 14b 0.94 0.65–1.36 33.3 .102 −0.06 .943
Frontal lesions 30c 1.54 1.27–1.88 43.4 .004 0.92 .132
Subcortical lesions 10d 1.06 0.81–1.38 0.0 .601 1.00 .186
Basal ganglia lesions 12e 1.78 1.20–2.66 65.3 .001 0.24 .884
PSA
Laterality 9 1.16 0.62–2.18 63.5 .005 1.69 .262
Type 4 0.82 0.19–3.53 75.2 .007 −3.92 .273
Frontal lesions 5 0.84 0.44–1.59 0.0 .635 2.71 .055
Subcortical lesions 2 1.03 0.38–2.80 0.0 .686 Not enough data
Basal ganglia lesions 4 1.32 0.79–2.21 0.0 .891 −0.42 .536

CI confidence interval, PSA post-stroke apathy, PSD post-stroke depression

a
Six of the 60 studies provided data on more than one time point
b
One of the 14 studies provided data on more than one time point
c
Five of the 30 studies provided data on more than one time point
d
Two of the 10 studies provided data on more than one time point
e
One of the 12 studies provided data on more than one time point
206 Neuropsychol Rev (2017) 27:202–219

Fig. 2 Forest plot of the

relationship between post-stroke
depression and lesion laterality.
Subanalyses on acute stroke
phase are presented. CI confi-
dence interval, OR odds ratio

Nine (39%) studies presented data on PSA and lesion Lesion Location
laterality. In the pooled analyses, the overall odds of PSA
were a bit higher after left-sided stroke (Table 1). A sub- In Table 2, an overview is provided of lesion locations that
group analysis stratified by study phase showed higher were significantly associated with PSD. As frontal/anterior,
odds after left-sided stroke in the post-acute phase, al- subcortical, and basal ganglia lesions were frequently associ-
though this effect was not statistically significant (OR ated with PSD, meta-analyses were performed on these loca-
1.90, 95% CI 0.88–4.09, I2 = 0.0%, see Fig. 4a). No tions. Thirty (23%) studies reported outcomes on frontal le-
significant association was found in the acute stroke phase sion location associated with PSD. Overall, a 54% higher odds
(OR 0.95, 95% CI 0.42–2.16, I2 = 72.0%, see Fig. 4a) of PSD after frontal stroke was found (Table 1). Subgroup
and no studies reported on the association in the chronic analysis suggested this association was limited to PSD in the
phase. post-acute stroke phase (OR 1.72, 95% CI 1.34–2.19,
I2 = 47.2%), as no significant association was found in the
Lesion Type acute stroke phase (OR 1.21, 95% CI 0.90–1.63,
I2 = 21.1%), see Fig. 6.
Fourteen (11%) studies reported outcomes on lesion type as- Ten (8%) studies reported outcomes on subcortical lesion
sociated with PSD. Overall, no significant association be- location associated with PSD. Pooled odds for PSD were not
tween PSD and lesion type was observed (Table 1). A sub- significantly higher after subcortical lesions (Table 1). A sub-
group analysis by study phase showed no significant associa- group analysis by study phase showed no significant associa-
tion between lesion type and PSD in the acute (OR 0.95, 95% tions between subcortical lesions and PSD in the acute (OR
CI 0.59–1.53, I2 = 14.0%), post-acute (OR 0.94, 95% CI 1.04, 95% CI 0.64–1.70), post-acute (OR 0.93, 95% CI 0.65–
0.47–1.87, I2 = 59.9%), or chronic stroke phase (OR 0.76, 1.32), or chronic stroke phase (OR 1.88, 95% CI 0.92–3.84),
95% CI 0.22–2.65, I2 = 0.0%, see Fig. 5). see Fig. 7a), but the latter association consisted only of two
Four (17%) studies reported outcomes on lesion type asso- studies. No significant heterogeneity was observed (each
ciated with PSA. Overall, the odds of PSA after hemorrhagic phase, I2 = 0.0%). Twelve (9%) studies reported outcomes
stroke was not higher than after ischemic stroke (Table 1). A on basal ganglia lesion location associated with PSD.
subgroup analysis by study phase showed higher odds after Overall, basal ganglia lesions were significantly associated
hemorrhagic stroke in the acute phase (OR 2.58, 95% CI with PSD (Table 1). A subgroup analysis by study phase
1.18–5.65, I2 = 0.0%, see Fig. 4b), whereas higher odds after showed that basal ganglia lesions were significantly associat-
ischemic stroke were found in the post-acute phase (OR 0.20, ed with PSD in the post-acute phase (OR 2.25, 95% CI 1.33–
95% CI 0.06–0.69, I2 = 0.0%, see Fig. 4b). Only two studies 3.84, I2 = 71.2%), but not in the acute stroke phase (OR 1.26,
were included per phase. 95% CI 0.74–2.14, I2 = 41.4%), see Fig. 7b).
Neuropsychol Rev (2017) 27:202–219 207

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

Five (22%) studies provided data on the association be- provided data on the association between PSA and basal gan-
tween PSA and frontal lesions. Overall, no significant associ- glia lesions. Overall, no significant association between PSA
ation between PSA and frontal lesions was found (Table 1). and basal ganglia lesions was found (Table 1). Stratification
Subgroup analyses showed different albeit no significant re- by study phase showed similar results, with no significant
sults per phase, with stronger associations with frontal lesions heterogeneity (acute phase: OR 1.45, 95% CI 0.42–4.95,
in the acute phase (OR 1.68, 95% CI 0.52–5.45, I2 = 0.0%), post-acute phase: OR 1.29, 95% CI 0.73–2.29), see Fig. 8c.
and an inverse relation in the post-acute phase (OR 0.63, 95%
CI 0.29–1.34, I2 = 0.0%), see Fig. 8a. No significant associa- Other Imaging Markers
tion between PSA and subcortical lesions was found (Table 1),
but this was only evaluated in two (9%) studies (OR 1.03, Several studies examined imaging markers other than lesion
95% CI 0.38–2.80, I2 = 0.0%), see Fig. 8b. Four (17%) studies location and type in association with PSD. These markers
208 Neuropsychol Rev (2017) 27:202–219

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 present-
ed. CI confidence interval, OR
odds ratio

could not be evaluated in a meta-analysis. Therefore, the most integrity in the frontal lobes was associated with mood defi-
important imaging markers are described qualitatively (see cits. This indicates that WM damage in certain brain regions is
Table 3). PSD was associated with total (Chatterjee et al. associated with the development of PSD. A resting-state func-
2010; Pavlovic et al. 2016), deep (Pavlovic et al. 2016), fron- tional MRI (fMRI) study showed that altered functional con-
tal (Chatterjee et al. 2010; Mok et al. 2010), and nectivity in regions involved in affect was associated with
periventricular WMH (Pavlovic et al. 2016). Also, cerebral higher levels of depression (Zhang et al. 2014). Atrophy also
microbleeds are associated with PSD (Choi-Kwon et al. seems to be an important predictor of PSD, as significant asso-
2012; Tang et al. 2014a; Tang et al. 2011a, b, 2014b), and ciations were found with frontal lobe atrophy (Tang et al.
several studies showed that PSD is more prevalent in patients 2013b), subcortical atrophy (Astrom et al. 1993; Starkstein
with a large lesion volume (Hama et al. 2007b; Ku et al. 2013; et al. 1988), and left inferior frontal gyrus atrophy (Fu et al.
MacHale et al. 1998; Morris et al. 1992; Nys et al. 2005; 2010). Interestingly, none of these studies reported on hippo-
Schwartz et al. 1993; Sharpe et al. 1990, 1994; Shimoda and campal atrophy. Recently, Chen et al. (2016) looked at medial
Robinson 1999; Zhang et al. 2012) or large number of lesions temporal lobe atrophy, but found no association with PSD in the
(Bendsen et al. 1997; Chatterjee et al. 2010; Jiang et al. 2014; acute or post-acute stroke phase. According to proton magnetic
Pavlovic et al. 2016; Tang et al. 2014b; Zhang et al. 2012). resonance spectroscopy (1H–MRS) studies, biochemical chang-
More recently, advanced diffusion tensor imaging (DTI) es in metabolite levels in frontal lobe (Glodzik-Sobanska et al.
techniques have been used to investigate the association be- 2006; Wang et al. 2012; Xu et al. 2008), hippocampus (Huang
tween microstructural abnormalities in white matter (WM) et al. 2010), and left thalamus (Huang et al. 2010) seem to
and PSD. Yasuno et al. (2014) showed that a reduction in accompany the development of PSD.
fractional anisotropy (FA) in the bilateral anterior limbs of Compared with PSD studies, only few studies evaluated
the internal capsule was associated with an increased risk of imaging markers related to PSA (see Table 3). PSA was sig-
PSD and Williamson et al. (2010) showed that decreased WM nificantly associated with degree of right-hemisphere
Neuropsychol Rev (2017) 27:202–219 209

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 confi-
dence interval, OR odds ratio

(Brodaty et al. 2005), right fronto-subcortical circuit (Brodaty supplementary Online Resource 6). However, some plots, es-
et al. 2005), and periventricular WMH (Tang et al. 2013a). In pecially for the PSA studies, only consisted of few studies.
addition, large lesion volume (Hama et al. 2007b), and large Meta-regression analyses were performed to assess poten-
number of lesions (Tang et al. 2013a) were associated with tial sources of heterogeneity between PSD studies reporting
PSA. A recent study by Mihalov et al. (2016) showed that on lesion laterality (n = 60). None of the included variables
frontal cortical atrophy was a strong predictor of PSA, and appeared to be a significant cause of heterogeneity. In addi-
this relation increased with higher age. In two DTI studies tion, meta-regression analyses were performed on PSD studies
reductions in FA in several brain areas were associated with reporting on frontal (n = 30) and basal ganglia lesions (n = 12).
an increased level of apathy (Yang et al. 2015c). In addition, Only study phase appeared to be a significant cause of hetero-
PSA was associated with reductions in regional cerebral blood geneity in both analyses (frontal: p = 0.041, residual
flow in the bilateral basal ganglia (Onoda et al. 2011), right I2 = 58.9%, Adj. R2 = 25.7%; basal ganglia: p = 0.044, resid-
dorsolateral frontal cortex, and left frontotemporal cortex ual I2 = 55.4%, Adj. R2 = 50.7%). To assess potential sources
(Okada et al. 1997) measured with single-photon emission of heterogeneity among PSA studies reporting on lesion
computed tomography. An H1-MRS study suggested that low- laterality (n = 9), meta-regression analyses were performed
er N-acetylaspartate/creatine ratio in the right frontal lobe was showing that only imaging method appeared to be an impor-
related to PSA (Glodzik-Sobanska et al. 2005). tant cause of heterogeneity (p = 0.052, residual I2 = 31.2%,
Adj. R2 = 64.6%).
Meta-Regression Analyses

Egger’s regression tests showed no evidence for statistically Discussion

significant small-study effects in above meta-analyses (see
Table 1), although it was not possible to calculate Egger’s This systematic review and meta-analysis summarizes the
regression coefficients for the association with subcortical le- most up-to-date information on a range of imaging markers
sions in PSA as the pooled sample size was too small. Visual associated with PSD and PSA during the acute, post-acute,
inspection of the shape of the funnel plots also did not reveal and chronic stroke phase. Meta-analyses indicated that PSD
convincing evidence of obvious asymmetry (see in the post-acute phase was significantly more frequent in
210 Neuropsychol Rev (2017) 27:202–219

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

Lesion location Studies

Acute phase Post-acute phase Chronic phase

PSD
Anterior Astrom et al. (1993); Herrmann et al. Dam et al. (1989); House et al. (1990); House et al. (1990)
(1993); Shimoda and Robinson Kim and Choi-Kwon (2000); Morris
(1999) et al. (1992); Shimoda and Robinson
(1999)
Frontal lobe Metoki et al. (2016); Robinson et al. Aben et al. (2006); Effat et al. (2011); –
(1984); Shi et al. (2014) Hama et al. (2007b); Morris et al.
(1996b); Murakami et al. (2013);
Singh et al. (2000); Stojanovic and
Stojanovic (2015); Tang et al. (2010);
Wichowicz et al. (2015); Zhang et al.
(2012)
Temporal lobe Metoki et al. (2016); Terroni et al. Zhang et al. (2012) –
(2015)
Posterior (occipital, parietal lobe) Metoki et al. (2016); Paradiso and Schwartz et al. (1993) Shimoda and Robinson
Robinson (1999); Starkstein et al. (1999)
(1989)
Subcortical Shi et al. (2014) Schwartz et al. (1993); Tang et al. Chatterjee et al. (2010)
(2005); Zhang et al. (2012)
Basal ganglia Herrmann et al. (1993); Yang et al. Herrmann et al. (1995); Morris et al. –
(2015b); Metoki et al. (2016) (1996b); Nishiyama et al. (2010);
Murakami et al. (2013); Wichowicz
et al. (2015)
Insular cortex Yang et al. (2015b) – –
Brainstem – Murakami et al. (2013) –
Left hemisphere Robinson et al. (1984); Robinson et al. Barker-Collo (2007); Jiang et al. (2014); Parikh et al. (1988);
(1985); Astrom et al. (1993); Morris Morris et al. (1996b); Rajashekaran Provinciali et al. (2008);
et al. (1996a); Paradiso and Robinson et al. (2013); Wichowicz et al. (2015) Rashid et al. (2013);
(1999); Shimoda and Robinson Stern and Bachman
(1999); Saxena and Suman (2015); (1991)
Wongwandee et al. (2012)
Right hemisphere Yang et al. (2015b) Andersen et al. (1995); Stern and Bachman (1991);
Castellanos-Pinedo et al. (2011); Dam Verdelho et al. (2004)
et al. (1989); MacHale et al. (1998);
Oladiji et al. (2009); Schwartz et al.
(1993); Singh et al. (2000)
Infratentorial – Iranmanesh and Vakilian (2009) –
ACA – Desmond et al. (2003); Jiang et al. Provinciali et al. (2008)
(2014); Tang et al. (2005)
PCA – Desmond et al. (2003) –
PSA
Basal ganglia Onoda et al. (2011) Hama et al. (2007b); Mihalov et al. Rochat et al. (2013)
(2016); Murakami et al. (2013); Santa
et al. (2008)
Thalamus – – Rochat et al. (2013)
Pons / brainstem – Murakami et al. (2013); Tang et al. –
(2013a)
Right hemisphere – Castellanos-Pinedo et al. (2011) –
Left hemisphere Kang and Kim (2008) – –
Frontal lobe Kang and Kim (2008) – –
CC / CG Kang and Kim (2008) – –
IC (posterior limb) Starkstein et al. (1993) – –

ACA anterior circulation area, CC corpus callosum, CG cingulate gyrus, IC internal capsule, PCA posterior circulation area, PSA post-stroke apathy, PSD
post-stroke depression

patients with frontal or basal ganglia lesions. No significant interest to mention that left-sided stroke occurred more often
association was found between PSD and lesion laterality in the in the PSD group in the acute phase. This result became in-
post-acute and chronic stroke phase. Nevertheless, it is of significant after the inclusion of four recent large studies
Neuropsychol Rev (2017) 27:202–219 211

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 confi-
dence interval, OR odds ratio

(Chen et al. 2016; Metoki et al. 2016; Wei et al. 2016; Zhang and PSD found a significant association between right hemi-
et al. 2016), which differed from the other studies in that they spheric lesions and risk of PSD in the post-acute stroke phase
reported a relatively low PSD prevalence (median 18.6%, IQR (1–6 months). In contrast to Wei et al. (2015), we defined the
17.4–30.2). Frequency of PSD was equal for ischemic and post-acute period as 15 days to 6 months, which could explain
hemorrhagic stroke in all stroke phases, but PSA was more the difference in results. In agreement with Caeiro et al.
frequent after hemorrhagic stroke in the acute phase, whereas (2013a) the prevalence of PSA was not associated with lesion
it was more frequent after ischemic stroke in the post-acute laterality. Both meta-analyses did not study associations with
phase. Since only four PSA studies were available, this find- markers other than lesion laterality and lesion type, while the
ing should be interpreted with caution. Also, PSA did not review of van Dalen et al. (2013) evaluated associations be-
depend on lesion laterality or location, but again the amount tween PSA and lesion location only qualitatively and conclud-
of available PSA studies was small in general. ed that no clear association could be found.
Our meta-analysis updates and extends previous studies. The present findings suggest that lesion location is an im-
The meta-analysis by Wei et al. (2015) on lesion laterality portant risk factor for PSD in the post-acute stroke phase.
212 Neuropsychol Rev (2017) 27:202–219

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 present-
ed. CI confidence interval, OR
odds ratio

However, in the past few years the hypothesis of PSD and microbleeds, and atrophy, were frequently associated with
PSA being associated with damage to specific lesion locations PSD. With respect to PSA, associations with degree of
has been shifted to the idea that damage to a neuronal network WMH, lesion volume, and number of lesions were found in
involved in affect is underlying the development of PSD and some extent. Co-occurring vascular lesions may make a stroke
PSA (Tang et al. 2011c; Terroni et al. 2011; Vataja et al. 2001), patient more vulnerable for developing PSD and PSA.
with different sub-circuits involved in PSD (Yang et al. Therefore, future studies should focus on a broader
2015b) and PSA (Yang et al. 2015a), see Table 4. DTI is a range of imaging markers, including lesion volume, at-
promising tool to identify more accurately how these brain rophy, WMH, and cerebral microbleeds, and also how
networks are affected after stroke. The qualitative overview lesion-related markers may interact with co-occuring in-
of imaging markers associated with PSD and PSA showed direct vascular markers. Besides, advanced imaging
that not only direct stroke-related features such as lesion loca- techniques (e.g. DTI, fMRI) are needed to evaluate
tion, lesion volume, and number of lesions, but also other how microstructural abnormalities and changes in func-
neurovascular, non-directly stroke-related but often co- tional connectivity contribute to the development of
occurring features, such as degree of WMH, cerebral PSD and PSA.
Neuropsychol Rev (2017) 27:202–219 213

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 re-
sults of the meta-analysis on sub-
cortical lesion location are pre-
sented. 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

Our study has the following strengths. A large amount of compromised in comparison with meta-analyses includ-
publications on PSD were identified, resulting in a rich pooled ing a larger amount of studies. In addition, moderate to
cohort of studies that were not included in earlier meta- high (unexplained) heterogeneity between studies in
analyses (Chen et al. 2013, 2016; Gozzi et al. 2014; Jiang some meta-analyses indicated large differences in meth-
et al. 2014; Metoki et al. 2016; Saxena and Suman 2015; odology between studies. Particularly the use of differ-
Terroni et al. 2015; Wei et al. 2016; Wichowicz et al. 2015; ent scales and cut-offs to define the presence of depres-
Zhang et al. 2016). Furthermore, beside information on lesion sion and apathy and different imaging methods (CT vs.
laterality, also data on other imaging markers was retrieved for MRI) are of influence on the comparability of findings.
quantitative and qualitative analysis. Therefore, the present Also differences in eligibility criteria (e.g. exclusion of
review provides an up-to-date and extended overview of find- patients with aphasia, differences in age range) can cre-
ings on the association between imaging markers and risk of ate heterogeneity among studies. Meta-regression analy-
PSD and PSA. ses were performed to identify potential sources of het-
One limitation of the present study was the small erogeneity, and only study phase for PSD studies and
amount of studies on PSA, which made it difficult to imaging method for PSA studies could be identified.
perform sub-analyses. Therefore, future studies are need- However, in addition to the included variables, also oth-
ed on imaging markers of PSA, covering a broad range er potential variables (e.g. years of education, cognitive
of imaging markers. Nevertheless, as heterogeneity was status), that could not be included in the analyses due to
small between PSA studies, we believe that the results the large variability in the methods and availability of
are still of importance, but should be interpreted with data between studies, might explain some of the
caution as the generalizability and validity is between-study difference in effect estimates. Therefore,
214 Neuropsychol Rev (2017) 27:202–219

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

Imaging marker Studies

Acute phase Post-acute phase Chronic phase

PSD
Degree of WMH – Deep WMH: Kim et al. (2011); Overall, BG, frontal WMC: Chatterjee et al.
Tang et al. (2010) (2010)
Left frontal WMH: Mok et al. Overall, deep, periventricular WMH: Pavlovic
(2010) et al. (2016)
Cerebral microbleeds Choi-Kwon et al. (2012) Tang et al. (2011a, b, 2014a, b) –
Large lesion volume Shimoda and Robinson (1999); Ku et al. (2013); Nys Hama et al. (2007b); MacHale Sharpe et al. (1990, 1994); Shimoda and
et al. (2005) et al. (1998); Morris et al. Robinson (1999)
(1992); Schwartz et al. (1993);
Shimoda and Robinson (1999);
Zhang et al. (2012)
Large number of lesions – Bendsen et al. (1997); Jiang et al. Chatterjee et al. (2010); Lacunar lesions:
(2014); Tang et al. (2014b); Pavlovic et al. (2016)
Zhang et al. (2012)
Metabolism Huang et al. (2010); Xu et al. (2008) Glodzik-Sobanska et al. (2006); –
Wang et al. (2012); Xu et al.
(2008)
Atrophy – Left IFG: Fu et al. (2010) FL: Subcortical: Astrom et al. (1993); Starkstein
Tang et al. (2013b) et al. (1988)
Regional cerebral blood flow – Left hemisphere: Wichowicz et al. –
(2006)
Functional connectivity / fractional an- Altered FC in left orbital part of IFG: Zhang et al. (2014) Frontal WM integrity: Williamson –
isotropy et al. (2010); Increased ratio FA
values in bilateral anterior limbs
of IC: Yasuno et al. (2014)
PSA
Degree of WMH – RH WMH, right fronto-subcortical –
circuit WMH: Brodaty et al.
(2005); Periventricular WMH:
Tang et al. (2013a)
Large lesion volume – Hama et al. (2007b) –
Large number of lesions – Tang et al. (2013a) –
Metabolism Glodzik-Sobanska et al. (2005) – –
Regional cerebral blood flow Bilateral BG: Onoda et al. (2011) – Right dlF and lFT: Okada et al. (1997)
Fractional anisotropy – Reduced FA in Genu of CC, left –
anterior corona radiata,
splenium of CC, and WM in the
right IFG: Yang et al. (2015c).
Reduced median FA, reduction
in WM integrity in anterior
cingulum, fornix and uncinate
fasciculus: Hollocks et al.
(2015)
Atrophy – Frontal cortical atrophy: Mihalov –
et al. (2016)

ATR atrophy, BG basal ganglia, CC corpus collosum, CMB cerebral microbleeds, dlF dorsolateral frontal, FA fractional anisotropy, FC functional
connectivity, FL frontal lobe, IFG inferior frontal gyrus, lFT left frontotemporal, RH right hemisphere, WM white matter, WMC white matter changes,
WMH white matter hyperintensities, PSA post-stroke apathy, PSD post-stroke depression

Table 4 Circuits associated with post-stroke depression and post- we performed random-effects meta-analyses, which take
stroke apathy the heterogeneity between studies into account.
Studies Phase Circuits - network
Conclusion
PSD
Terroni et al. (2011) Acute Disruption of limbic-cortical-striatal-
pallidal-thalamic circuit,
Medial PFC dysfunction The present study suggests that lesion location rather than
Yang et al. (2015b) Acute Frontal lobe, insula, limbic lesion laterality or type may be an important risk factor for
system, parietal lobe, basal
ganglia, temporal lobe PSD in the post-acute stroke phase. In contrast, lesion type
Vataja et al. (2001) Post-acute Higher number and lesion
volume in (left) rather than lesion laterality or location might be an important
prefronto-subcortical circuit
Tang et al. (2011c) Post-acute Lesions in frontal subcortical circuits factor in determining who is at risk to develop PSA in the
PSA acute and post-acute phase, though additional studies are
Yang et al. (2015a) Acute Limbic system, basal ganglia,
insula, frontal, temporal, needed to confirm this, as the sample size was small.
parietal, occipital lobe
Therefore, large multicenter cohort studies using advanced
PFC prefrontal cortex, PSA post-stroke apathy, PSD post-stroke imaging techniques and focusing on both PSD and PSA from
depression the acute to the chronic stroke phase are strongly needed.
Neuropsychol Rev (2017) 27:202–219 215

Compliance with Ethical Standards between biological impairment (CT scanning), physical disability
and clinical depression. European Psychiatry, 12(8), 399–404. doi:
Conflict of Interest The authors declared no potential conflicts of in- 10.1016/S0924-9338%2897%2983565-1.
terest with respect to the research, authorship, and/or publication of this Brodaty, H., Sachdev, P. S., Withall, A., Altendorf, A., Valenzuela, M. J.,
article. & Lorentz, L. (2005). Frequency and clinical, neuropsychological
and neuroimaging correlates of apathy following stroke–the Sydney
Stroke Study. Psychological Medicine, 35(12), 1707–1716. doi: 10.
Financial Disclosure Funding was received from Maastricht
1017/S0033291705006173.
University, Health Foundation Limburg, and the Adriana van Rinsum
Buisman, L. R., Tan, S. S., Nederkoorn, P. J., Koudstaal, P. J., &
Ponsen Stichting.
Redekop, W. K. (2015). Hospital costs of ischemic stroke and TIA
Open Access This article is distributed under the terms of the Creative in the Netherlands. Neurology, 84(22), 2208–2215.
Commons Attribution 4.0 International License (http:// Caeiro, L., Ferro, J. M., & Figueira, M. L. (2012). Apathy in acute stroke
creativecommons.org/licenses/by/4.0/), which permits unrestricted use, patients. European Journal of Neurology, 19(2), 291–297. doi: 10.
distribution, and reproduction in any medium, provided you give 1111/j.1468-1331.2011.03508.x.
appropriate credit to the original author(s) and the source, provide a link Caeiro, L., Ferro, J. M., & Costa, J. (2013a). Apathy secondary to stroke:
to the Creative Commons license, and indicate if changes were made. a systematic review and meta-analysis. Cerebrovascular Diseases,
35(1), 23–39.
Caeiro, L., Ferro, J. M., Pinho e Melo, T., Canhão, P., & Figueira, M. L.
(2013b). Post-stroke apathy: an exploratory longitudinal study.
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