c o r t e x 8 8 ( 2 0 1 7 ) 1 e7

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Meta-analysis of social cognition in amyotrophic

lateral sclerosis

Emre Bora a,b,*

a
Department of Psychiatry, Dokuz Eylul University School of Medicine, Izmir, Turkey
b
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health,
Carlton South, Victoria, Australia

article info abstract

Article history:
Received 3 August 2016
Reviewed 4 October 2016
Revised 15 October 2016
Accepted 16 November 2016
Action editor Brad Dickerson
Published online 5 December 2016
Keywords:
Theory of mind
Social cognition
Emotion recognition
Cognitive
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is associated with executive dysfunction and behav-
ioural impairment. Recent studies suggested that social cognitive deficits might also be a
prominent feature of ALS. Current meta-analysis aimed to summarize available evidence
for deficits in social cognition including theory of mind (ToM) and emotion recognition in
ALS. In this meta-analysis of 15 studies, facial emotion recognition and ToM performances
of 389 patients with ALS and 471 healthy controls were compared. ALS was associated with
significant impairments with medium effect sizes in ToM (d ¼ .65) and facial emotion
recognition (d ¼ .69). Among individual emotions recognition of disgust and surprise were
particularly impaired. Deficits in perspective taking (d ¼ .73) aspects of ToM (ToM-PT) was
more pronounced in comparison to decoding (d ¼ .28) aspects of ToM (ToM-decoding). The
severity of social cognitive impairment was similar to level of executive dysfunction and
there was a significant relationship between social cognition and executive dysfunction.
Deficits in social cognition are part of the cognitive phenotype of ALS.
© 2016 Elsevier Ltd. All rights reserved.

impairment is a relatively common (30e50%) feature of ALS and

1. Introduction a minority of patients with ALS (5e15%) also met criteria for
frontotemporal dementia (FTD) (Cui et al., 2015; Montuschi
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative
et al., 2015; Murphy et al., 2016; Phukan et al., 2012; Ringholz
disease that primarily affects lower motor neurons in the
et al., 2005). A meta-analysis of cognitive deficits found me-
brainstem and spinal cord, and the upper motor neurons in the
dium effect sizes for executive functions, fluency, language and
motor cortex. ALS had long been conceptualized as a degener-
memory in ALS (Beeldman et al., 2016). Many non-demented
ative disorder with isolated motor neuron involvement. How-
patients with ALS have also behavioural impairment (Mioshi
ever, research over the last few decades suggested that ALS is
et al., 2014; Murphy et al., 2007, 2016; Strong et al., 2009). It has
not a homogenous disease and can affect other neural systems
been argued that the non-motor cognitive manifestations of
such as basal ganglia, anterior cingulate cortex (ACC) and
ALS can be considered to reflect a heterogeneous group of
frontotemporal regions leading to non-motor symptoms (Shen
‘frontotemporal dysfunction syndromes’ that include cognitive
et al., 2016; Swinnen & Robberecht, 2014). Subtle cognitive
impairment (involving a dysexecutive syndrome) (ALSci),

* Alan Gilbert Building NNF Level 3, Carlton 3053, Australia.

E-mail addresses: ibora@unimelb.edu.au, emre.bora@deu.edu.tr.
http://dx.doi.org/10.1016/j.cortex.2016.11.012
0010-9452/© 2016 Elsevier Ltd. All rights reserved.
2 c o r t e x 8 8 ( 2 0 1 7 ) 1 e7
behavioural impairment (ALSbi) and, in a small proportion, FTD
(ALS-FTD) (Strong et al., 2009).
Social cognitive impairment, in addition to dysexecutive
syndrome, is one of the hallmark features of frontotemporal
dysfunction syndromes (Bertoux, O'Callaghan, Dubois, &
Hornberger, 2016; Bora, Velakoulis, & Walterfang, 2016; Bora,
Walterfang, & Velakoulis, 2015). Therefore, it might be ex-
pected that deficits in social cognition can be a feature of ALS. The
recognition of affect from perceptual cues and theory of mind
(ToM), the ability to attribute mental states (feelings, beliefs, in-
tentions, and desires) to others and understand and predict
others' behaviour based on their mental states, are the most
commonly studied domains of social cognition. ToM is a het-
erogeneous construct including abilities to infer others' mental
states perspective taking (ToM-PT) or decoding (ToM-decoding)
based on emotional/perceptual cues to infer others' thoughts,
beliefs, emotions (Bora & Ko € se, 2016; Sabbagh, 2004; Sabbagh,
Moulson, & Harkness, 2004). A review of studies investigating
emotion recognition abilities suggested that results of the
studies were mixed but recognition of anger, sadness and disgust
might be impaired in ALS (Sedda, 2014). Recently, a number of
studies have also investigated ToM in ALS (Burke et al., 2016;
Watermeyer et al., 2015). The outcomes of these studies were
inconsistent, especially for ToM-decoding. A number of studies
have not found significant differences between ALS and control
groups in ToM-decoding tasks (Cavallo et al., 2011; Watermeyer
et al., 2015). The findings of these studies were also inconsis-
tent regarding whether impaired performance in ToM-PT in ALS
reflects specific deficits in social cognition or general cognitive
deficits (Cavallo et al., 2011; Gibbons et al., 2007). Currently, it is
not known whether recognition of some emotions or different
aspects of ToM are differentially impaired in ALS. The severity of
social cognitive impairment in comparison to other neuropsy-
chological deficits in ALS is also unclear.
Some of the inconsistent findings of studies investigating
social cognition in ALS might be related to low statistical
power of individuals studies as most of the available studies
have small sample sizes. A meta-analysis can be helpful to
increase statistical power and estimate the effect size for
different aspects of social cognitive deficits in ALS. There has
been only one attempt to summarize social cognitive deficits
in ALS using meta-analytical methods, the meta-analysis of
Beeldman et al. (2016) included a preliminary analysis of a
small number of studies (k ¼ 5) including social cognitive
measures. Also, the social cognition measure in the meta-
analysis of Beeldman et al. (2016) included a combination of
facial emotion recognition, prosody and ToM. The primary
goal of this meta-analysis was to quantify the magnitude of
social cognitive deficits, to examine if some aspects of
emotion recognition and ToM are relatively more impaired in
ALS than others, and to explore the relationship between so-
cial cognitive impairment and other variables in ALS.
2. Methods
2.1. Study selection
We followed PRISMA guidelines in conducting this meta-
analysis (Moher, Liberati, Tetzlaff, Altman, & Group PRISMA,
2009). A literature search was conducted using the databases
Pubmed, PsycINFO, ProQuest and Scopus to identify the rele-
vant studies (January 1990eJuly 2016) using the combination
of keywords as follows: (ToM or emotion recognition or social
cognition) and “amyotrophic lateral sclerosis”. Reference lists
of published reports were also reviewed for additional studies.
Inclusion criteria were studies that: (1) Compared ToM or
facial emotion recognition performances of nondemented
ALS and healthy controls; (2) reported sufficient data to
calculate the effect size and standard error of the social
cognition measure. Studies investigating emotion recognition
abilities with methods other than facial recognition were
excluded as only a few studies investigated ALS using such
methods (i.e., vocal). Two studies were excluded as they
included a mixed sample of patients with and without de-
mentia (Table 1s in supplement). Savage et al. (2014) included
pure ALS and FTD-ALS groups, FTD-ALS sample of this study
was excluded from the current meta-analysis.
2.2. Social cognition measures
Studies have investigated facial emotion recognition with a
variety of methods (different sets of images of faces to label:
most commonly Ekman) (Ekman & Friesen, 1976). Different
ToM tasks have been utilized across studies, most commonly
Reading the Mind in the Eyes Task (RMET); other tasks have
included faux pas recognition (the task involves recognizing
faux pas in series of short stories), judgement of preference
test (JPT), Happe cartoons and stories, and The Awareness of
Social Inference Test (TASIT) sarcasm (Baron-Cohen,
Campbell, Karmiloff-Smith, Grant, & Walker, 1995; Baron-
Cohen, Wheelwright, Hill, Raste, & Plumb, 2001). In RMET,
individuals are instructed to look at a series of photographs of
just the eye region of the face, and picking which of four words
best describe what the person in the photo is thinking or
feeling. RMET was the only measure for ToM-decoding (Baron-
Cohen et al., 2001; Sabbagh et al., 2004). All other ToM tasks
were measuring ToM-PT (also called mental state reasoning
(Sabbagh, 2004)).
2.3. Statistical analyses
For studies that reported more than one ToM task, pooled
effect sizes (Cohen d) and standard error values were calcu-
lated. A pooled effect size of social cognition based on ToM
and/or total emotion recognition score was calculated for each
study. Individual tasks analyses for RMET (ToM-decoding)
were also possible. A pooled effect size of ToM-PT was also
calculated by averaging effect size of ToM tasks other than
RMET. In addition to the total emotion labelling score, sepa-
rate effect sizes for six basic emotions (anger, fear, disgust,
sadness, happiness, surprise) were also calculated. In 10
studies that co-administered cognitive assessments along
with social cognitive tasks, a pooled effect size for executive
dysfunction was calculated for each study. As a measure of
executive of functions, these studies included one or several
of Brixton Spatial Anticipation test, Hayling Sentence
completion test, Stroop interference, trail making B test, ver-
bal fluency tests and frontal assessment battery. Five studies
reported correlational coefficient for the relationship between
 c o r t e x 8 8 ( 2 0 1 7 ) 1 e7
social cognition and executive functions, we also conducted a
meta-analysis of correlational effect sizes (r) including these
studies.
Meta-analyses were performed using packages in the R
environment (OpenMetaAnalyst, Metafor) (Viechtbauer, 2010;
Wallace et al., 2012). Effect sizes were weighted using the in-
verse variance method. A random effects model (DerSimo-
nianeLaird estimate) was used. Homogeneity of the
distribution of weighted effect sizes was tested with the Q and
I2 tests. Tau-squared (t2), an estimate of between-study vari-
ance, was used as a measure of heterogeneity in the random
effects model. Publication bias was assessed by inspection of
funnel plots, Egger's test and trim and fill method. Egger's test
relies on the theory that small studies with significant rather
than negative findings in studies with small sample sizes
would be more likely to be reported while large-scale studies
would be more likely to be published regardless of the sig-
nificance of the findings. The significance threshold of Egger's
test was defined as p ¼ .1 due to small numbers of studies
included in some analyses.
Subgroup analyses were conducted for depressive symp-
toms (No difference vs significantly increased in ALS) and ALS
severity based on ALS Functional Rating Scale-revised form
(ALSFRS-R; Cedarbaum et al., 1999) [Mild vs Moderate (cut-off
score ¼ 37)]. A subgroup analysis of social cognition and ex-
ecutive dysfunction was conducted in 10 studies investigating
both social cognition and other cognitive functions. The Qbet
test was used to statistically compare subgroups in these an-
alyses. Meta-regression analyses were conducted for gender
(ratio of males in ALS group) and bulbar onset (ratio of patients
with bulbar onset) with a random effects model were using
the restricted-information maximum likelihood method with
a significance level set at p < .05. The effect of bulbar onset on
social cognitive impairment was investigated as previous
studies have associated bulbar-onset with more cognitive
deficits in ALS.
3. Results
Fifteen studies involving 389 (64.5% males) nondemented ALS
patients and 471 (58.0% females) healthy controls were
included (Table 1s in the supplement) (see Fig. 1 for the flow
chart of the study selection process). Most of the ALS patients
had spinal onset, the percentage of patients having bulbar
onset ranged from 7% to 34%. There was no significant
between-group difference for age (d ¼ .02, CI ¼ .15e.19,
p ¼ .78, k ¼ 13) and education (d ¼ .09, CI ¼ .06e.24, p ¼ .26,
k ¼ 12). Mean ALSFRS-R score in included studies was 35.95.
The range of ALSFRS-R scores (29.8e40) across studies sug-
gested that patients included in the current meta-analysis had
predominantly mild or moderate disease severity.
Social cognition was significantly impaired (d ¼ .64,
CI ¼ .50e.78) in ALS in comparison to healthy controls (Table
1). In separate analyses of the two main social cognitive do-
mains investigated, the performance of ALS patients was
significantly poorer than healthy controls for both emotion
recognition (d ¼ .69, CI ¼ .42e.97, Fig. 2) and ToM (d ¼ .65,
CI ¼ .47e.84) (Table 1). Distribution of effect sizes for social
cognition, ToM and emotion recognition were homogeneous
3
(Table 1). Egger's tests, trim and fill method (Table 1) and in-
spection of funnel plots provided evidence of publication bias
for social cognition and ToM. Estimated effect sizes with trim
and fill method for ToM (d ¼ .47) and social cognition (d ¼ .49)
were smaller.
In the analysis of individual emotions, ALS patients
significantly underperformed controls in disgust (d ¼ .65,
CI ¼ .29e1.02), surprise (d ¼ .65, CI ¼ .28e1.01) and sadness
(d ¼ .50, CI ¼ .13e.86) (Table 1). There were no significant
deficits for recognition of anger, fear and happiness in ALS
(Table 1). Among ToM domains, ToM-PT was particularly
impaired in ALS (d ¼ .73, CI ¼ .53e.93) (Fig. 3). There was also a
significant but a very mild impairment in ToM-decoding as
measured with RMET (d ¼ .28, CI ¼ .04e.52) (Table 1). Distri-
bution of effects sizes for ToM-PT, RMET, JPT and six basic
emotions were homogenous (Table 1).
3.1. Effect of confounding variables
In two studies, depression ratings were higher in ALS patients
compared to controls. However, the severity of social cogni-
tive impairment in ALS in these studies in were not signifi-
cantly different compared to other studies (d ¼ .83,
CI ¼ .39e1.28 vs d ¼ .62, CI ¼ .46e.77, Qbet ¼ 1.1, p ¼ .29). Also,
there was no significant effect of study level severity of ALS
symptoms (mild vs moderate on ALSFRS-R) on the social
cognitive impairment in patients (d ¼ .67 vs .79, Qbet ¼ .45,
p ¼ .50). There was a non-significant tendency for studies with
a higher percentage of ALS patients with bulbar onset
reporting more severe ToM impairment in ALS (Z ¼ 1.75,
p ¼ .08). Gender had no significant effect on between-group
differences in social cognition. Study-level meta-regression
analysis found a significant relationship between severity of
deficits in social cognition and executive functions (Z ¼ 1.95,
p ¼ .05, k ¼ 10). Also, a meta-analysis of correlational data
investigating the relationship between social cognition and
executive functions confirmed that social cognitive abilities
are associated with executive functions (r ¼ .52, CI ¼ .37e.67,
p < .001, k ¼ 5) (Fig. 1s in the supplement).
4. Discussion
The current meta-analysis investigated social cognitive defi-
cits in ALS in comparison with healthy controls. Current
findings showed that ALS patients significantly under-
performed healthy controls in ToM and facial emotion
recognition tasks. Executive dysfunction was significantly
associated with social cognitive deficits.
In the current meta-analysis, medium effect sizes were
found for ToM (d ¼ .65) and facial emotion recognition (d ¼ .69)
deficits in ALS. The severity of impairment in social cognition
was comparable in magnitude to other cognitive deficits as
reported in a previous meta-analysis in ALS (Beeldman et al.,
2016). Social cognitive impairment and executive dysfunc-
tion were significantly correlated in the current meta-
analysis. These findings suggest that cognitive profile of ALS
include, in addition to executive dysfunction and other
cognitive deficits, social cognitive impairment. Social cogni-
tive deficits are evident in ALS subtypes with cognitive and/or
4 c o r t e x 8 8 ( 2 0 1 7 ) 1 e7

IdenƟficaƟon
Unique records idenƟfied through AddiƟonal records idenƟfied
searching keywords through reference lists
(n =44 ) (n =3 )

Records screened Records excluded

(n =47) (n =9 )
Screening

Records assesed for

Inclusion criteria Not meeƟng criteria
(n =38 ) (n =21 )

ArƟcles meeƟng inclusion

criteria
Eligibility

Excluded
(n =17 )
Included demented ALS=2

Studies included in
quanƟtaƟve synthesis
(meta-analysis)
(n =15)
Included

Fig. 1 e Flow diagram for meta-analysis of social cognition deficits in ALS.

Table 1 e Mean weighted effect sizes for differences between patients with ALS and healthy controls on social cognition
tasks.

Test Study N ALS HC d 95% CI Z p Q Q (p) t2 Bias (p) I2 (%) Estimated Cohen d (CI)
Trim and fill
Social cognition 15 389 471 .64 .50e.78 8.8 <.001 13.8 .47 0 <.01 0 .49
ToM 11 311 339 .65 .47e.84 6.9 <.001 12.6 .25 .02 <.01 21 .47
- ToM-PT 11 311 339 .73 .53e.93 7.2 <.001 14.1 .17 .03 <.01 29
- RMET 5 166 170 .28 .04e.52 2.3 .02 14.1 .12 .01 .09 14
Facial emotion 5 92 152 .69 .42e.97 5.0 <.001 1.1 .89 .14 .41 0 No change
- Anger 3 56 74 .33 .18e.84 1.3 .20 3.9 .14 .10 .24 49
- Fear 3 56 74 .29 .08e.65 1.6 .12 .80 .67 0 .49 0
- Sad 3 56 74 .50 .13e.86 2.7 .007 0.5 .77 0 .16 0
- Happy 3 56 74 .13 .30e.57 0.6 .55 3.1 .21 .05 .36 36
- Disgust 3 56 74 .65 .29e1.02 3.5 <.001 0.4 .86 0 .71 0
- Surprise 3 56 74 .65 .28e1.01 3.5 <.001 1.1 .57 0 .20 20

ALS ¼ amyotrophic lateral sclerosis, HC ¼ healthy controls, d ¼ Cohen's d, ToM ¼ theory of mind, CI ¼ confidence interval.

behavioural impairment not reaching the threshold for de-
mentia. However, it is also important to note that executive
dysfunction and social cognitive deficits can be only partially
overlapping in ALS. The data-driven approach of Consonni,
 , Dalla Bella, and Cappa (2016) showed that social
Catricala
cognitive impairment co-exists with ALSci and ALSbi in most
of the subjects, there was a subgroup of ALS patients char-
acterized by social cognitive impairment and non-executive
dysfunction (language and episodic memory) but not execu-
tive dysfunction. Therefore, consensus criteria of Strong et al.
(2009) are inadequate for the classification of nondemented
ALS patients with mild behavioural and cognitive impair-
ments. Including social cognitive and other cognitive deficits
in the definition of ALSci should be considered.
Another important subject is the neural substrates of social
cognitive deficits in ALS. Previous studies found a relationship
between cognitive deficits and neuroanatomical abnormal-
ities including cortical atrophy and basal ganglia pathology in
nondemented ALS (Machts et al., 2015; Mioshi et al., 2013). It is
likely that social cognitive impairment is also related to more
 c o r t e x 8 8 ( 2 0 1 7 ) 1 e7 5

Fig. 2 e Forest plot for facial emotion recognition differences between ALS and healthy controls: CD ¼ Cohen d; Diamond
shape ¼ average effect size and its confidence interval based on random effects model.

Fig. 3 e Forest plot for ToM-PT differences between ALS and healthy controls.

widespread brain imaging abnormalities in ALS. Only three
studies which are also included in the current meta-analysis
investigated structural and functional brain imaging corre-
lates of social cognitive impairment in ALS. The findings of
these studies suggested that volumetric reductions and
reduced functional activity in medial and inferior prefrontal
cortex and white matter tracts connecting these regions to
other parts of the brain are associated with social cognitive
impairment in ALS (Carluer et al., 2015; Cerami et al., 2014;
Crespi et al., 2014).
The severity of social cognitive deficits was much less
pronounced and more circumscribed than FTD (Bora et al.,
2015, 2016). FTD is associated with broad deficits in all as-
pects of ToM and emotion recognition. However, cognitive
profile of ALS included more specific deficits in ToM-PT and
recognition of disgust and surprise. Abnormalities in the
frontal lobe and its insular and subcortical connections can
explain deficits in ToM-PT and in these some emotions. Basal
ganglia and insula have important roles for recognition of
disgust. In recognition of surprised faces inverse coupling
between ventromedial prefrontal cortex and amygdala is
important (Kim, Somerville, Johnstone, Alexander, & Whalen,
2003). Ventromedial prefrontal cortex dysfunction in ALS can
lead to impaired positive interpretation and misidentification
of surprised faces as fear. More widespread atrophy involving
temporal lobes in FTD can explain pronounced deficits in
decoding mental states which are best identified from eyes
(anger, fear and complex emotions) (Bassili, 1979; Mason et al.,
2015), which are spared in most patients with ALS. However,
ALS-FTD is associated with more extensive brain atrophy and
deficits in recognition of fear and anger were robust in a FTD-
ALS study (Savage et al., 2014). It might be hypothesized that
deficits in ToM-decoding and recognition of some emotions
can be a marker of a small group of individuals who are at risk
of developing FTD-ALS at follow-up or who have C9ORF72
expansions. However, longitudinal studies are needed to test
this hypothesis.
Social cognitive deficits observed in this meta-analysis
were not significantly related to ALS severity as measured
with ALSFRS-R. However, total ALSFRS-R score might not be a
sensitive measure to show the relationship between symptom
severity and social cognitive deficits in ALS. Two patients
might differ significantly in their bulbar and spinal scores but
might have the same ALSFRS-R total score. Unfortunately,
nearly none of the included studies reported separate sub-
scale scores of ALSFRS-R. The site of onset of ALS might be
related to social cognitive deficits in ALS. There was no suffi-
cient data to investigate the effect of bulbar onset on social
cognition quantitatively. However, one of the studies included
(19) suggested that ToM-decoding deficits might be evident
only in bulbar-onset ALS.
Another consideration was the relationship between
neuropsychiatric symptoms and social cognition in ALS.
Apathy is a common finding in ALS (Lillo et al., 2011) and it is
not known if apathy is related to social cognitive impairment
in ALS. Another neuropsychiatric condition in ALS is
6 c o r t e x 8 8 ( 2 0 1 7 ) 1 e7
depression. Social cognitive, especially ToM, deficits are
associated with depression in subjects without neurological
disorders (Bora & Berk, 2016). The lack of association between
depressive symptoms and social cognitive impairment in the
current meta-analysis suggests that social cognitive impair-
ment in ALS is not simply caused by low mood. However, most
individuals with ALS in included studies did not meet criteria
for clinical depression. Gender had no significant effect on
social cognitive impairment in ALS in the current meta-
analysis. However, it is important to control the effect of
gender in future studies using social cognitive tasks which are
sensitive to effects of gender (i.e., RMET).
There are a number of limitations to our meta-analysis. We
were not able to investigate emotion recognition deficits
beyond facial stimuli. The heterogeneity of ToM and emotion
recognition measures was another limitation. To overcome
this limitation, we conducted individual task analysis when
possible. We were not able to directly compare social cogni-
tion in bulbar versus spinal onset patients with ALS. There
was also evidence of publication bias for ToM. However, the
estimated effect size for ToM impairment remained to be
significant even after conservative trim and fill method. This
finding suggests that ToM is impaired in ALS but the estimate
of effect size in the current meta-analysis might be moder-
ately exaggerated. Another consideration is the potential
contribution of undiagnosed FTD-ALS patients to the current
findings. The studies explicitly including patients with FTD-
ALS were excluded in the current meta-analysis. However, a
small minority of patients included in the meta-analysis
might still have an undiagnosed early stage FTD-ALS as
cognitive and behavioural symptoms of FTD syndrome might
be very subtle and not all studies used genetic testing. Also,
number of available studies were small for some measures
and larger meta-analyses including future studies might
reveal subtle deficits in recognition in anger and fear in ALS.
In conclusion, current findings suggest that ALS is associ-
ated with significant deficits in social cognition. The severity
of these impairments is comparable to other cognitive deficits
in ALS. Future studies investigating the course of social
cognitive deficits, and studies further exploring the neural
correlates of these impairments in ALS are necessary.
Funding statement
This research received no specific grant from any funding
agency in the public, commercial or not-for-profit sectors.
Competing interests statement
Author has no conflicts of interest regarding subject of this
manuscript.
Acknowledgments
None.
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.cortex.2016.11.012.
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