Psychological Medicine (2015), 45, 1315–1325.

© Cambridge University Press 2014 OR I G I N A L A R T I C L E

doi:10.1017/S0033291714002426

Failure of deactivation in the default mode network:

a trait marker for schizophrenia?

R. Landin-Romero1,2, P. J. McKenna1,2,3*, P. Salgado-Pineda1,2, S. Sarró1,2, C. Aguirre1,3, C. Sarri1,3,

A. Compte1,3, C. Bosque1,3, J. Blanch4, R. Salvador1,2 and E. Pomarol-Clotet1,2
1
FIDMAG Germanes Hospitalàries, Barcelona, Spain
2
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain
3
Benito Menni Complex Assistencial en Salut Mental, Barcelona, Spain
4
Hospital Sant Joan de Déu Infantil, Barcelona, Spain

Background. Functional imaging studies in relatives of schizophrenic patients have had inconsistent findings, particu-
larly with respect to altered dorsolateral prefrontal cortex activation. Some recent studies have also suggested that failure
of deactivation may be seen.

Method. A total of 28 patients with schizophrenia, 28 of their siblings and 56 healthy controls underwent functional
magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance was
fitted to individual whole-brain maps from each set of patient–relative–matched pair of controls. Clusters of significant
difference among the groups were then used as regions of interest to compare mean activations and deactivations among
the groups.

Results. In all, five clusters of significant differences were found. The schizophrenic patients, but not the relatives,
showed reduced activation compared with the controls in the lateral frontal cortex bilaterally, the left basal ganglia
and the cerebellum. In contrast, both the patients and the relatives showed significant failure of deactivation compared
with the healthy controls in the medial frontal cortex, with the relatives also showing less failure than the patients. Failure
of deactivation was not associated with schizotypy scores or presence of psychotic-like experiences in the relatives.

Conclusions. Both schizophrenic patients and their relatives show altered task-related deactivation in the medial frontal
cortex. This in turn suggests that default mode network dysfunction may function as a trait marker for schizophrenia.

Received 29 April 2013; Revised 4 September 2014; Accepted 9 September 2014; First published online 21 October 2014

Key words: Default mode network, endophenotype, fMRI, schizophrenia, working memory.

Introduction endophenotype concept is that the abnormality is pres-

ent not only in patients with schizophrenia but is also
While the existence of a genetic factor in the aetiology
seen to a lesser degree in non-affected family members
of schizophrenia is uncontroversial (e.g. Gottesman,
at a higher rate than in the general population.
1991), studies to date have yielded only a few candi-
The first recognizably endophenotypic construct in
date genes, whose effects are small and some of
schizophrenia was schizotypy, a quantitative person-
which are also implicated in other forms of major psy-
ality trait with presumptive neurobiological correlates
chiatric disorder (Craddock & Owen, 2005; Collins &
(Meehl, 1962). A number of other endophenotypes
Sullivan, 2013). This, coupled with evidence that
have since been proposed, ranging from eye-tracking
schizophrenia shows a complex pattern of inheritance –
dysfunction to sensory gating deficits, cognitive im-
i.e. involving multiple genes and almost certainly environ-
pairment, neurological soft signs and brain structural
mental factors as well (McGue & Gottesman, 1989) – has
abnormality (for a review, see Allen et al. 2009). A
led to a search for so-called endophenotypes, clinical or
further candidate is brain functional abnormality;
biological findings that are more closely related to risk
here interest has focused on the reduced dorsolateral
genes than the disorder itself (Leboyer et al. 1998;
prefrontal cortex (DLPFC) activation that is well docu-
Gottesman & Gould, 2003). A key aspect of the
mented in schizophrenia (Hill et al. 2004), and more re-
cently the ‘hyperfrontality’ or increased activation that
has also been found during cognitive task performance
* Address for correspondence: P. J. McKenna, FIDMAG, Germanes
Hospitalàries, Benito Menni CASM, C/. Dr Antoni Pujadas 38, 08830
(Weinberger et al. 2001; Minzenberg et al. 2009).
Sant Boi de Llobregat, Barcelona, Spain. MacDonald et al. (2009) reviewed 20 task-related func-
(Email: mckennapeter1@gmail.com) tional imaging studies carried out on first-degree
1316 R. Landin-Romero et al.
relatives of patients with schizophrenia. Those using
working memory tasks and tasks requiring ‘cognitive
control’ (inhibition of a pre-potent response or ignor-
ing distraction) were found to have heterogeneous
findings, reporting increased, decreased and un-
changed activation in the dorsolateral and the ventro-
lateral prefrontal cortex, in some cases with increases
on one side and decreases on the other. Findings
were similar in studies using long-term memory and
language tasks. Studies carried out since this review
have continued to find evidence of both decreased
(Karch et al. 2009; Sepede et al. 2010; Meda et al.
2012) and increased (Karch et al. 2009; Woodward
et al. 2009; Stolz et al. 2012; Liddle et al. 2013;
Sambataro et al. 2013) prefrontal activation.
Recently, a further functional imaging abnormality
has been documented in schizophrenia: failure of de-
activation in the medial frontal cortex (Pomarol-
Clotet et al. 2008; Whitfield-Gabrieli et al. 2009;
Mannell et al. 2010; Salgado-Pineda et al. 2011;
Schneider et al. 2011; Dreher et al. 2012). The usual
interpretation of this finding is that it represents dys-
function in the default mode network, an intercon-
nected series of brain regions which are active at rest
but which deactivate during performance of a wide
range of cognitive tasks. The medial frontal cortex is
one of the principal constituents of this network,
along with the posterior cingulate cortex/precuneus,
parts of the parietal and temporal lobe cortex and the
hippocampus (for a review, see Buckner et al. 2008).
This interpretation is strengthened by studies that
have used another method of examining the default
mode network function, resting-state functional con-
nectivity (Buckner et al. 2008; Greicius, 2008). These
have typically found changes in schizophrenia (Liang
et al. 2006; Bluhm et al. 2007; Mannell et al. 2010;
Ongur et al. 2010; Rotarska-Jagiela et al. 2010;
Salvador et al. 2010; Camchong et al. 2011), although
there is currently no consensus about whether connec-
tivity is increased, decreased or shows a more complex
pattern of abnormality.
Examination of the default mode network in rela-
tives of patients with schizophrenia has so far been
limited. In the first study of this type, Whitfield-
Gabrieli et al. (2009) found that 13 first-degree relatives
of schizophrenic patients showed failure to deactivate
in the medial frontal cortex compared with 13 controls
during performance of the n-back working memory
task. Additionally, the failure of deactivation was
found to correlate negatively with scores on a measure
of psychiatric symptomatology in the relatives. In
contrast, Sepede et al. (2010) found no differences
in medial frontal cortex deactivation in 11 siblings of
schizophrenic patients compared with 11 healthy con-
trols during performance of the Continuous Performance
Task; instead, the relatives showed exaggerated deacti-
vation in the posterior cingulate and retrosplenial cortex
when making correct responses. Using a choice reaction
time task, Liddle et al. (2013) found no overall differences
in deactivation between 18 siblings of schizophrenic
patients and 26 healthy controls. However, the relatives
showed failure of deactivation in response to non-target
as opposed to target stimuli in both the medial frontal
cortex and the precuneus.
The aim in the present study was to examine task-
related activations and deactivations in relatives of
schizophrenic patients, using a prototypical frontal/
executive task, the n-back working memory task. We
also compared relatives with their siblings with schizo-
phrenia. A particular focus of interest was on failure
of deactivation, which we were able to examine in a
larger sample than the three other studies carried out
on relatives to date.
Method
Subjects
A total of 28 patients with schizophrenia and 28 of
their healthy siblings were recruited. The schizo-
phrenic patients all met Diagnostic and Statistical
Manual of Mental Disorders, fourth edition (DSM-IV)
criteria, based on interview by a psychiatrist and re-
view of case-notes by a member of the research team
(P.J.M. or S.S.). They were excluded if: (1) they were
younger than 18 or older than 65 years; (2) they had
a history of brain trauma or neurological disease; or
(3) they had shown alcohol/substance abuse within
12 months prior to participation. They all had chronic
illnesses (mean duration 15.66, S.D. = 8.18 years; range
3.5 to 41 years) and were all taking antipsychotic
medication (20 atypical neuroleptics, four typical
neuroleptics, four both types). The mean daily dose
(in chlorpromazine equivalents) was 707.83 mg (S.D. =
319.95 mg, range 200–1274 mg).
The unaffected first-degree relatives had a mean dif-
ference in age from the patients of 5.25 years (S.D. = 3.70
years, range 0 to 13 years; one pair were non-identical
twins). They met the same exclusion criteria as the
patients, and were also excluded if they reported a
history of mental illness and/or treatment with psycho-
tropic medication. Twenty-seven (one declined)
additionally underwent assessment using the
Computerized Diagnostic Interview Schedule IV
(C DIS-IV; Robins et al. 2000), a structured psychiatric
interview designed to detect lifetime presence of
major psychiatric disorders.
Healthy subjects were recruited via poster and web-
based advertisement in the hospital and local com-
munity, plus word-of-mouth requests from staff in the

research unit. They met the same exclusion criteria as the
patients and, like the relatives, were excluded if they
reported a history of mental illness and/or treatment
with psychotropic medication. Two healthy subjects
were recruited for each patient–relative pair, matching
for age, sex and estimated intelligence quotient (IQ).
This strategy was adopted in order to be able to match
properly in those cases where the patient–relative pair
consisted of a male and a female.
All patients and their relatives were right-handed
with the exception of one pair, who were both
left-handed. All the controls were right-handed. IQ
(pre-morbid IQ in the patients) was estimated using
the Word Accentuation Test (Test de Acentuación de
Palabras; TAP; Del Ser et al. 1997), a word reading
test requiring pronunciation of Spanish words
whose accents have been removed. The TAP has
been standardized against the Wechsler Adult
Intelligence Scale III (WAIS-III; Wechsler, 2001) and
scores can be converted into IQ estimates (Gomar
et al. 2011). Patients, relatives and controls were also
required to have a current IQ in the normal range
(i.e. 570), as measured using four subtests of the
WAIS-III: vocabulary, similarities, block design and
matrix reasoning.
Symptoms in the patients were rated using the
Positive and Negative Syndrome Scale (PANSS; Kay
et al. 1987). Relatives were rated on a schizotypy scale,
the Rust Inventory of Schizotypal Cognitions (RISC;
Rust, 1989). Lifetime presence of psychotic-like experi-
ences in the relatives was also assessed. For this, ratings
on the psychotic subscales of the C DIS-IV were used.
This section contains 22 items, 17 for delusion-like and
five for hallucination-like experiences, each of which
are rated as ‘absent’, ‘questionable’ or ‘present’.
All participants gave written informed consent and
the study was approved by the hospital research ethics
committee. All procedures were carried out according
to the Declaration of Helsinki.
Procedure
The participants performed a sequential-letter version of
the n-back task (Gevins & Cutillo, 1993). Two levels of
memory load (1-back and 2-back) were presented in a
blocked design manner. Each block consisted of 24 let-
ters that were shown every 2 s (1 s on, 1 s off) and all
blocks contained five repetitions (1-back and 2-back
depending on the block) located randomly within the
blocks. Individuals had to indicate repetitions by press-
ing a button. Four 1-back and four 2-back blocks were
presented in an interleaved way, and between them a
baseline stimulus (an asterisk flashing with the same fre-
quency as the letters) was presented for 16 s. To identify
which task had to be performed, characters were shown
Failure of deactivation in the default mode network 1317
in green in 1-back blocks and in red in the 2-back blocks.
All participants first went through a training session
outside the scanner.
The behavioural measure used was the signal detection
theory index of sensitivity, d (Green & Swets, 1966).
Higher values of d′ indicate better ability to discriminate
between targets and distractors. If subjects showed nega-
tive d values in either or both of the 1-back and 2-back ver-
sions of the task, which suggests that they were not
performing it, they were not included in the study.
Functional magnetic resonance imaging (fMRI)
data acquisition
In each individual scanning session 266 volumes were
acquired from a 1.5-T GE Signa scanner. A gradient
echo planar imaging (EPI) sequence depicting the
blood oxygenation level-dependent (BOLD) contrast
was used. Each volume contained 16 axial planes
acquired with the following parameters: repetition
time = 2000 ms, echo time = 20 ms, flip angle = 70°, sec-
tion thickness = 7 mm, section skip = 0.7 mm, in-plane
resolution = 3 × 3 mm. The first 10 volumes were dis-
carded to avoid T1 saturation effects.
Analysis of fMRI activations and deactivations
fMRI image analyses were performed with the FEAT
module included in FSL software (Smith et al. 2004).
At a first level, images were corrected for movement
and then co-registered to a common stereotaxic space
[Montreal Neurological Institute (MNI) template]. To
minimize unwanted movement-related effects, indivi-
duals with an estimated maximum absolute movement
>3.0 mm or an average absolute movement >0.3 mm
were excluded from the study.
The signal:noise ratio (SNR) was computed for indi-
vidual functional scans across the three groups accord-
ing to the definition that models SNR based on the
mean signal of the fMRI time series and the standard
deviation of the noise in the time series (Welvaert &
Rosseel, 2013).
General linear models were fitted to generate indi-
vidual activation maps for the 1-back v. baseline and
2-back v. baseline contrasts. We also carried out a sup-
plementary analysis examining the effect of increasing
working memory load on group differences. To do this
we fitted models that assume a linear relationship
through the baseline, 1-back and 2-back levels of the
task, reporting significant differences on regression
slopes between the relatives, patients and controls.
Group analysis
Individual activation maps for baseline v. 1-back and
baseline v. 2-back contrasts were used as inputs for
1318 R. Landin-Romero et al.

Table 1. Demographic characteristics of the patients (n = 28), healthy relatives (n = 28) and controls (n = 56)

Schizophrenic patients (n = 28) Relatives (n = 28) Controls (n = 56) p

Sex, n
Male 21 17 38 0.38
Female 7 11 18
Age, years
Mean (S.D.) 35.71 (9.72) 36.82 (8.80) 36.58 (9.87) 0.89
Range 19–57 19–52 19–60
Estimated pre-morbid IQ by TAP
Mean (S.D.) 95.08 (9.73) 102.66 (6.99) 100.23 (7.93) 0.004
Range 77–110 87–112 81–114 CTRL, REL > SCZ
Current IQ by WAIS-III
Mean (S.D.) 93.60 (12.81) 110.07 (11.47) 104 (12.16) <0.001
Range 71–121 81–128 72–128 CTRL, REL > SCZ
Behavioural performance
d′ 1-back
Mean (S.D.) 3.52 (0.91) 4.26 (0.68) [3.07–4.96] 4.33 (0.71) <0.001
Range 1.35–4.96 3.07–4.96 CTRL, REL > SCZ
d′ 2-back
Mean (S.D.) 2.31 (0.68) 3.37 (0.84) 3.36 (0.93) <0.001
Range 0.95–4.06 1.45–4.96 0.62–4.96 CTRL, REL > SCZ
GAF score
Mean (S.D.) 51.65 (11.34) – – –
Range 35–77
PANSS score
Mean (S.D.) 66.19 (14.96) – – –
Range 35–96

S.D., Standard deviation; IQ, intelligence quotient; TAP, Word Accentuation Test (Test de Acentuación de Palabras); CTRL,
controls; REL, relatives; SCZ, schizophrenic patients; WAIS-III, Wechsler Adult Intelligence Scale III; d′, d-prime; GAF, Global
Assessment of Functioning; PANSS, Positive and Negative Syndrome Scale.

the group analysis. Since each patient was sampled
together with his/her sibling, creating covariation be-
tween pairs, a simple one-way analysis of variance
(ANOVA) was not appropriate, and this lack of inde-
pendence between subjects had to be modelled
through a repeated-measures ANOVA. Each set of
patient–relative–matched pair of controls was con-
sidered as a unit in the repeated-measures design,
and an F test was performed to highlight any statistical
differences between groups. This F test was carried out
with the FEAT module at the cluster level with a p
value of 0.05 corrected for multiple comparisons across
space using Gaussian random field methods. The de-
fault threshold of Z = 2.3 was used to define the initial
set of candidate clusters.
Any clusters showing significant differences among
the groups in the ANOVA were used as regions of
interest (ROIs) to perform pair-wise comparisons.
for age and sex. There was a significant group effect
for TAP-estimated IQ; this was due to a significant dif-
ference between the patients with schizophrenia and
the other two groups. Therefore, TAP score was
entered as a covariate in all analyses. As expected,
the patients had a significantly lower current IQ than
both the relatives and the healthy controls.
There was little evidence of co-morbidity in the
schizophrenic patients. One had experienced depressive
symptoms over a period of months but these did not
amount to a diagnosable major affective syndrome. No
patients had a recorded history of depression, anxiety
or obsessive–compulsive disorder prior to the onset of
schizophrenia. Similarly, no patients had received
other Axis I diagnoses such as attention-deficit/hyperac-
tivity disorder (ADHD), post-traumatic stress disorder
or autistic spectrum disorder, prior to or concurrently
with their index diagnosis of schizophrenia.

Results Behavioural performance

Demographic data on the patients, relatives and con- The three groups’ d′ scores are shown in Table 1. There
trols are shown in Table 1. The groups were matched was a main effect of group on performance in both the

1-back and 2-back versions of the task (F = 11.36 and
F = 16.17, respectively, both p < 0.01). This was due to
the schizophrenic patients performing more poorly
than the controls on the 1-back (t = −4.48, p < 0.001)
and the 2-back (t = −5.03, p < 0.001) versions of the
task. They also performed more poorly than the rela-
tives on both versions of the task (1-back: t = −3.66,
p = 0.01; 2-back: t = −5.90, p < 0.001). There were no
significant differences between the relatives and the
healthy controls on either version of the task (1-back:
t = −0.43, p = 0.66; 2-back: t = −0.07, p = 0.94).
fMRI findings
Average values for SNR did not differ significantly
among the three groups (schizophrenic patients 5.51,
S.D. = 1.88; relatives 5.73, S.D. = 1.97; healthy controls
5.88, S.D. = 1.51; p = 0.62).
Activations and deactivations were generally more
marked in the 2-back v. baseline than in the 1-back v.
baseline contrast. To avoid redundancy, therefore, in
what follows the focus is on the former contrast (the
supplementary working memory load analysis takes
into account performance during the 1-back task).
Within-group activations and deactivations
The findings are shown in Fig. 1. The healthy subjects
and the relatives both showed activation in predomi-
nantly lateral frontal regions. This included clusters in
the precentral gyrus bilaterally, which extended ante-
riorly to reach both the left and right DLPFC and the
supplementary motor area. These clusters also included
the frontal operculum and the anterior insula bilaterally.
Other clusters of activation were seen in the basal gang-
lia and thalamus, the cerebellum, and bilaterally in
regions of the temporal, occipital and parietal cortex.
The healthy subjects and the relatives also showed
task-related deactivations in the medial frontal cortex
and the posterior cingulate cortex/precuneus.
Deactivation was additionally seen in the temporal
poles bilaterally, extending to the amygdala, parahip-
pocampal gyrus and marginally to the hippocampus.
These latter clusters also involved the middle temporal
cortex/posterior insula, the left angular gyrus and the
pre/post-central cortex.
Activations in the schizophrenic patients were gen-
erally less marked. Regions included the DLPFC bilat-
erally, the anterior insula bilaterally and neighbouring
regions of the frontal operculum, the precentral gyrus
and the supplementary motor area. Activation was
also seen in the left temporal cortex and the occipital
cortex. Unlike the controls and the relatives, no acti-
vation was seen in the basal ganglia or thalamus.
The patients showed deactivation only in the posterior
Failure of deactivation in the default mode network 1319
cingulate cortex/precuneus and not in the medial fron-
tal cortex.
Between-group differences
Results of the ANOVA comparing the three groups are
shown in Fig. 2. Five clusters of significant difference
were found. One cluster was in the right lateral pre-
frontal cortex, including the DLPFC and extending to
the right insula (cluster size 868, peak activation at
MNI coordinates 44, 16, 12, Z max = 3.51, p = 0.03). The
second cluster included regions of the parietal lobe
extending from the left angular gyrus to the left supra-
marginal gyrus and the left inferior parietal cortex (clus-
ter size 875, peak activation at MNI coordinates −36,
−44, 32, Z max = 4.20, p = 0.03). A third cluster was
seen in the cerebellum bilaterally extending to the ver-
mis (cluster size 1015 voxels, peak activation at MNI
coordinates 8, −80, −22, Z max = 4.27, p = 0.01). The
fourth cluster centred on the medial and inferior frontal
cortex bilaterally, also including portions of the orbito-
frontal cortex (cluster size 1858 voxels, peak activation
at MNI coordinates 0, 40, −42, Z max = 5.02, p =
0.0003). Finally, there was a cluster in the left caudate
and putamen and thalamus that extended to the left lat-
eral prefrontal cortex, including the left DLPFC, and to
left insula, the precentral gyrus and supplementary
motor area (cluster size 4408 voxels, peak activation at
MNI coordinates −18, −8, 16, Z max = 4.91, p = 0.001).
Analysis by working memory load
This revealed four clusters of significant difference,
which were broadly of approximately the same size as
and in similar locations to those in the 2-back v. baseline
contrast. However, in this analysis the previously found
cluster in the right DLPFC/insula was no longer evident.
These four clusters were located in the left parietal cor-
tex (cluster size 952 voxels, peak activation at MNI coor-
dinates −36, −58, 48, Z max = 4.43, p = 0.02), the bilateral
cerebellum (cluster size 1002 voxels, peak activation at
MNI coordinates 8, −80, 22, Z max = 4.32, p = 0.01), the
anterior cingulate cortex (cluster size 2529 voxels, peak
activation at MNI coordinates −2, 38, −6, Z max =
4.72, p = 0.00002) and the left caudate nucleus, globus
pallidus and putamen, and the left DLPFC (cluster
size 4575 voxels, peak activation at MNI coordinates
−18, −8, 16, Z max = 5.12, p = 0.00000001).
Pair-wise comparisons within ROIs
Mean activation values for each of the five clusters in
the 2-back v. baseline contrast were extracted and the
groups were compared using either paired (patient v.
relative comparisons) or unpaired (patient v. control
and relative v. control comparisons) t tests; once
1320 R. Landin-Romero et al.

Fig. 1. Brain regions showing a significant effect in the 2-back v. baseline contrast in (a) controls, (b) healthy first-degree
relatives and (c) schizophrenic patients. Yellow indicates a positive association (activation) with the task. Blue indicates areas
where the task led to a decrease in the blood oxygenation level-dependent response (deactivation). Numbers refer to Montreal
Neurological Institute z coordinates of the slice shown. The right side of each image represents the right side of the brain.
Colour bars indicate Z scores from the group-level analysis. (For clarity, the results for this figure are thresholded at Z = 3.5.)

again TAP-estimated pre-morbid IQ was entered as a
covariate. Since there were 15 individual comparisons,
the statistical threshold was corrected for using false
discovery rate (FDR; Benjamini & Yekutieli, 2001).
The findings from this analysis are also shown in
Fig. 2, and further details are given in online
Supplementary Table S1. Cluster 1 (right DLPFC/
insula), cluster 2 (left parietal cortex), cluster 3 (bilat-
eral cerebellum) and cluster 5 (left DLPFC, insula and
basal ganglia), were all regions where the controls
showed activation compared with baseline. In all of
these clusters the patients showed significantly
reduced activation compared with both the controls
and the relatives, but the relatives and controls did
not differ significantly from each other.
In cluster 4, the healthy controls showed deacti-
vation from baseline. The schizophrenic patients
showed significantly less deactivation than the healthy
controls in this cluster. Here, unlike in the other four
clusters the relatives also showed significant failure
 Failure of deactivation in the default mode network 1321

Fig. 2. Location of the clusters and blood oxygenation level-dependent (BOLD) response in schizophrenic patients (SCZ,
n = 28), their first-degree healthy relatives (REL, n = 28) and healthy controls (CTRL, n = 56): (a) the right dorsolateral
activation, (b) left parietal cortex activation, (c) bilateral cerebellum activation, (d) caudate gyrus, globus pallidus, putamen
and left dorsolateral activation, (d) anterior cingulate deactivation and (e) left dorsolateral activation. The right side of each
image represents the right side of the brain. Results are thresholded at Z = 2.3. MNI, Montreal Neurological Institute.
* p < 0.05, ** p < 0.01. A colour version of this figure is available at http://journals.cambridge.org/psm

of deactivation compared with the controls. Their de-
gree of failure of deactivation was also significantly
less marked than in the schizophrenic patients.
Relationship to clinical features
In the relatives there were no correlations between RISC
scores and mean activation/deactivation values in any
the five ROIs (cluster 1: Spearman r = 0.01, FDR corrected
p = 0.92; cluster 2: Spearman r = 0.03, FDR corrected p =
0.87; cluster 3: Spearman r = 0.05, FDR corrected p = 0.78;
cluster 4: Spearman r = −0.34, FDR corrected p = 0.07;
cluster 5: Spearman r = −0.11, FDR corrected p = 0.57).
To examine whether activations/deactivations in
these five clusters were associated with the presence
of psychotic-like experiences, the relatives were dichoto-
mized into 17 who gave no positive responses to any of
the delusion-like or hallucination-like items, and 10 who
1322 R. Landin-Romero et al.
gave one or more positive or questionable ratings. There
were no significant differences in mean activation/de-
activation values between those with negative and posi-
tive ratings for these experiences for any cluster (cluster
1: 20.98, S.D. = 10.53 v. 17.15, S.D. = 11.02, t = 0.89, FDR
corrected p = 0.47; cluster 2: 19.02, S.D. = 10.30 v. 17.40,
S.D. = 10.04, t = 0.39, FDR corrected p = 0.69; cluster 3:
25.54, S.D. = 14.97 v. 19.09, S.D. = 15.01, t = 1.08, FDR cor-
rected p = 0.47; cluster 4: −15.52, S.D. = 13.45 v. −24.32,
S.D. = 13.50, t = 1.64, FDR corrected p = 0.47; cluster
5:16.41, S.D. = 6.01 v. 13.46, S.D. = 5.75, t = 1.25, FDR cor-
rected p = 0.47; the first-reported values are for relatives
without experiences).
In the patients, there were no significant correlations
between PANSS total or positive, negative and disorga-
nization syndrome scores and mean activation/deacti-
vation values in any of the above five clusters after
FDR correction (see online Supplementary Table S2).
There were no significant correlations between
n-back test performance, as measured using d′ and ac-
tivation/deactivation in any of the five clusters in the
controls, relatives or schizophrenic patients (see online
Supplementary Table S3).
Discussion
In this study, a group of non-affected siblings of
patients with schizophrenia did not show functional
imaging changes in the prefrontal cortex – although
the DLPFC was an area of significantly reduced acti-
vation in the schizophrenic patients, this did not separ-
ate the relatives from the controls. They did, however,
show failure of deactivation in the medial frontal cor-
tex, a finding that implies default mode network dys-
function. This failure was significantly less marked
than in the patients with schizophrenia.
The absence of activation changes in the relatives in
our study appears at first sight to be at variance with
the conclusions drawn in the review of MacDonald
et al. (2009), where evidence of altered DLPFC function
was found in over two-thirds of 20 studies and
changes were also frequently seen in the ventrolateral
prefrontal cortex. However, in this review the direc-
tionality of the changes was not consistent; in fact, in
all of the four cognitive domains the authors examined
(cognitive control, working memory, memory and lan-
guage) the studies were approximately evenly divided
between those finding decreased activation, those
finding increased activation and those finding no
change. One interpretation of this pattern of results is
that it simply reflects scattering around a true finding
of no change; however, meta-analysis of these and
later studies (Meda et al. 2008; Karch et al. 2009;
Whitfield-Gabrieli et al. 2009; Woodward et al. 2009;
Sepede et al. 2010; Choi et al. 2012; Sambataro et al.
2013; Liddle et al. 2013; Stolz et al. 2012) would be
necessary to establish this with certainty.
In contrast, the relatives showed significant failure of
deactivation in the medial frontal cortex compared
with the healthy controls. This finding replicates that
of Whitfield-Gabrieli et al. (2009), and also extends it,
since they found the failure of deactivation to be not
statistically distinguishable from that seen in schizo-
phrenia, whereas we found it to be intermediate be-
tween the levels seen in patients and healthy
controls. As noted in the introduction, Liddle et al.
(2013) also found failure of deactivation not only in
the medial frontal cortex but also in the precuneus;
however, as in the study of Whitfield-Gabrieli et al.
(2009), this was similar in degree to that seen in schizo-
phrenic patients.
We did not replicate the finding of
Whitfield-Gabrieli (2009) that medial frontal failure
of deactivation was correlated with the presence of
schizophrenia-related symptomatology in relatives. In
our study there was no association between the rela-
tives’ mean deactivation values in this region and mea-
sures of either schizotypy or psychotic-like
experiences. It may be relevant here that the rating
scale that Whitfield-Gabrieli et al. (2009) used, the
Hopkins Symptom Checklist Revised (SCL-90-R)
(Derogatis, 1983), is a general measure of psychiatric
symptomatology and does not actually include items
related to psychotic-like experiences.
If it is not associated with symptomatic features,
could medial frontal failure of deactivation be related
to another proposed endophenotype for schizo-
phrenia, cognitive impairment? As reviewed by
Anticevic et al. (2012), there is clear evidence that
default mode network activity varies with cognitive
function in healthy subjects, with, for example,
increased activity being associated with lapses of atten-
tion during task performance and reduced activity
being associated with better performance. In our
study, however, there was no correlation between de-
activation in the relatives and performance on the
n-back task. Nor do the findings of Liddle et al.
(2013) provide much support for this idea – they
found that failure of deactivation was present in rela-
tives of schizophrenic patients despite the fact that
they showed normal performance on the task used.
It should be noted that that even in schizophrenia it-
self whether there is a relationship between failure of
deactivation and cognitive impairment is a vexed ques-
tion. Whitfield-Gabrieli et al. (2009) found that medial
frontal failure of deactivation in schizophrenic patients
continued to be evident after differences in n-back
performance from controls were controlled for.
Pomarol-Clotet et al. (2008) had similar findings, but
they noted that the size of the cluster of failure of

deactivation became smaller after n-back performance
was introduced as a covariate. In the only other rel-
evant study to date, Anticevic et al. (2013) examined
schizophrenic patients and controls during perform-
ance on the Sternberg task, using a strategy whereby
task difficulty was adjusted so that all subjects per-
formed at a level of about 80% correct. With perform-
ance balanced in this way, whole-brain analysis
revealed no deactivation differences between schizo-
phrenic patients and healthy controls in the territory
of the default mode network, but the patients did
show failure of deactivation in a region outside this,
the right superior lateral frontal cortex. A subsequent
masked analysis (based on regions showing
meta-analytic evidence of involvement in working
memory in healthy subjects) found failure of deacti-
vation in the right parietal cortex similar in location
to the parietal component of the default mode net-
work. All these studies, it should be noted, only exam-
ined the default mode network function in relation to
performance on the task used during scanning. This
is at best a proxy measure for cognitive impairment
in schizophrenia, and examination of the relationship
of failure of deactivation to more orthodox measures
of cognitive function is something that would clearly
be desirable in future studies.
As noted in the Introduction, resting-state connec-
tivity represents a complementary way of examining
the function of the default mode network, and a
small number of such studies have been carried out
in the relatives of schizophrenic patients. Currently,
their findings are inconclusive: Whitfield-Gabrieli
et al. (2009) and van Buuren et al. (2012) found that rela-
tives showed increased resting-state connectivity be-
tween the medial frontal cortex and other regions
within the default mode network. Liu et al. (2012)
also found increased connectivity, although this time
between the posterior cingulate cortex/precuneus and
the bilateral inferior temporal gyri. On the other
hand, Jang et al. (2011) found significantly reduced
connectivity within multiple regions of the default
mode network in individuals who had two relatives
with schizophrenia. Two further studies (Repovs
et al. 2011; Meda et al. 2012) found no differences in de-
fault mode network connectivity between siblings and
controls.
Conclusion
This study adds to existing evidence that failure of de-
activation in the medial frontal cortex characterizes not
only schizophrenia but also the first-degree relatives of
schizophrenic patients. The dysfunction appeared to be
present to a lesser degree in this latter group, some-
thing that would be expected if it were a trait marker
Failure of deactivation in the default mode network 1323
or endophenotype for the disorder. However, caution
needs to be exercised before coming to such a con-
clusion. In the first place, the failure seems from our
study to be clinically ‘silent’ – we did not find associa-
tions with either schizotypy or psychosis-like experi-
ences, or with cognitive impairment, in so far as this
was indexed by poor n-back task performance.
Second, failure of deactivation in the default mode net-
work is not specific to schizophrenia, having also been
found in all forms of major affective disorder (Sheline
et al. 2009; Allin et al. 2010; Pomarol-Clotet et al.
2012), as well as in other psychiatric and disorders
such as ADHD (Broyd et al. 2009) and autistic spec-
trum disorder (Kennedy et al. 2006; Spencer et al.
2012). The integrity of the network is also compro-
mised in cognitive disorders such as mild cognitive im-
pairment and normal ageing (Buckner et al. 2008;
Broyd et al. 2009; Dennis & Thompson, 2014).
Supplementary material
For supplementary material accompanying this paper
visit http://dx.doi.org/10.1017/S0033291714002426
Acknowledgements
This work was supported by: (i) the Centro de
Investigación Biomédica en Red de Salud Mental
(CIBERSAM); (ii) several grants from the Instituto de
Salud Carlos III [Miguel Servet Research Contract to
R.S. (CP07/00048) and to E.P.-C. (CP10/00596);
Intensification grant to S.S. (10/231)]; and (iii) the
Comissionat per a Universitats i Recerca del DIUE
from the Catalonian Government (grant 2009SGR211).
Declaration of Interest
None.
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