Neuroscience and Biobehavioral Reviews 35 (2011) 688–698

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

Suicidal brains: A review of functional and structural brain studies in association

with suicidal behaviour
C. van Heeringen, S. Bijttebier ∗ , K. Godfrin
University of Ghent, Department of Psychiatry and Medical Psychology, Unit for Suicide Research, Ghent, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Evidence of an association between a vulnerability to suicidal behaviour and neurobiological abnormali-
Received 17 May 2010 ties is accumulating. Post-mortem studies have demonstrated structural and biochemical changes in the
Received in revised form 2 August 2010 brains of suicide victims. More recently, imaging techniques have become available to study changes in
Accepted 26 August 2010
the brain in vivo. This systematic review of comparative imaging studies of suicidal brains shows that
changes in the structure and functions of the brain in association with suicidal behaviour are mainly
Keywords:
found in the orbitofrontal and dorsolateral parts of the prefrontal cortex. Correlational studies suggest
Suicide
that these changes relate to neuropsychological disturbances in decision-making, problem solving and
Neuroimaging
Suicidal brain
fluency, respectively. As a consequence, the findings from these studies suggest that suicidal behaviour is
Neurobiology associated with (1) a particular sensitivity to social disapproval (2) choosing options with high immediate
Decision-making reward and (3) a reduced ability to generate positive future events. Further study is needed to elaborate
Prefrontal cortex these findings and to investigate to what extent changes in the structure and function of suicidal brains
DTI are amenable to psychological and/or biological interventions.
fMRI © 2010 Elsevier Ltd. All rights reserved.
MRI
PET
SPECT

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
2.1. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
3.1. Structural imaging studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
3.1.1. CT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
3.1.2. MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
3.1.3. DTI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
3.2. Functional imaging studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
3.2.1. SPECT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
3.2.2. PET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
3.2.3. fMRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697

1. Introduction

∗ Corresponding author at: University of Ghent, Department of Psychiatry and

As the global annual rate of suicide approximates 15 per 100,000
Medical Psychology, Unit for Suicide Research, University Hospital Ghent, University
individuals, it is estimated that one million people worldwide
Department of Psychiatry – 1K12F, De Pintelaan 185, 9000 Ghent, Belgium.
Tel.: +32 9 332 58 94; fax: +32 9 332 49 89. commit suicide each year (WHO, 2002). Annual rates of non-fatal
E-mail address: Stijn.bijttebier@ugent.be (S. Bijttebier). suicidal behaviour are 10–20 times higher than those of completed
URL: http://www.unitforsuicideresearch.be. suicide (Kerkhof, 2000). Suicidal behaviour thus constitutes a major

0149-7634/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2010.08.007
 C. van Heeringen et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 688–698 689

public health problem, and costs at societal and individual levels Electronic search references Manual search
are huge. In addition, suicidal behaviour poses a major challenge N = 531 N = 19
to clinicians, health care workers and policy makers due to its lim-
ited predictability (Hawton and van Heeringen, 2009). Problems
in predicting and thus preventing suicidal behaviour are due to the N = 512 N=3
multiplicity of possible causes and a limited insight in predisposing
mechanisms. N = 19
N = 16
Based upon the current state of knowledge a stress-diathesis
model of suicidal behaviour has been proposed to describe the
interaction between proximal risk factors and such predisposing
mechanisms (Hawton and van Heeringen, 2009). The vast majority Studies excluded ( N = 528):
Studies meeting
of suicidal behaviours are associated with depression, but indeed selection criteria 1. No comparison suicide –
require the presence of an additional diathesis or predisposition. In N = 22 non suicide attempters: N =
vivo brain imaging is a promising tool for the investigation of the 499
diathesis predisposing to suicidal behaviour, and the last decade 2. Unclear definition suicidal
behaviour:N = 1
has witnessed a steady increase in the number of such studies
3. Imaging technique: N = 28
(Mann, 2005). A first advantage of using brain-imaging techniques
is to confirm post-mortem findings of involved brain areas and
Fig. 1. Overview of number of studies included and excluded.
neurobiological systems such as the serotonin system. Second,
brain imaging provides a possibility to demonstrate a biological
substrate for neuropsychological changes in relation to suicidal 2. Methods
behaviour, thus providing support of a causal interpretation of this
relation. A comprehensive literature search yielded the set of relevant
The findings from brain-imaging studies have not been system- articles for this review. First, we did an electronic search using the
atically reviewed yet. Imaging studies of suicidal behaviour fall Web of Science, MEDLINE, PsycINFO (and PubMed) databases for
into two broad categories, i.e. the study of the neural correlates articles published in English, from 1990 onward. Search terms were
of suicidal behaviour directly, and studies addressing clinical traits suicidal, suicide, suicide attempt, and imaging, CT, MRI, SPECT, PET,
typically associated with suicidal behaviour, such as aggressive and fMRI, DTI. Unpublished studies, case reports or conference abstracts
impulsive behaviours. The current review focuses on the first cat- were not included in this review. Second, the reference lists of
egory of studies and therefore aims at the identification, synthesis relevant papers were checked manually for additional relevant
and appraisal of structural and functional neuroimaging studies of publications not previously identified. Studies, for which electronic
suicidal behaviour. full text was available, were selected if based on commonly used

Fig. 2. Graphical summary of the reviewed articles: main findings, localized in the lateral left hemisphere. Abbreviations: 5-HT2A = Serotonin-2A ; ␣[11 C]MTrp = ␣-[11 C]methyl-
l-tryptophan; rCMRglu = regional cerebral glucose metabolism; ↓ = decrease; ↑ = increase; BA = Brodmann area; HL = high lethality; SA = suicide attempter.
690 C. van Heeringen et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 688–698
imaging techniques and if individuals were included with a history
of suicidal behaviour.
2.1. Selection criteria
Inclusion of studies in this review was based on three crite-
ria. First, studies needed to report neuroanatomical differences
between study groups composed of individuals with a history of
suicide attempts (suicide attempters; SA) and those without a his-
tory of such behaviour. Studies comparing two groups of SA with
different characteristics were also included. Second, taking into
account the heterogeneity of definitions of suicidal behaviour, stud-
ies in order to be included needed to provide clear definitions
of suicidal behaviour. Third, studies were included only if Com-
puted Tomography (CT), Magnetic Resonance Imaging (MRI), Single
Photon Emission Computed Tomography (SPECT), Positron Emis-
sion Tomography (PET), functional Magnetic Resonance Imaging
(fMRI) or Diffusion Tensor Imaging (DTI) were used as imaging
techniques.
3. Results
As shown in Fig. 1, the search produced 550 publications.
Twenty-two articles met the inclusion criteria and were thus
included in this review, categorized as ‘structural imaging studies’
(CT, MRI, DTI) or ‘functional imaging studies’ (SPECT, PET, fMRI).
In the following part of the paper, studies will be reviewed
in chronological order; studies from the same research group are
reported together. Table 1 summarizes the sample characteristics
and detailed results of the reported studies. Figs. 2–5 summarize
the main results in a visual manner.
Fig. 3. Graphical summary of the reviewed articles: main findings, localized in the medial left hemisphere. Abbreviations: rCMRglu = regional cerebral glucose metabolism;
␣[11 C]MTrp = ␣-[11 C]methyl-l-tryptophan; ↓ = decrease; ↑ = increase; BA = Brodmann area; SA = suicide attempter; HL = high lethality.
Good quality of included studies has been ensured by the use
of strict criteria. Among the selected articles, the good quality of
the studies by Audenaert et al. (2002), Meyer et al. (2003), Ehrlich
et al. (2005), Monkul et al. (2007), Jovev et al. (2008), Pompili et
al. (2008) and Jollant et al. (2008, 2010) is noteworthy due to the
control for comorbidity, specifically for depression.
3.1. Structural imaging studies
3.1.1. CT
No studies of suicidal behaviour using CT and meeting the selec-
tion criteria were found.
3.1.2. MRI
Structural imaging, using MRI, within the suicide research can
be divided into two main fields.
3.1.2.1. White matter hyperintensities. A substantial number of
studies have demonstrated an association between suicidal
behaviour and white matter hyperintensities (WMH), i.e. deep
WMH (DWMH), periventricular hyperintensities (PVH) or subcor-
tical gray matter hyperintensities (SCH).
Ahearn et al. (2001) were the first to demonstrate hyperinten-
sities associated with a history of SA. As noted in Table 1, SA had
significantly more SCH and tended to have more PVH than controls.
Ehrlich et al. (2004) reported an increased prevalence of WMH (par-
ticularly PVH) in (psychiatrically hospitalized) children and youth
with unipolar depression and a history of SA. Unipolar depressed
subjects with WMH were 18.6 times more likely to have a history
of SA than subjects with unipolar depression or another psychi-
atric disorder with no evidence of WMH. There was no significant
Table 1
Neuroimaging of suicidal behaviour—key features of brain-imaging studies of suicide attempters.
Studya Designb
Ahearn et al. (2001) MRI: hyperintensities
Ehrlich et al. (2004) MRI: hyperintensities
Ehrlich et al. (2005)* MRI: T2 hyperintensities
Monkul et al. (2007)* MRI: fronto-limbic brain
abnormalities
Pompili et al. (2007) MRI: White matter
hyperintensities
Aguilar et al. (2008) MRI: Whole brain structural
abnormalities
Jovev et al. (2008)* MRI: pituitary gland volume
Pompili et al. (2008)* MRI: deep white matter
hyperintensities and
periventricular white matter
hyperintensities
Rüsch et al. (2008) MRI: gray and white matter
volumetric differences
Matsuo et al. (2010) MRI: white matter of the
anterior medial regions of the
corpus callosum
Targeted brain regionc Subjectsd
Whole brain 40 unipolar depressed patients (M + F):
20 patients have attempted suicide
(mean 66.0 yr) and 20 patients have
not attempted suicide (mean 66.4 yr)
Whole brain 153 patients with a primary DSM-III-R
or -IV Axis I diagnosis (M + F), 6–21 yr
(mean 14.6 yr)
Whole brain 102 young adult patients with MDD
(M + F), mean 26.7 yr
OFC amygdala 34 unipolar depressed patients (F): 7
cingulate hippocampus patients have attempted suicide (mean
31.4 yr), 10 patients have not
attempted suicide (mean 36.5) and 17
subjects did not attempt suicide or
have a unipolar depression (mean
31.3 yr)
Whole brain 65 patients with a diagnosis of MDD or
BD, without an additional Axis I
diagnosis of schizophrenia or psychosis
(M + F): 29 patients have attempted
suicide (mean 42.17 yr) and 36 patients
have not attempted suicide (mean
44.61 yr)
Whole brain OFC 37 patients meeting the DSM-IV
Amygdala criteria for schizophrenia (M): 13
patients have attempted suicide (mean
37.12 yr) and 24 patients have not
attempted suicide (mean 42.65 yr)
Pituitary gland 20 patients meeting the DSM-IV
criteria for BPD (M + F), mean 17.3 yr
Whole brain 99 patients with a diagnosis of MDD,
BD-I or BD-II (M + F): 44 patients have
attempted suicide (mean 45.57 yr) and
55 patients have not attempted suicide
(mean 42.27 yr)
Whole brain 105 subjects (M + F): 10 patients had a
DSM-IV diagnosis of schizophrenia and
have attempted suicide (mean 30.3 yr),
45 patients had a DSM-IV diagnosis of
schizophrenia and have not attempted
suicide (mean 37.3 yr), 50 healthy
controls were matched with the
patients (mean 36.0 yr)
Corpus callosum 47 subjects (F): 10 patients with BD
who attempted suicide (mean 36.2 yr),
10 patients with BD who have not
attempted suicide (mean 44.2 yr) and
27 healthy subjects (mean 36.9 yr)
Resultse
Significantly more SCH and PVH in the patients
who attempted suicide
Patients with unipolar depression and white
matter hyperintensities have increased
prevalence of suicide attempts
Significant increase in prevalence of PVH (not
DWMH) in patients who attempted suicide
Smaller bilateral OFC gray matter volume and
larger right amygdale volume in patients who
attempted suicide
Significantly increased prevalence (4.7 times)
of WMH in patients who attempted suicide
Gray matter density reduction in the left
superior temporal lobe and left OFC in patients
who attempted suicide. No amygdale volume
differences between patients who attempted
suicide and who did not attempt suicide
Age and number of parasuicidal behaviours are
significant predictors of pituitary gland volume
Patients who attempted to commit suicide are
more likely to have higher PVH. The presence
of PVH makes the risk for suicidal behaviour 8
times higher
Significantly larger bilaterally inferior frontal
white matter volumes in patients who
attempted suicide, with significant positive
correlation between current self-aggression (in
past 6 months) and white matter volume
(1) Suicidal BD patients have an inverse partial
correlation between the anterior genu area and
the total score on the Barratt Impulsivity Scale
(2) Smaller anterior corpus callosum predicts
higher impulsivity in suicidal BD patients
(3) No difference in size of the anterior corpus
callosum areas between suicidal BD patients
and the control groups
Limitations
Small sample size; age of first suicide
attempt and severity of each
depressive episode not available
No comparison group; no assessment
of comorbidity; small sample size;
unclear causality
Possible selection bias; age and
severity of suicide attempt not taken
into account; unclear causality
C. van Heeringen et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 688–698
Possible wrong evaluation of severity
of depressive episode; small sample
size; study limited to women
Selection bias; retrospective
assessment of suicide attempts; not
able to disclose effects of medication
on suicidality; significant age
difference between experimental
groups; no differentiation between
subtypes of WMH
Only male schizophrenic subjects; age
difference between experimental
groups; No healthy subjects included
Small sample size; retrospective data
collection of parasuicide history
Small sample sizes; DWMH not
discriminated by location; influence of
medication not taken into account;
unclear causality
Small suicidality sample size;
significant differences between groups
on substance abuse; no general
psychiatric comparison group
Small sample size; purely female
sample; psychiatric medication; lack of
comparison between patients with or
without comorbid cluster B disorder;
lack of comparison between patients
with or without family history of risk
factors for suicidality
691

Table 1 (Continued )
Studya
Lo et al. (2007)
Audenaert et al. (2001)
Audenaert et al. (2002)*
van Heeringen et al. (2003)
Lindström et al. (2004)
Ryding et al. (2006)
Amen et al. (2009)
Designb
DTI: hyperintensities
SPET: Serotonin-2A -receptor
functioning
SPECT: binding potential
SPECT: Serotonin-2A -receptor
functioning
SPECT: brain serotonin and
dopamine transporters
SPECT: serotonin transporter
and dopamine transporter
SPECT: In vivo brain differences
Targeted brain regionc Subjectsd
Centrum semiovale 12 subjects (M + F): 6 patients with
carbon monoxide intoxication (suicide
attempt) and 6 matched healthy
subjects
Frontal cortex 21 subjects, mean 30.4 yr (M + F): 9
patients who have attempted suicide
and 12 healthy subjects
Whole brain PFC 40 subjects (M + F): 20 depressed
patients who recently (<7 days)
attempted suicide (19–49 yr) and 20
healthy subjects (18–50)
PFC 21 subjects (M + F): 9 patients who
have attempted suicide (mean 32.4 yr)
and 12 healthy subjects (mean 28.9 yr)
Whole brain 24 subjects, mean 38.8 yr (M + F): 12
patients who attempted suicide (5
violent and 7 non-violent) and 12
healthy matched subjects
Whole brain 24 subjects (M + F): 12 patients who
attempted suicide (mean 38.8 yr) and
12 matched healthy subjects
Whole brain PFC 36 subjects (M + F): 12 patients
subgenual cingulate meeting DSM-IV criteria for depression
who committed suicide since the brain
imaging (mean 33.8 yr), 12 patients
meeting DSM-IV criteria for depression
who did not commit suicide and 12
healthy subjects
692
Resultse Limitations
(1) Suicidal patients have hyperintensities in Small sample size
the centrum semiovale, next to PVH
(2) 4 patients have bilateral globi pallid
necrosis
Significant decrease in bilateral frontal 5- HT2A Impact of alcohol and medication on
binding index in patients who attempted clearance of the ligand; possible effect
suicide of physical trauma on binding index
Blunted perfusion in the left inferior PFC Influence of medication; selection bias;
(during a category fluency task), bilateral gyrus at random division of subgroups
temporalis medius (during a letter fluency
task) and the AC (while performing both a
C. van Heeringen et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 688–698
letter fluency and a category fluency task)
Binding potential in the prefrontal 5-HT2A Small sample size; composition of
receptors is decreased in patients who patient sample; possible effect of
attempted suicide, next to higher levels of physical trauma on binding index;
hopelessness, harm avoidance and effects of alcohol and medication
self-transcendence and lower scores on
self-directedness and cooperativeness. In
patients who attempted suicide, prefrontal
5-HT2A binding potential correlates negatively
with hopelessness and harm avoidance and
positively with self-directedness and
cooperativeness. Also, hopelessness correlates
positively with harm avoidance and negatively
with cooperativeness and self-transcendence
No significant 5-HTT or DAT binding potential Possible type 2 error
differences were found. A significant
correlation between 5-HTT and DAT, next to a
significant positive correlation between 5-HTT
and impulsiveness, is found in patients
attempting suicide
Patients, who have attempted suicide, show a
significant correlation between whole brain
5-HTT BP and impulsiveness in the right
inferior frontal, bilateral temporal, midbrain,
thalamic bilateral basal ganglia and left
cerebellar regions. These patients also show
significant negative correlation between whole
brain DAT BP and mental energy in the
bilateral basal ganglia regions
Patients who attempted suicide, compared to Heterogeneous sample; lack of data for
non-attempter patients, had higher rCBF at all subjects; medication
rest in the right insular cortex, dorsal AC gyrus
and inferior parietal lobule. Patients who
attempted suicide, compared to non-attempter
patients, had perfusion deficits in the left
frontal lobe, the right thalamus and part of the
right medial temporal lobe during
concentration. Areas of high rCBF were noticed
in the right ACC and the left cerebellar
pyramid. Patients who attempted suicide have
general lower rCBF at rest than healthy
subjects
 Meyer et al. (2003)* PET: serotonin agonism PFC 69 subjects: 22 patients with MDD
(mean 31.0 yr), 18 patients with
self-injurious behaviour (mean 31.0 yr)
and 29 healthy subjects (mean 31.0 yr)
Oquendo et al. (2003) PET: regional brain Whole brain 25 patients (M + F) meeting DSM-III-R
serotonergic function criteria of a major depressive episode
and who have attempted suicide: 16
patients had a history of high-lethality
suicide attempts (mean 42.9 yr), 9
patients had a history of lo-lethality
suicide attempts (mean 30.4 yr)
Leyton et al. (2006) PET: ␣[11 C]MTrp trapping PFC 26 subjects (M + F): 10 patients have
attempted suicide (mean 37.7 yr) and
16 healthy subject (mean 35.5 yr)
Jollant et al. (2008)* fMRI: neural activity Whole brain 43 subjects (M): 13 patients with a
past history of MDD and suicidal
behaviour, 14 patients with a history of
MDD and no suicidal behaviour and 16
healthy subjects
Jollant et al. (2010)* fMRI: whole brain and Whole brain 40 subjects: 13 patients with a past
orbitofrontal cortex activity history of MDD and suicidal behaviour
(mean 38 yr), 12 patients with a history
of MDD and no suicidal behaviour
(mean 43 yr) and 15 healthy subjects
(mean 30 yr)
a
Study: * Study of good methodological quality.
b
Design: fMRI = functional Magnetic Resonance Imaging; MRI = Magnetic Resonance Imaging; PET = Positron Emission Tomography; SPECT = Single Photon Emission Computed Tomography; SPET = Single Photon Emission
Tomography; ␣[11 C]MTrp = ␣-[11 C]methyl-l-tryptophan.
c
Targeted brain region: AC(C) = anterior cingulate (cortex); DLPFC = dorsolateral prefrontal cortex; OFC = orbitofrontal cortex; PFC = prefrontal cortex.
d
Subjects: BD = bipolar disorder, BD-I = bipolar depression type I, BD-II = bipolar depression type II; BPD = borderline personality disorder; F = female; M = male; MDD = major depressive disorder.
e
Results: 5-HT = Serotonin; 5-HT2 = Serotonin-2 ; 5-HT2A = Serotonin-2A ; 5-HTT = the serotonin transporter; BA = Brodmann area; BP: binding potential; DAT = dopamine transporter; DWMH = deep white matter hyperintensities;
PVH: periventricular white matter hyperintensities; rCBF = regional cerebral blood flow; rCMR = regional cerebral glucose metabolism; SCH = subcortical gray matter hyperintensities; WMH = white matter hyperintensities.
No significant differences in 5-HT2 BP are Indirect measurement of 5-HT
found between patients with self-harm concentrations in the brain
behaviour and healthy subjects
rCMR glucose uptake in PFC, ACC and superior Small sample size; direct brain injuries
frontal gyri is associated with high lethality of not ruled out
suicide attempt; lower ventromedial
prefrontal activity associated with lower
lifetime impulsivity, higher suicidal intent and
higher-lethality suicide attempts; rCMR
glucose uptake in right midcingulate and
superior frontal gyri correlated negatively with
executive functions, memory and attention,
and positively with language fluency
High-lethality suicide attempters have Effects of drugs on 5-HT transmission;
C. van Heeringen et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 688–698
significantly reduced serotonin synthesis in small sample size; imaging technique
the OFC and ventromedial PFC (BA 11), next to possibly not the best to assess 5-HT
an elevation in the right paracentral lobule, the neurotransmission
left thalamus, the left middle occipital cortex
and the hippocampal gyrus
(1) Prototypical faces: patients with suicidal Generalizability; small sample size;
behaviour, compared to patients without such difficult comparison between groups
behaviour, have greater activity in the right due to lack of matching; medication
lateral OFC and lower activity in the right
superior frontal gyrus in response to angry
(versus neutral) faces
(2) Mild faces: patients with suicidal behaviour,
compared to patients without such behaviour,
have greater activity in the right ACC and the
right cerebellum to mild happy versus neutral
faces
(3) Neutral faces: healthy subjects, compared to
the patients, have greater activity in the right
cerebellum to neutral faces versus fixation
baseline
(1) Significantly poorer decision-making in Small sample size; differences between
suicide attempters, compared with healthy patient groups and healthy controls
subjects and patients without a history of a
suicide attempt
(2) Suicide attempters, compared with patients
without a history of suicidal behaviour, have
decreased activation during risky versus safe
choices in the left lateral OFC (BA47) and left
occipital cortex (BA19)
693
694 C. van Heeringen et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 688–698
Fig. 4. Graphical summary of the reviewed articles: main findings, localized in the lateral right hemisphere. Abbreviations: rCMRglu = regional cerebral glucose
metabolism; ␣[11 C]MTrp = ␣-[11 C]methyl-l-tryptophan; ↓ = decrease; ↑ = increase; BA = Brodmann area; SA = suicide attempter; HL = high lethality; WM = white matter;
5-HT2A = Serotonin-2A.
increase in a history of SA in patients with WMH and other psy-
chiatric disorders. With regard to localization, DWMH in the right
parietal lobe, but not in the frontal lobe, appeared to be associated
with a significantly higher prevalence of a history of SA. In their
sample of young adults with major depressive disorder (MDD),
Ehrlich et al. (2005) showed a significantly increased prevalence of
PVH, most commonly located in the right hemisphere, in patients
with a history of SA as compared to those without such a history.
Pompili et al. (2007) found a significantly increased prevalence
of WMH in adults with MDD/bipolar disorder (BD) with a history
of attempted suicide and elevated suicide risk, compared to similar
patients without such a history. There was no significant difference
in the frequency of previous suicide or WMH between subjects with
MDD and BD. In a subsequent study, Pompili et al. (2008) inves-
tigated whether WMH are associated with suicidal behaviour in
patients with a mood disorder. Attempters and non-attempters dif-
fered only in the presence of PVH, with a more common presence
of PVH in attempters than in non-attempters. Study groups did not
differ with regard to the presence of DWMH.
3.1.2.2. Gray matter volume and density. Monkul et al. (2007) com-
pared fronto-limbic brain structures between females diagnosed
with a unipolar mood disorder and a history of one or more SA and
unipolar females without such a history, to those of female healthy
controls. As indicated in Table 1, the presence of a history of SA
was associated with volumetric changes in the bilateral OFC gray
matter and the right amygdala. There were no differences in gray
matter volumes between unipolar patients without a history of SA
and healthy controls.
Two studies investigated gray and white matter in the brains
of patients suffering from schizophrenia according to suicidal
behaviour. Male patients with a history of SA, compared to those
without such a history, showed a significant reduction in gray mat-
ter density in specific left hemispheric areas (see Table 1) (Aguilar
et al., 2008). Rüsch et al. (2008) found significantly larger white
matter volumes in patients with a history of SA as compared to
patients without such a history and to healthy controls (Table 1).
No other significant white or gray matter volume differences were
observed.
The study of Jovev et al. (2008) showed a correlation between
number of suicidal behaviours and pituitary gland volume in young
patients diagnosed with borderline personality disorder and with
minimal exposure to treatment.
Matsuo et al. (2010) specifically studied the association between
a history of SA and anterior corpus callosum volumes, but found no
differences between bipolar patients with a history of SA and those
without such a history.
3.1.3. DTI
One study by Lo et al. (2007) showed bilateral PVH and cen-
trum semiovale hyperintensities after deliberate carbon monoxide
intoxication.
3.2. Functional imaging studies
3.2.1. SPECT
Compared to normal controls, patients with a recent history
of suicide attempts showed a significantly lower 5-HT2A binding
index (reflecting a decrease in the number and/or in the binding
affinity of 5-HT2A receptors) (Audenaert et al., 2001). The decrease
was more marked in dorsolateral than in orbitofrontal regions. The
decrease was also significantly more marked among patients who
 C. van Heeringen et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 688–698
Fig. 5. Graphical summary of the reviewed articles: main findings, localized in the medial right hemisphere. Abbreviations: rCMRglu = regional cerebral glucose metabolism;
␣[11 C]MTrp = ␣-[11 C]methyl-l-tryptophan; ↓ = decrease; ↑ = increase; BA = Brodmann area; HL = high lethality; PVH: periventricular white matter hyperintensities.
used violent methods to attempt suicide (self-injury) than among
those who attempted suicide by means of self-poisoning. Further
analysis revealed a significant negative correlation between 5-
HT2A -receptor binding and levels of hopelessness, one of the most
important clinical predictors of suicidal behaviour (van Heeringen
et al., 2003).
Audenaert et al. (2002) used a neuropsychological split-dose
activation paradigm to assess brain perfusion in SA. They pre-
sented a verbal fluency task to depressed patients who had recently
attempted suicide and to healthy controls. When compared to the
controls, SA showed a blunted increase in perfusion in the left infe-
rior PFC, in the gyrus temporalis medius bilaterally, and in the
anterior cingulate during specific verbal fluency tasks (see Table 1)
(Audenaert et al., 2002).
Two studies assessed the binding potential of the serotonin
transporter (5-HTT) and dopamine transporter (DAT) using the
123 I-␤-CIT ligand (Lindström et al., 2004; Ryding et al., 2006). In
both studies binding potentials were compared between patients
with a recent SA and healthy controls, and between violent and
non-violent SA. The findings from both studies were negative.
Amen et al. (2009) compared regional cerebral blood flow (rCBF)
in the brains of psychiatric patients who committed suicide, with
brain rCBF in groups of healthy and non-suicidal depressed indi-
viduals. In the baseline condition, i.e. at rest, rCBF in the suicide
group differed from that in the non-suicidal depressed control
group through a significantly higher perfusion in the right hemi-
sphere. During the Continuous Performance Test, the suicide group
showed perfusion deficits in the left frontal lobe, in addition
to a deficit in the right thalamus and part of the right medial
temporal lobe, compared with depressed non-suicidal patients,
while clusters of high rCBF were noted in the right anterior cin-
695
gulate cortex (ACC; BA 32) and the left cerebellar pyramid. In
comparison with healthy subjects, the suicide group showed a
generally lower rCBF throughout the cortex during the baseline
condition.
3.2.2. PET
Meyer et al. (2003) found that depressed subjects with
extremely dysfunctional attitudes had higher 5-HT2 binding poten-
tial, compared to healthy subjects, particularly in BA 9.
By measuring relative regional cerebral uptake of fludeoxyglu-
cose F 18 (rCMRglu), Oquendo et al. (2003) showed that depressed
high-lethality suicide attempters had lower rCMRglu in ventral,
medial, and lateral PFC compared with low-lethality attempters.
This difference was more pronounced after fenfluramine adminis-
tration, particularly in the anterior cingulate and the medial frontal
gyri (BA 32 and 8) bilaterally, and the right midcingulate and supe-
rior frontal gyri (BA 24 and 6). Lower ventromedial PFC activity was
associated with different characteristics (Table 1). Verbal fluency
correlated positively with rCMRglu in the same regions.
Leyton et al. (2006) compared high-lethality SA with healthy
controls with regard to the level of their ␣-[11 C] methyl-l-
tryptophan (␣[11 C]MTrp) trapping, an index of serotonin (5-HT)
synthesis. High-lethality SA had significantly reduced normalized
␣[11 C]MTrp trapping values in parts of the PFC, while an elevation
in ␣[11 C]MTrp trapping was seen in more posterior parts of the
brain (see Table 1). A significant association between ventromedial
␣[11 C]MTrp trapping and suicidal intent was found.
3.2.3. fMRI
Jollant et al. (2008) investigated neural reactivity following
exposure to angry and happy versus neutral faces in currently
696 C. van Heeringen et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 688–698
euthymic men with a history of major depressive disorder, whether
or not with suicidal behaviour (SA and affective comparison sub-
jects) and male healthy comparison subjects. The main results of
this study are summarized in Table 1. In a subsequent study, Jollant
et al. (2010) not only confirmed their earlier findings of a compar-
atively poor performance on a decision-making task in SA (Jollant
et al., 2005), but they also demonstrated a change in activation in
the orbitofrontal cortex and the occipital cortex during disadvan-
tageous versus safe choices in SA (Table 1).
4. Discussion
Suicidal behaviour constitutes an important public health prob-
lem and poses a major challenge to health care because of
difficulties in its prediction and thus prevention. This paper reviews
studies of the association between structural or functional brain
characteristics and suicidal behaviour. Such a review is relevant as
knowledge of neural characteristics may contribute to our under-
standing, and thus to the prediction and prevention of suicidal
behaviour.
The findings from this review can be summarized as follows.
White matter hyperintensities, whether or not in the periventric-
ular area, appear to be associated with the occurrence of suicide
attempts in depressed children, adolescents and adults. Limbic gray
matter hyperintensities are more commonly found in case of a his-
tory of suicide attempts than if such a history is not present.
With regard to inferior frontal and orbitofrontal areas white
matter volumes are increased, while gray matter volumes of the
orbitofrontal cortex of suicide attempters appear to be reduced.
Tryptophan trapping, an index of serotonin synthesis, is reduced in
significant correlation with suicidal intent. In persons with a history
of depressive episodes, a history of attempted suicide is associated
with greater activity in the right orbitofrontal cortex in response
to angry (versus neutral) faces than in such persons without a his-
tory of suicidal behaviour. In normothymic suicide attempters a
reduction in activation in the left lateral orbitofrontal cortex dur-
ing disadvantageous (versus safe) choices is found, when compared
to normothymic subjects without a history of suicide attempt and
healthy controls.
Regarding the ventral and medial prefrontal cortex the findings
point at a reduction in tryptophan trapping and glucose uptake,
both correlating negatively with suicidal intent. Ventromedial glu-
cose uptake also correlates negatively with lethality of suicide
attempts but positively with impulsivity.
Several findings point at a role of the dorsolateral and supe-
rior frontal areas in the development of suicidal behaviour. Suicide
attempters show a significant reduction in 5-HT2A -receptor bind-
ing in the prefrontal cortex, particularly in the dorsolateral area. The
reduction is significantly more marked among violent attempters
than among non-violent attempters. Depressed suicide attempters
show a blunted increase in perfusion during activation using a
verbal fluency task. High-lethality attempters show less glucose
uptake than low-lethality-attempters and verbal fluency appears to
be related to glucose metabolism in these areas. Following exposure
to angry faces the right superior frontal gyrus shows less activation
in individuals with a history of depression and attempted suicide
than in those with a history of depression but not attempted suicide.
Regarding limbic areas, a history of suicidal behaviour is associ-
ated with larger right amygdala volumes. Suicidal behaviour is also
associated with increased activity in the right insular cortex, dorsal
anterior cingulate cortex. . ., and with increased tryptophan trap-
ping in the hippocampal gyrus and left thalamus. Lethality of the
most serious lifetime suicide attempt correlates negatively with
glucose uptake after fenfluramine administration in the anterior
cingulate gyrus. Increased activity in the right anterior cingulate
gyrus is found following exposure to mild happy (versus neutral)
faces in case of a history of suicidal behaviour.
Finally, suicidal behaviour appears to be associated with
changes in structural and functional characteristics of the parieto-
occipito-temporal areas. Studies have indeed shown decreased gray
matter density in the left superior temporal gyrus, increased activ-
ity in the inferior parietal lobule, and increased tryptophan trapping
in the left middle occipital cortex.
Preceding a discussion of these findings, methodological issues
need to be addressed. The comparability of findings from different
studies is limited because of variations in imaging and analytic tech-
niques (Cannon et al., 2007). Radioligands differ in their binding
specificity, and, in spite of the use of Statistical Parametric Map-
ping in many studies, anatomical localization of findings is often
imprecise. Small sample sizes, whether or not due to high dropout
rates, limit the power of studies to detect small group differences
(Soloff et al., 2007) or can tend to amplify individual differences
due to biological heterogeneity (Soloff et al., 2003). Other poten-
tial biases may be due to the lack of (e.g. healthy or psychiatric)
comparison groups.
Studies, which control for comorbidity, offer the possibility to
distinguish between predispositions for comorbid disorders such
as depression and suicide (Audenaert et al., 2002; Meyer et al.,
2003; Ehrlich et al., 2005; Monkul et al., 2007; Jovev et al., 2008;
Pompili et al., 2008; Jollant et al., 2008, 2010). In some studies,
however, patients and controls are not matched for potentially
biasing characteristics, such as demographic variables, psychiatric
(co-) morbidity, nature and severity or chronicity of associated
disorders, treatment, and exposure to risk and protective factors
(Pompili et al., 2007; Aguilar et al., 2008; Rüsch et al., 2008). Alcohol
dependence, which may lead to changes in brain areas such as the
cerebellum, was an exclusion criterion in the majority of reviewed
studies.
Generalizability of findings may be limited due to inclusion of
only male or female individuals or patients with particular disor-
ders such as schizophrenia. In the majority of studies, assessment
of imaging is not blind to behavioural history.
The possibility of publication bias cannot be ruled out and may
therefore limit the interpretability of the current results.
Taking these methodological limitations in mind, the ques-
tion as to what extent the findings from this review may help
to understand the development of suicidal behaviour needs to
be answered. Many of the areas involved in suicidal behaviour,
as described in this review, are part of emotion-regulating cir-
cuits in the brain. Such circuits comprise the prefrontal cortex, the
amygdala–hippocampus complex, the thalamus, the basal ganglia
and the extensive connections between these areas (Soares and
Mann, 1997). Lesions in one specific part or disruption of intercon-
nections may thereby result in malfunctions in other areas. Those
abnormalities may trigger the onset of mood disorder and confer a
biological vulnerability, which, in combination with environmen-
tal stressors, may result in suicidal behaviour (Ehrlich et al., 2004,
2005).
The possibility to study clinical and/or neuropsychological cor-
relates of brain characteristics constitutes an important advantage
of imaging studies over post-mortem studies, and may help to
find an answer to this question by the identification of clusters of
disturbed brain functions, neuropsychological and/or clinical char-
acteristics, and suicidal behaviour. The identification of a biological
substrate for neuropsychological and/or clinical characteristics
related to suicidal behaviour thereby supports a causal interpre-
tation of this relationship.
First, the results from this review point at the involvement of the
orbitofrontal cortex in the development of suicidal behaviour. Early
studies in relation to suicidal behaviour have focused on the associ-
ation between orbitofrontal dysfunction and impulsive-aggressive
 C. van Heeringen et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 688–698
traits. Findings have, however, not been equivocal, which may
be due to the multifaceted nature of the impulsivity construct.
Behavioural indices of impulsivity, such as response inhibition,
are more basic constructs and thus quantifiable in a more reliable
way (Mann, 2005). Response inhibition has not yet been studied
in relation to suicidal behaviour, but functional imaging in healthy
volunteers indeed shows involvement of the (right) orbitofrontal
cortex, the cingulate cortex and the inferior parietal lobule (Horn et
al., 2003). As described in this review these areas are also involved
in suicidal behaviour.
With regard to the orbitofrontal cortex, attention has more
recently been drawn to the association between orbitofrontal cor-
tex dysfunctioning, disturbances in decision-making and suicidal
behaviour. A first study showed that violent suicide attempters
differed from affective controls in their performance on a decision-
making task in that suicide attempters make more disadvantageous
choices, i.e. choose options with high immediate reward (Jollant
et al., 2005). A subsequent functional neuroimaging study indeed
showed that suicide attempters (1) performed worse on a decision-
making task than affective controls and (2) showed reduced
activation in the orbitofrontal (and occipital) cortex for the contrast
between risky (disadvantageous) and safe (advantageous) choices
(Jollant et al., 2010). The insufficient contrast between risky and safe
choices prevents advantageous guiding of long-term behaviour.
Taken together with the findings of increased orbitofrontal activa-
tion following exposure to angry faces in suicide attempters (Jollant
et al., 2008), these findings suggest that suicidal behaviour is corre-
lated with disturbances in the attribution of importance to stimuli,
i.e. undue importance to signals of others’ disapproval and insuffi-
cient importance to risky choices. The development of unbearable
emotional pain following perception of signals of others’ disap-
proval may be associated with a choice for immediate reward (i.e.
alleviation of pain). The association between mental pain and risk
of suicidal behaviour has indeed recently been demonstrated in
depressed individuals (van Heeringen et al., 2010). While decision-
making in general is associated with the activation of ventromedial
prefrontal regions, it appears that the orbitofrontal cortex could be
related with deciding between advantageous and disadvantageous
choices following exposure to particular stimuli, such as angry faces
in suicide attempters. A number of reviewed studies point at a cor-
relation between orbitofrontal functioning and suicidal intent or
lethality of suicide attempts. In addition, decision-making appears
to be disturbed more in violent than in non-violent attempters.
The interpretation of these correlational findings requires
further study.
A second potential cluster of findings concerns the role
of the dorsolateral prefrontal cortex in the development of
suicidal behaviour. Prefrontal, and in particular dorsolateral 5-
HT2A -receptor binding correlates significantly with levels of
hopelessness, a strong clinical predictor of suicidal behaviour (van
Heeringen et al., 2003). Prefrontal (i.e. superior frontal) seroton-
ergic activity also correlates with verbal fluency (Oquendo et al.,
2003). It is of particular interest that dysfunctional attitudes, which
correlate with hopelessness, are associated with prefrontal 5-
HT2A -receptor binding (Meyer et al., 2003). A negative correlation
between fluency and hopelessness has been described previously
(MacLeod et al., 1993). Taken together these findings point at a
possible role of the dorsolateral prefrontal cortex in the develop-
ment of suicidal behaviour: findings of reduced activity, reduced
5-HT2A -receptor binding, reduced fluency and increased hopeless-
ness appear to cluster in attempted suicide patients. The reduced
fluency thereby particularly concerns a reduced ability to generate
positive future events.
Among particular functional and structural characteristics of
suicidal brains this review of studies thus identifies two clusters of
findings, which involve changes in the functions of the orbitofrontal
697
cortex and the dorsolateral prefrontal cortex, associated with
increased preference for immediate reward and decreased ability to
generate positive events in the future, respectively. Research out-
side the domain of suicidology has demonstrated that the ability
to select an action by considering delays and amount of reward
outcome is critical for survival and wellbeing (Schweighofer et al.,
2007).
In daily life, people indeed make decisions based on prediction
of rewards at different time scales. In many instances the choice
for a longer-term positive outcome is more appropriate than a
choice for immediate reward. However, the vulnerability to sui-
cidal behaviour appears to be associated with choosing immediate
reward (possibly the alleviation of emotional pain) in the absence
of the ability to generate future rewards. We have recently indeed
demonstrated an association between emotional pain and suicide
risk in depressed individuals (van Heeringen et al., 2010).
It has recently been shown that the prediction of immediate and
future rewards differentially recruits cortico-basal ganglia loops
(Tanaka et al., 2004a, 2004b). More specifically, it appears that the
orbitofrontal cortex is involved in predicting immediate reward,
while the dorsolateral prefrontal cortex is involved in future reward
prediction. Taking into account the clearly demonstrated role of
serotonin in the vulnerability to suicidal behaviour, it is worthy
to note that serotonin appears to be involved in action selection
by modulating the evaluation of delayed rewards. More particu-
larly, experimental data show that delayed rewards have a low
value with low serotonin levels leading agents to choose immediate
over delayed rewards (Schweighofer et al., 2007). The availability of
serotonin thus appears to correlate with the extent to which future
events are taken into account when choosing between behavioural
options.
Further research is clearly needed to assess the applicability
of such neuropsychological models to suicidal behaviour. Atten-
tion should thereby be given to functional neuroimaging studies of
decision-making and reward prediction.
Conflicts of interest
The authors have neither financial interest in, nor financial sup-
port for writing this review.
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