Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies

Abstract

Identifying brain alterations that contribute to suicidal thoughts and behaviors (STBs) are important to develop more targeted and effective strategies to prevent suicide. In the last decade, and especially in the last 5 years, there has been exponential growth in the number of neuroimaging studies reporting structural and functional brain circuitry correlates of STBs. Within this narrative review, we conducted a comprehensive review of neuroimaging studies of STBs published to date and summarize the progress achieved on elucidating neurobiological substrates of STBs, with a focus on converging findings across studies. We review neuroimaging evidence across differing mental disorders for structural, functional, and molecular alterations in association with STBs, which converges particularly in regions of brain systems that subserve emotion and impulse regulation including the ventral prefrontal cortex (VPFC) and dorsal PFC (DPFC), insula and their mesial temporal, striatal and posterior connection sites, as well as in the connections between these brain areas. The reviewed literature suggests that impairments in medial and lateral VPFC regions and their connections may be important in the excessive negative and blunted positive internal states that can stimulate suicidal ideation, and that impairments in a DPFC and inferior frontal gyrus (IFG) system may be important in suicide attempt behaviors. A combination of VPFC and DPFC system disturbances may lead to very high risk circumstances in which suicidal ideation is converted to lethal actions via decreased top-down inhibition of behavior and/or maladaptive, inflexible decision-making and planning. The dorsal anterior cingulate cortex and insula may play important roles in switching between these VPFC and DPFC systems, which may contribute to the transition from suicide thoughts to behaviors. Future neuroimaging research of larger sample sizes, including global efforts, longitudinal designs, and careful consideration of developmental stages, and sex and gender, will facilitate more effectively targeted preventions and interventions to reduce loss of life to suicide.

Full text

Molecular Psychiatry
https://doi.org/10.1038/s41380-019-0587-x
EXPERT REVIEW
Imaging suicidal thoughts and behaviors: a comprehensive review
of 2 decades of neuroimaging studies
Lianne Schmaal1,2 ●Anne-Laura van Harmelen 3●Vasiliki Chatzi3●Elizabeth T. C. Lippard4●Yara J. Toenders1,2 ●
Lynnette A. Averill5,6 ●Carolyn M. Mazure7●Hilary P. Blumberg8
Received: 20 December 2018 / Revised: 21 October 2019 / Accepted: 29 October 2019
© The Author(s) 2019. This article is published with open access
Abstract
Identifying brain alterations that contribute to suicidal thoughts and behaviors (STBs) are important to develop more targeted
and effective strategies to prevent suicide. In the last decade, and especially in the last 5 years, there has been exponential
growth in the number of neuroimaging studies reporting structural and functional brain circuitry correlates of STBs. Within
this narrative review, we conducted a comprehensive review of neuroimaging studies of STBs published to date and
summarize the progress achieved on elucidating neurobiological substrates of STBs, with a focus on converging findings
across studies. We review neuroimaging evidence across differing mental disorders for structural, functional, and molecular
alterations in association with STBs, which converges particularly in regions of brain systems that subserve emotion and
impulse regulation including the ventral prefrontal cortex (VPFC) and dorsal PFC (DPFC), insula and their mesial temporal,
striatal and posterior connection sites, as well as in the connections between these brain areas. The reviewed literature
suggests that impairments in medial and lateral VPFC regions and their connections may be important in the excessive
negative and blunted positive internal states that can stimulate suicidal ideation, and that impairments in a DPFC and inferior
frontal gyrus (IFG) system may be important in suicide attempt behaviors. A combination of VPFC and DPFC system
disturbances may lead to very high risk circumstances in which suicidal ideation is converted to lethal actions via decreased
top-down inhibition of behavior and/or maladaptive, inflexible decision-making and planning. The dorsal anterior cingulate
cortex and insula may play important roles in switching between these VPFC and DPFC systems, which may contribute to
the transition from suicide thoughts to behaviors. Future neuroimaging research of larger sample sizes, including global
efforts, longitudinal designs, and careful consideration of developmental stages, and sex and gender, will facilitate more
effectively targeted preventions and interventions to reduce loss of life to suicide.
Introduction
Around 1 million people die by suicide annually [1]. Glob-
ally, suicide is the tenth leading cause of death for all ages and
the second leading cause of death among young people aged
15–29 years [1]. In 2013, it was estimated that 9.3 million
These authors contributed equally: Lianne Schmaal, Anne-Laura van
Harmelen
*Hilary P. Blumberg
hilary.blumberg@yale.edu
1Orygen, The National Centre of Excellence in Youth Mental
Health, Parkville, VIC, Australia
2Centre for Youth Mental Health, The University of Melbourne,
Parkville, VIC, Australia
3Department of Psychiatry, University of Cambridge,
Cambridge, UK
4Psychiatry, Dell Medical School, University of Texas, Austin, TX,
USA
5Psychiatry, Yale School of Medicine, New Haven, CT, USA
6Department of Veterans Affairs National Center for PTSD,
Clinical Neurosciences Division, West Haven, CT, USA
7Psychiatry and Women’s Health Research at Yale, Yale School of
Medicine, New Haven, CT, USA
8Psychiatry, Radiology and Biomedical Imaging, Child Study
Center, Yale School of Medicine, New Haven, CT, USA
Supplementary information The online version of this article (https://
doi.org/10.1038/s41380-019-0587-x) contains supplementary
material, which is available to authorized users.
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adults 18 years and older in the United States had suicidal
thoughts and 1.3 million attempted suicide [2]. In addition, a
2011 report estimated that 13% of adolescents planned a
suicide attempt (SA) in the previous year and 8% attempted
suicide [3]. Unfortunately, suicide death rates have continued
to rise. For example, since 1999, rates in the United States
have increased by 30% [4]. The predictive value of currently
identified nonbiological risk factors for suicide is limited [5],
and a reliable biological risk marker has yet to be identified.
In order to prevent suicide more effectively, there is an urgent
need to better understand the mechanisms that confer
increased risk for suicidal thoughts and behaviors (STBs), and
to identify biological markers of risk to generate more tar-
geted successful prevention strategies and monitor responses
to them. In the last decade, and especially in the last 5 years,
there has been exponential growth in the number of neuroi-
maging studies reporting structural and functional brain cir-
cuitry correlates of STBs (Fig. 1). In the last 10 years, a
number of excellent reviews on aspects of this research have
emerged [6–10]. Here we review research across structural,
functional, and neurochemical neuroimaging modalities,
providing a narrative review of 131 neuroimaging studies
with a focus on the most researched brain circuitries and
findings that converge across studies.
Methods
A search was performed in PubMed for original research
articles published before March 12, 2018. The following
terms were used: “MRI,”“SPECT,”“PET,”“magnetic
resonance imaging,”“positron emission tomography
(PET),”“single-photon emission computed tomography,”
“DTI,”“diffusion tensor imaging,”“diffusion weighted
imaging,”“neuroimaging,”“functional MRI (fMRI),”
“functional magnetic resonance imaging,”and “spectro-
scopy”(separated by OR) in combination with the terms
“suicide,”“suicidal,”and “suicidality”(separated by OR).
We selected articles that: (i) were published in a peer-
reviewed journal in English and (ii) included groups with
suicidal ideation (SI) and/or history of SA. Of note, non-
suicidal self-injury (NSSI) was not included in this review,
and studies that did not differentiate NSSI from suicidal
behaviors were excluded, because these can be differ-
entiated on the basis of intention, frequency, and lethality
and may have partly distinct underlying mechanisms [11].
Results
We identified 131 unique articles meeting review criteria
(Supplementary Tables 1–3). The populations studied reflect
reports that the majority of people with STBs have a
diagnosable mental illness. Major depressive disorder (MDD)
or bipolar disorder (BD) account for over half of suicide
deaths [12]. After mood disorders and borderline personality
disorder (BPD), the prevalence of suicide deaths is highest
among people with substance use disorders and schizophrenia
(SZ), followed by posttraumatic stress disorder (PTSD) and
anxiety disorders [12]. The mental disorders researched varied
by study, with each study typically including a single dis-
order, and the majority of studies conducted in individuals
with mood disorders. Most studies compared people with a
mental disorder and a history of SA (suicide attempters, SAs)
to people with a mental disorder and/or healthy controls
(HCs) without a history of attempt. Fewer studies focused on
SI. Most studies employed a cross-sectional design and a
single structural or functional imaging modality. The majority
were conducted with adults; only a small proportion exam-
ined adolescents (Fig. 1). A subset of studies provided pre-
liminary findings of associations between neuroimaging
measures and key risk factors for suicide, e.g., medical leth-
ality of prior attempts, emotion dysregulation, anhedonia,
impulsiveness, and reduced cognitive control (for reviews see
[13–15]).
Despite modest sample sizes of studies, and the hetero-
geneity of their clinical samples and neuroimaging acqui-
sition and analysis methods, converging evidence is
emerging to support roles for specific brain regions/circui-
tries in STBs. These are particularly in cortico-striatolimbic
systems that subserve emotion and impulse regulation and
include prefrontal, cingulate, and insula cortices, amygdala,
hippocampus, thalamus, and striatum regions (Supplemen-
tary Tables 1–3). Within the prefrontal cortex (PFC), studies
vary widely in the selection of regions studied, with regions
of interest (ROIs) often including overlapping regions that
encompass ventral and dorsal, medial as well as lateral,
PFC. Thus, while we identify the importance for future
study of specific PFC subregions, given their differing
Fig. 1 Number of neuroimaging studies on suicidal thoughts and
behaviors published in the last 2 decades. The figure was based on the
studies included in this review, calculated separately for studies
only including adolescents and studies only including adults and
divided into separate 4-year time bins for publication date
L. Schmaal et al.

connectivity, cellular and molecular features and functions,
we discuss the PFC grouped broadly into the ventral PFC
(VPFC; divided into medial and lateral portions), which has
the highest concentration of reported findings, the dorsal
PFC (DPFC; divided into lateral and medial portions), and
the anterior cingulate cortex (ACC). We also discuss find-
ings in the insula, and mesial temporal (hippocampus,
amygdala), subcortical (basal ganglia, thalamus), and pos-
terior regions (posterior cingulate cortex (PCC), lateral
temporal lobes and cerebellum). See Fig. 2for definitions of
the brain regions. Since the VPFC, DPFC, ACC, insula,
mesial temporal, basal ganglia, thalamus, and posterior
regions have been studied most frequently in relation to
STBs and because most converging evidence exist for the
involvement of these regions, we specifically focus our
review on findings within these brain areas, as well as in the
connections between them. However, additional studies and
positive and negative findings not discussed below can be
found in Supplementary Tables 1–3.
We focus our discussion below on findings that are pri-
marily derived from comparisons of individuals with a
mental disorder and STBs vs individuals with a mental
disorder without STBs (diagnostic controls (DCs)), rather
than comparisons with HCs, unless otherwise specified.
Findings based on a comparison between DCs and indivi-
duals with the same mental disorder plus STBs are more
commonly reported in the literature and are more likely to
reflect specific effects of STBs in that disorder, whereas
comparisons with HCs may include more general effects of
having a mental disorder. Below we first detail structural,
functional, and neurochemical findings within regions and
end each section on a region with a summary. We then
follow with a section devoted to studies of connectivity
among regions within major implicated brain systems.
Ventral PFC
The lateral VPFC (VLPFC) refers to the inferior lateral areas
of the frontal cortex encompassing lateral orbitofrontal cortex
(OFC, Brodmann area (BA)47, lateral BA11), inferior frontal
gyrus (IFG, BAs 44, 45), and lateral aspects of the rostral PFC
(RLPFC, lateral BA10) (Fig. 2). The VLPFC plays a key role
in cognitive control, including response inhibition, and is
activated when behavioral responses are modulated in
response to the emotional or motivational context [16,17].
The medial VPFC (VMPFC) refers to the medial OFC (medial
BA11) and medial aspects of the rostral PFC (RMPFC, medial
BA10) (Fig. 2). The VMPFC has a well-established role in
self-reflection [18], appraisal of internally generated emotions
(both positive and negative) [16,19], appraisal of past and
imagined future events, and reward processing [20,21].
Structural, functional, and neurochemical alterations in these
regions have been associated with maladaptive strategies for
regulation of negative affect (e.g., rumination), negative self‐
referential thinking [22,23], and diminished positive affect
(e.g., anhedonia) [24]. Evidence is mounting that emotion
dysregulation has a central role in the generation of STBs.
This includes elevations in negative, and blunting in positive,
subjective emotions, self-referential thoughts, and responses to
valenced stimuli [9]. These alterations are thought to
Fig. 2 Overview of brain regions included in this review. These brain
regions have been most reported in neuroimaging studies investigating
structural, functional, and molecular brain alterations associated with
suicidal thoughts and behaviors, with a subset of regions grouped more
broadly into ventral prefrontal cortex, dorsal prefrontal cortex, insula,
mesial temporal, subcortical, and posterior regions. DMPFC dor-
somedial prefrontal cortex, dACC dorsal anterior cingulate cortex,
RMPFC rostromedial prefrontal cortex, mOFC medial orbitofrontal
cortex, vACC ventral anterior cingulate cortex, PCC posterior cingu-
late cortex, Thal thalamus, VS ventral striatum, Hippo hippocampus,
Amyg amygdala, DLPFC dorsolateral prefrontal cortex, RLPFC ros-
trolateral prefrontal cortex, IFG inferior frontal gyrus, lOFC lateral
orbitofrontal cortex, Put putamen, Caud caudate
Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies

contribute to key clinical risk symptoms for STBs including
depression, anxiety, rumination, guilt, reduced self-esteem,
helplessness, anhedonia, and hopelessness [22–30].
VLPFC
Structural MRI studies have consistently shown lower gray
matter volumes of the VLPFC in adult SAs, including SAs
with MDD [31–33], BD [34,35], and schizoaffective dis-
order (SZA) [36]. Findings of lateral OFC volume decrea-
ses, extending to medial OFC, in adolescent and young
adult SAs with BD [35], suggest these may be early dif-
ferences. Lower VLPFC thickness, but not volume, is one
of the rare findings related to SI in adults with MDD [37],
suggesting the VLPFC may be involved not only in suicide
behavior but also in the ideation that may generate it.
Gray matter volume decreases in VLPFC were also
associated with high lethality of prior SA in MDD [24] and
BPD [35,36]. This converges with longstanding findings
from both postmortem studies demonstrating VPFC (ROIs
including both VLPFC and VMPFC) differences in people
who died by suicide [38], and PET studies of high lethality
or high intent SAs, showing VPFC (VLPFC and VMPFC)
alterations in serotonin (5-HT) synthesis, transporters and
5-HT1a receptors [39,40] (Supplementary Table 2). Lower
5-HT1a binding in the OFC was associated with interim SI
during a 2-year follow-up in adults with MDD and past
attempts [41]. Although conflicting findings exist [42–45],
these data provide some consistent findings of a location
and a potential mechanism, i.e., lateral extending to
VMPFC serotonergic dysfunction, as a potential biomarker
of risk for high lethality STBs. There have been few
molecular imaging studies of other neurotransmitter sys-
tems and neurochemicals implicated in STBs.
fMRI studies performed while participants conducted
specific behavioral tasks provide evidence that STBs are
associated with VLPFC functional abnormalities in response
to emotional and other hedonically valenced stimuli.
Increased activation of the IFG and lateral and medial OFC
while viewing angry (but not happy, sad, or neutral) faces was
reported in adult SAs with MDD [46,47]. Higher IFG acti-
vation in response to angry faces was also associated with
poorer attempt planning and higher impulsivity in adult SAs
with MDD [48]. Furthermore, young adult SAs with BPD
displayed higher lateral OFC activation while instructed to
experience and regulate negative autobiographical memories
[49]. Increased activation in a region of interest that included
both the medial and lateral OFC was also seen in response to
winning a reward [46] in adult SAs with MDD.
The IFG also plays a critical role in cognitive control and
response inhibition [50]. During the performance of a con-
tinuous performance task, higher IFG, RLPFC, and lateral
OFC responses were associated with both attempts and SI in
adults with mood disorders with psychotic features, in the
absence of task performance differences [51]. Higher lateral
OFC was also reported during error trials in a response inhi-
bition task in veterans with SI [52]. In contrast, a second study
in adult SAs with SZ using the same continuous performance
task showed that reduced activation in a cluster encompassing
the RLPFC and IFG, extending to the VMPFC and ventral
ACC, was associated with SI but did not further distinguish
between ideators with and without a history of attempt [53].
VMPFC
In addition to the structural and PET study findings reported
for the VLPFC above that extended to the VMPFC or that
were based on an ROI including both VLPFC and VMPFC,
lower VMPFC cortical thickness was also associated with
greater motor impulsivity in adolescent SAs with MDD
[54]. As cortical thickness and surface area contributions to
volume are thought to be genetically independent [55] and
result from different neurobiological processes [56], it is
important to examine these separately in studies of STBs.
However, the majority of studies have either not examined
thickness and surface area separately from volume or
examined only thickness without examination of surface
area in SAs with MDD [31,57]. Cortical thickness is
thought to be influenced by the number and the size of cells
within a column, packing density, as well as by the number
of connections and the extent of their myelination, while
cortical surface area is driven by the number ontogenetic
columns that run perpendicular to the surface of brain [58].
Functionally, in addition to higher activation in the lat-
eral and medial OFC in response to angry faces and to
winning a reward in adult SAs with MDD [46] as reported
above, a recent study using machine learning to investigate
adolescent SAs (with and without SI) showed that the
medial VMPFC was among the most discriminating
regions, within a multivariate pattern of fMRI brain acti-
vation in response to actively thinking about life- and death-
related concepts, for distinguishing between adolescent
suicidal ideators with and without a history of attempt,
although in a very small sample size [59].
Summary
Structural neuroimaging studies have consistently shown that
alterations in the VLPFC and VMPFC are implicated in SAs
across a range of mental disorders and age ranges. Reduced
VLPFC volumes were also associated with lethality of
attempts, potentially mediated by serotonergic dysfunction,
although findings of serotonergic dysregulation remain
inconsistent. The involvement of structural and functional
VLPFC and VMPFC alterations in SI remains understudied.
Viewing and regulating negative emotions and motivationally
L. Schmaal et al.

valenced stimuli has been linked to increased activation of the
lateral and medial OFC in adult (including young adults) SAs
with MDD and BPD, and associated with poorer attempt
planning and higher impulsivity. Finally, higher VLPFC
activity, including in the IFG, RLPFC, and lateral OFC,
during cognitive control and response inhibition in relation to
SAs and SI in adults with mood disorders has been reported
across a number of studies. These increased activations may,
in the absence of task performance differences, reflect a need
for greater engagement of these regions for reaching similar
performance in these individuals with STBs. In contrast, adult
SAs with SZ showed reduced activation in these regions
during cognitive control, which may suggest that there are
some differences in the neural signatures of STBs between
mood and psychotic disorders, which will be an important
direction for future study.
Dorsal PFC
The DPFC can be broadly divided into dorsolateral (DLPFC)
and dorsomedial PFC (DMPFC). The DMPFC and the
DLPFC together support top-down control of emotions and
behaviors [17], cognitive flexibility, and complex decision-
making [60]. Deficits in these processes are thought to have an
important role in STBs, particularly in the transition from SI to
behavior, as the threshold to acting is lowered by decreased
top-down behavioral inhibition, and diminished flexibility in
generating alternate and more adaptive behavioral choices
[15,61]. Neuroimaging evidence suggests that the DMPFC
(medial portions of BAs 8 and 9) is robustly recruited during
tasks that require mental state inference [62,63]. The DMPFC
is further involved in tracking decision conflict and reinfor-
cement history [64], as well as in emotion regulation [65]. The
DLPFC (BA46, lateral BA9) is involved in the conscious
active control of planned behavior and cognition, as well as
workingmemory[66]. Access of the DLPFC to memory
processing in hippocampal regions is shared by the ros-
trolateral PFC (lateral frontal pole BA10), which has been
implicated in meta-cognitive awareness [67,68].
DLPFC
Although the amount of evidence to date has been less than in
VPFC, accumulating findings also support a role for the
DLPFC in STBs. Structural MRI studies support lower
volume in DLPFC in adult SAs across MDD [31,32,69]and
BD [32,34]. Studies showed lower DLPFC thickness in adult
SAs with MDD [57]andSZ[70], but have not examined
cortical surface area. In addition, lower DLPFC volume was
associated with attempt lethality in mood and psychotic dis-
orders [31,36]. Higher baseline 5-HT1a receptor binding
potential in the DLPFC was also associated with higher leth-
ality of future attempts and SI during a 2-year follow-up [41].
Functionally, decreased lateral (and medial) DPFC acti-
vation when ten adults with self-reported depression lis-
tened to their own narrative of their attempt was reported in
a study in which imaging was conducted close to the time of
the attempts (1–4 weeks prior [71]). A study of adolescents
with a history of SI showing lower right DLPFC activation
during passive viewing of negative emotional scenes sug-
gests that DLPFC decreases during processing of negative
emotional stimuli might be present early in the course of SI
[72]. Higher right DLPFC engagement was observed during
regulation of responses to negative emotional scenes in the
same adolescents, suggesting the direction of DLPFC dif-
ferences depends on the specific task requirements (passive
viewing vs regulating) [72]. Another study in adolescent
SAs with MDD suggests that the direction may also relate
to the specific emotion, as passive viewing of angry faces,
but not happy faces, elicited higher DLPFC responses [73],
perhaps due to the high sensitivity to criticism and social
rejection previously reported in individuals with STBs
[74,75].
The DLPFC’s critical role in decision-making in the
context of evaluating the motivational value of choices [76]
may be especially relevant to STBs. Blunted DLPFC acti-
vation was observed when evaluating risky vs safe options
in adult SAs with MDD [46] and when evaluating lower
immediate rewards vs larger delayed rewards in older adults
with MDD and well-planned SA [77]. This is in line with a
behavioral study of older adult SAs with MDD showing an
association between lower levels of delay discounting (or
impulsive decision-making) and better planning in indivi-
duals with SA [78]. Increased DLPFC activation has also
been observed in adults with STBs across a range of “cold”
cognitive control tasks, especially those requiring inhibition
of automatic response tendencies. These included para-
digms such as continuous performance, stop signal, go-no-
go and stroop tasks studied in adult SAs with MDD or BD
with psychotic features [51], SZ [79], and ideators with SZ
[80] or PTSD and MDD in veterans [52]. Elevated activa-
tion in DLPFC was observed in suicidal ideators with past
attempts compared with ideators without attempts while
performing a continuous performance task [51]. Single-
photon emission tomography (SPECT) and PET studies
have shown lower resting regional cerebral blood flow
(rCBF) and glucose metabolic rates (rCMRglu) in the
DLPFC in adult SAs with mood disorders [81,82]. More-
over, lower DLPFC rCMRglu was associated with higher
lethality of attempt [83] and with SI with a plan vs ideation
without a specific plan [84] in adults with MDD.
DMPFC
Structural MRI studies also support lower volume in
DMPFC in adult SAs with MDD [31,69] and BD [32,34].
Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies

Although less studied than DLPFC in functional neuroi-
maging, lower DMPFC was reported in the study in which
adults with depression listened to their own narrative of
their recent attempt, which was especially pronounced
during mental pain aspects of the narrative [71]. Further-
more, decreased activation was also found in DMPFC
during viewing of angry faces in adult SAs with MDD [47].
Summary
Structural alterations in both the DLPFC and DMPFC have
been consistently observed in adults across mental disorders
and structural alterations in the DLPFC have been associated
with attempt lethality. This latter finding, together with find-
ings of serotonergic dysfunction in the DLPFC being asso-
ciated with higher lethality of future attempts during a 2-year
follow-up, implicates DLPFC structure and serotonergic
system functioning in STB risk. With regard to DLPFC and
DMPFC functioning, there is convergence in showing dif-
ferences related to STBs during processing of negative
emotional stimuli, although the direction of effects (activation
increases vs decreases) in the DLPFC differed across studies,
with contributions to the differences unclear as the studies
differed across multiple variables. Elevated activation while
performing cognitive control tasks (in the absence of perfor-
mance differences) together with lower resting rCBF and
glucose metabolic rates in the DLPFC could suggest that
increased DPFC may be recruited for reaching similar task
performance perhaps due to lower baseline levels of activa-
tion in the DPFC regions. Findings from one study suggests
that functional DLPFC alterations during cognitive control
can discriminate between suicidal ideators with past attempts
and ideators without attempts. Moreover, blunted DLPFC
activation when evaluating the value of different decision
options may also represent a risk marker for SAs, and espe-
cially for well-planned attempts. Well-planned vs impulsive
SAs have been suggested to be different phenotypes [85].
From the papers reviewed, there was a greater concentration
of findings in the VPFC in impulsive SAs and in DPFC in
planful SAs. Therefore, we speculate that the relative ventral
vs. dorsal localization of the PFC abnormalities may con-
tribute to the differing phenotypes.
Anterior cingulate cortex
The ventral ACC consists of BA25 and ventral BA32 sub-
and pregenual to the corpus callosum and plays a critical
role in valuation and control of autonomic viscero-sensory
signals, the modulation of physiological responses to stress,
and the appraisal of internal feelings [16]. The dorsal ACC
(dACC) (dorsal BAs 24 and 32) plays an important role in
the appraisal of actions (and adaptively adjusting behavior
as a consequence) and reward-based decision-making [16].
Structural MRI studies support lower volume in both
ventral and dACC in adult SAs with MDD [33,57] and BD
[34], which was related to a higher number of attempts in
adolescents with BPD and MDD [86] and to higher lethality
of attempts in adults with BPD [87] and psychotic BD [36].
Lower dACC rCMRglu was associated with higher lethality
of attempts [83]. In addition, lower 5-HT1a binding in the
ACC was associated with interim SI during a 2-year follow-
up in adults with MDD and past attempts [41]. A few stu-
dies that investigated neurotransmitter systems other than
5-HT implicated the ACC in relation to SI. For example, a
positive association was shown between SI and ACC
monoamine oxidase-A density in adults with BPD [88]. A
relation between SI and increased ACC neuroinflammation
(as assessed by translocator protein (TSPO) availability)
was reported in adults with MDD [89]. Furthermore, dACC
gamma-aminobutyric acid (GABA) concentrations were
lower in adult female SA +SI compared with clinical
controls without SA or SI, however, this effect was no
longer significant after correcting for age [90].
Viewing of angry faces elicited higher dACC responses
in adolescent SAs with MDD [73], perhaps due to the high
sensitivity to criticism and social rejection previously
reported in individuals with STBs [74,75]. In contrast,
decreased activation was found in the ACC (ROI capturing
both ventral and dACC) during the viewing of sad faces in
adult SAs with MDD [46]. With regard to positive stimuli,
blunted ventral ACC responses were found during the
anticipation of reward in adult [91], including elderly [92],
SAs with MDD. Elevated responses in the ventral ACC
have also been reported in relation to positive stimuli. For
example, higher activation in the ventral ACC was seen in
response to happy facial expressions [47] and in response to
actual winning [46] (in contrast to blunted responses during
reward anticipation) in adult SAs with MDD.
Summary
The ACC has mostly been studied in relation to emotional
processing. Although various studies have observed dorsal
and ventral ACC activation alterations in adolescents and
adults with MDD and SAs, the direction of alterations seem
to be complex and dependent on task condition and sti-
mulus type (positive vs. negative). One could perhaps
interpret the findings of increased dorsal and ventral acti-
vation in response to angry faces and to positive stimuli,
together with blunted ventral ACC activation during reward
anticipation, as negative biases, as they may reflect reduced
reward anticipation (anticipation phase) vs. increased acti-
vation in response to negative stimuli and in relation to
positive prediction errors in response to positive stimuli
(outcome phase). The finding of a positive relation between
SI and ACC neuroinflammation, together with findings of
L. Schmaal et al.

increased inflammatory markers in the ACC in postmortem
studies of people who died by suicide [47], and in the blood
and cerebrospinal fluid of people with SI and a history of
violent or high intent attempts [48,49], suggests that neu-
roinflammation in the ACC may constitute a promising
target for future studies of STBs.
Insula
The insular cortex is a key hub in emotional processing with
connectivity to the PFC, particularly VPFC, as well as
mesial temporal structures [93]. The insula plays an
important role in interoceptive awareness for positive and
negative internal states [94], including emotional and other
types of pain, and understanding and sharing of other
people’s emotional states [95,96]. Only in more recent
studies has insula structure and function and related beha-
vior been investigated for its role in STBs. For example, on
a behavioral level, interoceptive deficits have been reported
among SAs compared with individuals who only thought
about or planned suicide among general psychiatric out-
patient adults [97] and predicted SI severity at 6-month
follow-up in community adolescents [98].
Smaller insula volume has been reported in adult SAs
with BPD [99], in a combined group with SZ/SZA/psy-
chotic BD [36] and elderly with MDD [69]. Lower insula
thickness was observed in adults in relation to SA in SZ
[70]andSIinMDD[37]. Smaller insula volume was
associated with higher attempt lethality and lower
impulsivity in BPD [87,99]. In contrast, larger insula
volumeswerereportedinrelationtoattemptlethalityin
adults with BD [100]. It is possible that the type of insula
differences relate to specific characteristics of the high
lethality attempters, since larger insula volumes were also
found in association with higher lifetime history of
aggression in BPD [87]. Some findings in the PFC noted
above in MDD extended to the insula, including asso-
ciations between baseline 5-HT1a binding potential with
SI and lethality of future attempts within a 2-year follow-
up period [41] and of increased neuroinflammation (TPSO
availability) [89].
SPECT research showed higher insula rCBF in adult SAs
with MDD [101] at rest and higher insula fMRI activation
was found in adults with MDD or BD with psychotic fea-
tures during a cognitive control task with insula activity
related to higher intensity of SI [51]. Higher insula fMRI
activation was also associated with lower subjective value
of gain and loss in adult SAs with MDD [91]. Lower
activation in the posterior insula during social exclusion was
found in adult SAs with MDD or BD, which was suggested
to indicate a higher tolerance to pain via repeated exposure
to painful and provocative experiences in subjects vulner-
able to suicide [102].
Summary
Smaller insula volume has been associated with SAs and
lower impulsivity in adults across various mental dis-
orders, whilst, both smaller and larger insula volumes
have been associated with higher attempt lethality. fMRI
studies found higher insular activation during reward
processing and cognitive control in adult SAs with MDD,
while lower insula activation was associated with a higher
tolerancetosocialpaininadultSAswithMDDorBD.
Thus, there is preliminary evidence for an involvement of
insular structural and functional alterations in SI and SAs.
However, since very few studies have focussed on the
insula and that both decreases and increases in
insula alterations have been reported, more research is
needed to elucidate the role of the insula in STBs. Inter-
estingly, immune challenges activate interoceptive brain
pathways (including the insula), triggering alterations in
mood and cognition, motivation, and neurovegetative
processes [103]. Together with preliminary evidence of
increased neuroinflammation in the insula related to SI,
this suggests that the insula may be an important region
for future studies of neuroinflammation and STBs.
Amygdala and hippocampus
Due to their roles in processing of emotion, emotional
memory and stress response [104–107], the mesial temporal
amygdala, hippocampus, and entorhinal cortex (BA28,
within the adjacent parahippocampal gyrus) are also thought
to be involved in STBs. However, findings reported have
been inconsistent. Larger amygdala volumes were reported
in adult SAs with MDD [108] and SZ [109], but more studies
have not detected significant amygdala findings
[32,37,99,100,110–112]. Smaller hippocampal volumes
were reported in adult SAs with MDD [113] and adolescent
and young adult SAs with BD [35], and one study reported a
smaller parahippocampal gyrus [114]. However, more stu-
dies have not detected associations of hippocampal or para-
hippocampal volume with STBs [32–34,37,100,108–111].
While difficulties detecting differences in these small mesial
temporal structures may relate to imaging methods used, it
may be that mesial temporal alterations are only present in
specific subgroups of people with STBs. For example, high
lethality attempts were associated with smaller volumes of
the hippocampus and parahippocampal gyrus in adult SAs
with BPD [87,99]. In addition, amygdala and hippocampal
volumes were negatively associated with impulsivity in
individuals with low lethality attempts [87], and amygdala
volume was positively associated with self-aggression in SAs
with SZ [109].
PET studies have shown preliminary evidence for a role
of serotonergic alterations in the amygdala and hippocampus
Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies

in STBs. Increased hippocampus 5-HT2a receptor binding
and 5-HT release was observed in adult SAs with BPD [115]
and in adults with MDD and high lethality attempts [39],
respectively, compared with HCs. Recently, baseline
5-HT1a receptor binding in the amygdala, hippocampus, and
parahippocampal gyrus was associated with higher SI during
a 2-year follow-up in adults with MDD [41].
Few fMRI studies have focused on mesial temporal
ROIs. An activation study focusing on the amygdala found
no association between SI and amygdala functioning during
emotion processing in ten ideators [116]. Increases were
observed during autobiographical recall of mental pain
experienced during an ideator’s own attempt in right para-
hippocampal gyrus vs suicide action in left hippocampus
[71]. In contrast, parahippocampal gyrus activation was
blunted in adult SAs with MDD choosing between a smaller
immediate reward vs. a larger but delayed reward, espe-
cially when the two rewards were more than 1 year apart
[77]. Given the role of the parahippocampal gyrus in pro-
spection [117], its blunted response to prospects with longer
vs. shorter delays may represent a neural substrate of
impaired prospection in SAs [118–120], potentially under-
mining the deterrents and the generation of alternative
solutions during a suicidal crisis.
Summary
Although structural alterations in the amygdala and the
hippocampus have been consistently implicated in mental
disorders [121–123], the majority of studies reviewed do not
report structural alterations in these regions in relation to
STBs. These mixed findings could perhaps be explained if
additional involvement of the amygdala and hippocampus in
STBs beyond their role in mental disorders is subtle with
small effects only apparent in studies with very large sample
sizes. This is consistent with a post hoc power analysis based
on observed effect sizes in the largest study on subcortical
volumes in STBs to date [110]. Alternatively, mesial tem-
poral structural alterations may only be present in specific
subgroups of people with STBs. Preliminary evidence sug-
gests serotonergic alterations in the amygdala and hippo-
campus are linked to SAs as well as SI across mental
disorders, and altered functioning in these regions is related
to increased autobiographical recall of mental pain, blunted
immediate reward processing, and impaired prospection in
individuals who made SAs, although molecular and func-
tional studies focussing on these regions are still scarce.
Striatum and thalamus
The ventral striatum includes the nucleus accumbens and
ventral parts of the putamen and caudate [124] and is a core
region of the reward network [125]. Dorsal striatum, including
dorsal caudate and putamen, functions include initiating
action, inhibitory control, and stimulus-response learning
[126]. The striatum projects to the frontal lobe via the thala-
mus [124], which is also involved in sensory processing [127].
Lower caudate and putamen volumes have been reported
in adult SAs with MDD in comparison to MDD non-
attempters [33,128] and HCs [129], and putamen volumes
were negatively associated with impulsivity [128]. Lower
putamen binding of the serotonin transporter (5-HTT) was
also reported in adult SAs with MDD compared with HCs
[130], and was negatively associated with impulsivity
[131]. However, striatal 5-HT binding was positively
associated with SI in adult SAs with MDD [132]. With
regard to the thalamus, higher volumes were reported in
veterans with traumatic brain injury and SAs [133] and
higher 5-HT synthesis was reported in adult SAs with a mix
of psychiatric diagnoses [39]. However, other studies,
including the largest study to date of individuals with STBs
(N=451), have not detected associations of striatum and
thalamus volume with STBs [32,37,110].
Few fMRI studies have examined striatum and thalamus
regions. Positive correlations were observed between
the intensity of past SI and dorsal striatum responses during
cognitive control in adults with MDD or BD with psychotic
features [51]. Lower putamen activation in adults with BD
during a motor task was associated with higher SI [134].
Higher thalamus activation was observed when viewing
knives (vs. landscapes) [135] and higher thalamus activa-
tion during response inhibition (go-no-go task) was asso-
ciated with higher levels of mental pain and suicide intent
[136] in adults with SAs and MDD.
Summary
Mixed findings were reported for the involvement of
structural alterations in the striatum and thalamus in relation
to STBs, with the largest sample to date showing no asso-
ciations in people with MDD. Increased dorsal striatum
responses were found during cognitive control in the
absence of performance differences in individuals with SI,
suggesting greater engagement of this region to reach
similar levels of cognitive control. Higher thalamus acti-
vations were reported during emotion processing and inhi-
bition and associated with SI in adult SA with MDD.
Structural and 5-HTT alterations in the dorsal striatum
specifically linked to impulsivity in adult MDD with SA
converge with findings of functional alterations in the dorsal
striatum in relation to diminished cognitive and affective
control associated with SI. Of note, alterations in the ventral
striatum have been proposed to underlie reduced reward
anticipation and anhedonia in individuals with STBs [137].
No studies reported ventral striatal activity, however, ven-
tral striatal connectivity findings during reward processing
L. Schmaal et al.

and during rest are discussed in the “Structural and func-
tional connectivity”section below.
Posterior structures
The temporal association cortices are involved in the percep-
tual processing of faces and other complex object features
[138,139], auditory information and language [140]. Con-
sistent with this, structural MRI findings in lateral temporal
cortex were observed in adult SAs with SZ/SZA/psychotic
BD and other disorders in which psychotic misperceptions can
be observed. Lower middle and superior temporal gyrus
volume was found in adult SAs with primary psychotic dis-
orders [36,141]andBPD[99], and lower thickness of middle
and superior temporal gyri were observed in adult SAs with
SZ [70]. Lower middle and superior temporal volumes were
also associated with high lethality attempts in adults SAs with
BPD [87,99]. Serotonin system studies have yielded various
results including lower 5-HTT temporal binding associated
with higher impulsivity in adult SAs with different mental
disorders [131], and higher baseline 5-HT1a temporal lobe
receptor binding in adults SAs with MDD [41] associated with
higher levels of SI at 2-year follow-up. fMRI studies also
suggest a role of the lateral temporal lobe in emotion pro-
cessing in STBs. Specifically, adolescent SAs with MDD
showed enhanced right middle temporal gyrus activation
during passive viewing of angry, happy, and neutral facial
expressions [73] and during recall and reimagination of sui-
cidal episodes in adult SAs with MDD [71]. SI was associated
with increased superior temporal activation during error pro-
cessing in veterans with traumatic brain injury [52]. In con-
trast, lower perfusion in these temporal regions during rest
(measured by rCBF) was reported in adults with MDD and
SA [81,142].
A few studies implicate other posterior brain regions
including the PCC and cerebellum in STBs (Supplementary
Tables 1–3). The PCC is implicated in psychological pro-
cesses that may be linked to STBs, including controlling the
vividness of negative mental imagery [143] and enhancing
self-referential processing [144]. Lower PCC gray matter
volume was found in adult SAs with MDD [145].
Decreased PCC activation was observed during cognitive
control in adult SAs with psychotic mood disorders [51] and
during self-referential processing in adolescent ideators with
MDD [146], although adult SAs with depressive disorders,
compared with HCs, showed increased PCC response when
viewing knives [135].
The cerebellum is increasingly recognized for its invol-
vement in emotional processes [147,148]. Lower volumes
of the cerebellum were reported in adult and adolescent SAs
with MDD or BD [35,69,145,149]. Functionally, while
adult SAs with MDD showed increased cerebellum acti-
vation during recall and reimagination of their own suicidal
episode [71] and while viewing angry faces, they showed
decreased activation while viewing happy faces [47].
Decreased activation was also observed while passively
viewing negative emotional pictures in adolescents with a
history of SI [72]. Finally, ketamine-induced reductions in
SI were associated with increases in rCMRglu including in
cerebellum [150].
Summary
Lower middle and superior temporal gyri volumes have
been reported in six studies across a range of mental dis-
orders, and were related to high lethality attempts and
higher impulsivity. Serotonergic alterations in these regions
have not been extensively investigated and directions of
reported effects are mixed. Increased activation in middle
and superior temporal gyri have also been reported in adults
and adolescents with SA and MDD, especially in relation to
emotion processing. Preliminary evidence suggests a role
for the PCC and cerebellum in STBs, especially in relation
to self-referential and (autobiographical) emotion proces-
sing, but studies investigating these regions remain scarce.
Of interest, one study suggests that ketamine-induced
changes in SI are associated with ketamaine-induced
increases in cerebellum rCMRglu. This medication-related
finding is a potential lead in understanding brain mechan-
isms that may be helpful targets for suicide prevention
interventions, but requires replication.
Structural and functional connectivity
Disturbances in the structure and function within brain
regions can result in alterations in brain networks, including
the ability of brain regions to coordinate their activity in a
system. System dysfunction can also result from abnorm-
alities in the connections between regions. Increasingly,
abnormalities in the structural and functional connections
between brain regions within larger-scale brain networks
have been reported in studies of STBs.
Connections of the VMPFC with other cortical midline
structures (PCC, precuneus) and temporal and parietal regions
are implicated in the brain’s default mode network and play an
important role in self-referential processes, social cognition,
autobiographical memory, and prospective imagery [117].
Lower resting functional connectivity was reported in the
default mode network in adolescents with MDD and SI [151].
These findings are in line with findings of lower resting
functional connectivity of rostral ACC with medial OFC,
precuneus, and temporal pole in adults with MDD and SI
[152] and within the precuneus in young adult SAs with MDD
[153]. Structurally, lower fractional anisotropy (FA; thought to
reflect the structural integrity of white matter and the neuronal
connections it contains [154]) in the VMPFC was reported in
Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies

adult SAs with BD, which was associated with higher motor
impulsivity [155]. Lower FA was also reported in the ventral
cingulum (connecting posterior and temporal default mode
network regions) in adults with MDD and SI [37]. Lower FA
of the corpus callosum genu, which provides connections of
interhemispheric anterior default mode network regions, was
associated with a higher number of SAs in BD, MDD, and
BPD [156,157].
The limbic network includes the amygdala, medial and
lateral OFC, medial temporal regions, thalamus, and basal
ganglia and is involved in emotional and autonomic processes
[158]. Using task fMRI, lower amygdala-VMPFC/rostral PFC
connectivity was found in adolescent and young adult SAs
with BD while viewing happy and neutral facial expression,
and associated with higher lethality of attempts and current SI
[35]. During rest, greater amygdala connectivity with lateral
OFC, insula, and middle temporal gyrus was found in adult
SAs with MDD, with greater amygdala–parahippocampus
connectivity associated with SI [159]. These functional con-
nectivity alterations are in line with lower FA in the uncinate
fasciculus, which provides major amygdala connections, in
adolescents SAs with BD [35].
The medial OFC together with ventral striatum and the
ventral tegmental area form core hubs of a reward network,
with additional limbic regions, DLPFC and dACC forming a
wider reward network subserving reward-related memory and
evaluation [125]. An fMRI study investigating connectivity
during reward processing showed a positive correlation
between SI and connectivity of the left ventral striatum with
dACC, DMPFC, and DLPFC during loss trials in adults with
MDD [160]. Using resting state fMRI, Kim et al. [161]found
reduced connectivity in a circuitry resembling this reward
network, including the OFC, striatum, and thalamus, in adults
with MDD and recent (past month) SI. This is in line with
findings of lower structural connectivity between VPFC/OFC
and striatal regions in adults with MDD and SI (33% also had
apriorSA)[162], and between the ACC and OFC (as mea-
sured by graph theory) in adult SAs with MDD [163]. Lower
FA was also reported in the anterior limb of the internal
capsule (connecting striatal and thalamic regions with the
PFC) in adults with MDD and attempts [164,165].
The left and right DLPFC and DMPFC together with
parietal regions comprise a network that plays a key role in
cognitive control of thought, emotion, and behavior
(executive control network [166]). Lower executive control
network coherence during rest has been associated with
both lifetime SI and past attempts in adolescents with MDD
[151], in line with findings of lower DLPFC resting state
connectivity in young adult SAs with MDD associated with
higher impulsivity [167] and reduced white matter integrity
(FA) in the DMPFC in adult SAs with MDD [168].
Alterations in dACC connectivity have been linked to
STBs in the context of conflict monitoring, with different
patterns of dACC connectivity associated with SI vs SAs in
adults with recent-onset SZ [169]. That is, the presence of
lifetime SI was positively associated with magnitude of
functional connectivity of dACC with the precuneus, a core
hub of the default mode network. This may suggest a
reduced capacity of the dACC to “switch off”default mode
network activity associated with more internally focused
attention, when activation of externally focused cognitive
processing is required [169]. In contrast, history of SA was
negatively associated with dACC connectivity with DPFC
(BA9, 8, lateral BA10), VLPFC (BA45), PCC, parietal
regions (BA7, 40) and superior and middle temporal gyri
(BA22, 39, 40) [169]. These findings may suggest that SI
and SAs have divergent bases in dACC connectivity with
default mode network vs lateral PFC circuitries, respec-
tively, in the context of monitoring conflict in adult SAs
with recent-onset SZ. This is supported by findings of
abnormal conflict-related dACC connectivity with VLPFC,
OFC, insula, and striatum associated with SI intensity, but
altered dACC connectivity with DLPFC and frontal motor
regions associated with past SA in adults with MDD or BD
with psychotic features [170]. In addition, decreased func-
tional connectivity of the dACC with bilateral insula while
viewing angry faces was also reported in adolescent SAs
with MDD [73]. Connectivity between the dACC and insula
plays an important role in detecting salient internal and
external stimuli to guide behavior [171] and has been
implicated in the anticipation of aversive experiences,
especially in depressed individuals [172]. Reduced con-
nectivity between the dACC and bilateral insula may indi-
cate inefficient strategies to process the salience of, and
select contextually appropriate behavioral responses to,
negative emotional stimuli.
Summary
Emerging evidence suggests that resting state functional
connectivity in the default mode network, and white matter
tracts connecting regions within this network, play a role in
both SI and SAs across mental disorders. Functional and
structural connectivity alterations in the affective network
have also been associated with SI and SAs, as well as
lethality of attempts, both during emotion processing and
during rest. Connectivity abnormalities in the reward net-
work have mostly been examined in adults with MDD, and
both structural and functional connectivity changes in
regions of this network have been associated with SI and
SAs in this group. Connectivity changes within and
between regions implicated in the cognitive control network
have been less extensively studied in relation to STBs, and
the few studies conducted suggest a role of lower resting
state functional connectivity within this network in STBs in
adolescents and young adults with MDD. In addition,
L. Schmaal et al.

functional connectivity of dACC is implicated in STBs, but
with divergent connectivity patterns related to SI vs SAs.
Discussion
While the literature primarily includes cross-sectional stu-
dies with small sample sizes, differing clinical populations,
and a wide range of imaging methods, there is emerging
convergence in the brain regions implicated in STBs. Taken
together with the recent increased momentum in studies on
STBs (Fig. 1), it is very hopeful that significant advances in
our understanding of brain mechanisms contributing to
STBs are on the horizon. A critical frontier is to identify
markers for elevated risk, especially short term risk in the
transition from SI to attempt. While the majority of studies
to date were on SAs, some studies specifically investigated
associations with SI, and brain regions found to be asso-
ciated with STBs have known roles in processes thought to
contribute to STBs. Below, we briefly summarize the most
convergent findings from the literature reviewed above, and
propose directions for future neuroimaging studies on the
neurobiology of STB.
A tentative brain model of STBs
Figure 3summarizes convergent findings emerging from the
reviewed literature on brain alterations associated with
STBs. Abnormalities in an extended VPFC system,
including regions of the default mode, affective and reward
networks such as the ACC, insula, medial and lateral OFC,
RPFC, mesial temporal regions, ventral striatum and pos-
terior structures (lateral temporal, PCC, precuneus, cere-
bellum), and in the connections among these regions, may
be important in the excessive negative and blunted positive
internal states that can stimulate SI. This is in line with the
well-established role of this extended VPFC system in
functions implicated in SI including appraisal of internally
generated emotions, self-referential processing, recall of
emotional episodic memories, imagining future positive and
negative events, valuation of rewards, and integrating
environmental stimuli to modulate subjective emotional
states [16,17,66,117,125,147]. A more lateral and dorsal
system, including DMPFC, DLPFC, and dACC, together
with the IFG and RPFC, may facilitate suicide behaviors
through their role in cognitive control of thought, emotion
and behavior as well as cognitive flexibility, complex
decision-making (e.g., valuation of different decision
options) and planning [16,17]. A combination of VPFC and
DPFC/IFG system disturbances may lead to very high risk
circumstances in which SI may convert to lethal actions via
decreased top-down inhibition of behavior or maladaptive,
and inflexible decision-making and planning.
Alterations in the connections between these systems
may contribute to the transition from suicidal thoughts to
behaviors. For example, the dACC has connections to both
the “emotional”ventral limbic system and the “cognitive”
dorsal prefrontal system [173]. Consistent with this,
Fig. 3 A tentative brain circuitry model of suicidal thoughts and
behaviors. Medial VPFC (ventral ACC, OFC, and RPFC), insula,
amygdala, hippocampus, lateral temporal regions, posterior midline
structures (posterior cingulate cortex and precuneus), dACC, ventral
striatum, thalamus, and cerebellum contribute to the generation of
suicidal ideation through their roles in excessive negative and blunted
positive internal states, negative self-referencing, impairments in future
thinking and rumination. DPFC (DLPFC and DMPFC), IFG,
RPFC and dACC alterations further exacerbate suicidal thoughts and
facilitate suicide behaviors due to their involvement in diminished
cognitive control of thought, emotion, and behavior and impairments
in cognitive flexibility and valuation of different decision options.
Alterations in bottom-up and top-down connections between these
extended medial VPFC and DPFC/IFG systems may contribute to the
transition from suicidal thoughts to behaviors. The dACC and insula
may mediate this transition. Dashed lines indicate speculative asso-
ciations that need further confirmation by future structural and func-
tional connectivity studies. DMPFC dorsomedial prefrontal cortex,
dACC dorsal anterior cingulate cortex, RPFC rostral prefrontal cortex,
OFC orbitofrontal cortex, vACC ventral anterior cingulate cortex, PCC
posterior cingulate cortex, Thal thalamus, VS ventral striatum, Hippo
hippocampus, Amyg amygdala, DLPFC dorsolateral prefrontal cortex,
IFG inferior frontal gyrus, Put putamen, Caud caudate
Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies

findings suggest differential connectivity of the dACC in
relation to SI vs. a history of attempt, with dACC con-
nectivity with VPFC, insula, and striatal regions primarily
associated with SI and dACC connectivity with DPFC
regions associated with SA. The insula is also implicated in
both SI and attempts and may perhaps be important for the
transition from SI to attempt. Although the involvement of
the insula in STBs has had little direct research focus, its
critical involvement in interoceptive processing, detecting
salient internal and external stimuli, experiencing emotion,
and self-awareness [174–176] suggests an important role of
the insula in SI. In addition, the insula is implicated in
disconnection from bodily experiences, which in turn may
lower the threshold to engaging in behaviors that harm the
body (in line with the acquired capability theory [177]) thus
suggesting a role of the insula in suicide behaviors. In line
with important roles of dACC and insula circuitry (as part
of the “salience network”) in mediating or switching
between the extended VMPFC (default mode, affective,
reward) systems and the DPFC/IFG (executive control)
system [178–180], the dACC and insula may represent
integral hubs that facilitate the transition from SI to attempt.
However, this suggestion of the dACC and insula’s ability
of mediating dynamic interactions between the VMPFC and
DPFC/IFG systems and through these interactions playing a
role in the transition from SI to attempt remains highly
speculative and will need to be confirmed in future, pre-
ferably longitudinal, studies on the neurobiology of STB.
Future directions
The literature reviewed underscores the need for future
studies to include larger sample sizes and careful attention
to developmental stages. In addition, studies employing
longitudinal designs are critically needed to identify risk
markers for future SAs in order to develop improved pre-
ventive strategies. Recent preliminary evidence, from a rare
longitudinal study of adolescents and young adults with
mood disorders over about 3 years, showed that those with
future attempts had lower VPFC volume and decreased FA
in VPFC and DPFC connections [181], suggesting that
these may be potential predictors for STBs already present
in adolescence. Longitudinal study over short time intervals
are largely absent from the literature and are critically
needed to assess proximal suicide risk.
Furthermore, studies focusing on identifying brain
alterations that predict or fluctuate with changes in STBs
following treatment could provide urgently needed bio-
markers for response of STBs to existing interventions and
could help develop novel treatments specifically targeting
these biomarkers. Preliminary evidence has implicated brain
circuitry that may mediate the reduction of suicide risk by
treatments such as lithium and ketamine [182–184]. For
example, ketamine-induced reductions in SI were associated
with increases in baseline rCMRglu in a cluster including
the cerebellum and occipital cortex [150]. In addition, in 57
adults with BD with and without a history of attempt,
lowest DLPFC, OFC, ACC, superior temporal cortex, par-
ietal and occipital cortex volumes were observed in SAs off-
lithium, followed by SAs and nonattempters on lithium,
with the largest volumes in people with nonattempting BD
on lithium [34]. However, the study of other pharmacolo-
gical and nonpharmacological treatments that can directly
(e.g., deep brain stimulation) or indirectly target the
involved circuitry is needed.
Although adolescents have been less studied than adults,
some findings have been similar. For instance, alterations in
structure of the VMPFC, VLPFC, DLPFC, DMPFC, ACC,
lateral temporal regions, and parahippocampal gyrus were
observed in both adolescents and adults with SAs. Fur-
thermore, lower connectivity in regions related to the
default mode network during rest have been consistently
reported across adolescents, young adults, and adults with
SI and/or SAs. Greater DLPFC activation in response to
angry faces was also observed in both adolescents and
adults with STBs. The highly limited number of studies in
adolescents and a lack of different life stages in single
studies prevents drawing conclusions about the overlap in
functional brain alterations across different stages of life and
brain maturation. Thus, there is some converging evidence
across adolescent and adult samples, however, not all adult
findings have been observed in adolescents (see Supple-
mentary Tables 1–3 for a complete overview). This may at
least in part be due to the continued maturation of involved
brain systems so that not all features may be expressed until
adulthood [185,186].
Most studies only included a single disorder, impeding
conclusions around shared vs. unique neural substrates of
STBs across different mental disorders. Different studies
employed different inclusion and exclusion criteria, imaging
methods, and STB assessments. Nonetheless, gray matter
alterations in the VLPFC, DLPFC, ACC, and insula have
been consistently reported across the diagnostic categories
reviewed (i.e., MDD, BPD, BD, and SZ), while lateral
temporal alterations were more uniquely observed in psy-
chotic disorders and BPD. Reduced white matter integrity in
VPFC regions was reported in relation to STBs in both BD
and MDD and lower FA in the corpus callosum was asso-
ciated with a higher number of attempts across BD, MDD,
and BPD. Functional brain alterations in relation to emotion
processing and regulation was investigated only in MDD,
BD, and BPD, with consistent findings of increased VLPFC
activation in response to negative emotional stimuli across
MDD and BPD, while the only study of adolescents with
BD focused on amygdala-PFC connectivity [35]. Higher
DLPFC activation during cognitive control tasks, in the
L. Schmaal et al.

absence of task performance differences, was also con-
sistently reported across MDD, BD, SZ, and PTSD. In
contrast, higher vs. lower IFG activation during cognitive
control was observed in mood disorders vs SZ, respectively.
Alterations in dACC connectivity with default mode,
affective and reward network related regions in relation to
SI, and alterations in dACC connectivity with DLPFC in
relation to SAs during cognitive control, have been
observed across MDD, BD, and SZ. Other functional
domains such as reward processing, decision-making, social
exclusion, and self-referential processing, as well as func-
tioning at rest, have only been investigated in a single
disorder, i.e., depression. In one of the few studies to assess
SAs across MDD and BD (published subsequent to our
literature search), VPFC gray matter volume reductions and
uncinate fasciculus FA reductions were common to both
disorders, suggesting that they may be important in risk for
attempts across mood disorders [187]. Preliminary findings
of that study also indicated there may be differences in
involved regions in SAs between the disorders, with greater
uncinate involvement in attempters in BD and dorsal frontal
white matter in MDD. These findings suggest both trans-
diagnostic and unique gray and white matter targets for
suicide prevention across mental disorders.
The examination of sex differences in STBs is a major gap
in the neuroimaging literature and a critical area for study.
There are well-established sex-dependent features known in
STBs [188], such as a higher rate of attempts in females and
a higher lethality of attempts in males [189–191]. Moreover,
increased death rates by suicide between 1999 and 2017 as
reported by the CDC showed the rate of increase was sub-
stantially higher for females than males (53% and 26%,
respectively). Female suicide rate increases were particularly
high in youth/early adulthood (ages 10–24 years) and middle
age (45–64 years), when females have their highest risk,
while the highest risk for males is age 75 years and older
[192]. Of the studies in this review, 11 (8.4%) had exclu-
sively female and 15 (11.5%) exclusively male samples.
Authors of six studies (4.6%) commented on this homo-
geneity as a limitation, and 14 (10.7%) provided a rationale
for single-sex studies. These included the need to avoid
potential confounds of previously reported sex-based effects,
e.g., previous reports of sex differences in cortical responses
with similar fMRI tasks (n=5) and corpus callosum struc-
ture (n=2); high male representation in the group under
investigation, such as military veterans (n=3); female-
skewed prevalence of BPD (n=1); males and females
imaged on different scanners (n=1); small number of male
SAs (n=1); and an attempt to replicate previous work (n=
1). Ninety studies (68.7%) included sex as a covariate,
controlling for potential differences. A small percentage of
studies (13.8%) included sex as a variable to assess potential
interactions with STBs. Five studies (3.8%) reported sex-
related findings, though no relationship with STBs
[36,146,193–196] and one study (0.8%) reported more
females than males studied were SAs but reported no
neuroimaging-related findings [197]. Chase et al. [198], in a
study that controlled for sex, noted that one participant
identified as transmale. Careful consideration is warranted in
how sex and gender are evaluated and categorized for ana-
lyses, including the importance of allowing subjects to
identify by gender and that this self-identification of gender
is considered in all studies. This is particularly important
because transgender and sexual-minority individuals are at
increased risk for STBs and death by suicide [199,200].
Collectively, these STB neuroimaging research data high-
light the urgent need for future work on sex and gender.
Integration of neuroimaging research across differential
mechanistic levels including genetic, molecular, social, and
environmental risk factors will be crucial to the elucidation of
a holistic view of STB pathophysiology and mechanisms
associated with vulnerability and resilience and thus tailored
intervention development. Sophisticated analytic methods,
such as machine learning techniques [59], can be utilized to
allow imaging risk markers to be identified at the level of the
individual instead of at a group level, a key ingredient for
clinically viable biomarkers [201] and precision medicine. In
addition, the use of high-resolution ultrahigh field strength
MRI methods and more specific functional neuroimaging
tasks may further enhance ability to parse roles of specific
brain regions, such as PFC subregions [202]. Molecular
imaging has produced important leads, such as in serotonergic
and inflammation mechanisms (Supplementary Table 2),
consistent with postmortem, genetic, and peripheral bio-
marker studies implicating an important role of the ser-
otonergic system and inflammatory mechanisms in STBs
[203,204]. Imaging of molecular mechanisms other than
serotonin remains scarce, with for example only four mag-
netic resonance spectroscopy (1H-MRS) studies examining
glutamatergic and GABA-ergic mechanisms published to date
(Supplementary Table 2). Given postmortem findings of
altered glutamatergic and GABA-ergic gene expression and
receptor availability in suicide victims mainly in the PFC,
ACC, and hippocampus [205–207], future 1H-MRS should
clarify the role of these neurotransmitters in STBs in vivo. In
addition, a generation of new methods to identify other cur-
rently implicated and novel molecular mechanisms is needed.
For example, a link between oxytocin and SI was recently
suggested [208].
Future studies should also further investigate the more
elusive subjective aspects of suicide risk, such as SI, as well
as implicated psychological constructs such as hope-
lessness, rumination, and anhedonia [209–211], which may
be relevant across diagnoses. Similarly, social experiences
such as childhood maltreatment and peer bullying form a
strong prelude to STB in later life [208,212,213], and
Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies

impact on the neural structures implicated in STB (e.g.,
DMPFC structure and function [214,215]). Therefore,
adverse experiences should be taken into account in future
studies on the neurobiology of STB.
Links identified between neuroimaging measures and
behaviors outside of the scanner could facilitate the devel-
opment of less invasive and more easily and widely dis-
seminated risk detection methods. Furthermore, investigations
of larger samples can be facilitated by international colla-
borations that pool existing data across many different sam-
ples, such as the MQ HOPES (https://www.mqmentalhealth.
org/research/profiles/overcome-and-predict-the-emergence-of-
suicide)andENIGMASTB(http://enigma.ini.usc.edu/
ongoing/enigma-stb/) consortia. These initiatives represent
cost-effective ways to substantially increase statistical power,
which could provide more robust and reliable findings [216],
and the ability to study age, gender, and sex effects, as well as
unique and shared mechanisms associated with STBs across
different mental disorders. Furthermore, large combined
datasets will provide a unique opportunity to identify and test
reproducibility of different pathways to suicide that may differ
across many parameters including a range from the impulsive
to the highly planned. Such efforts will need to take into
account the variety of assessment methods used for STBs
across studies. One way to address this important challenge is
through the examination of the presence vs. absence of sui-
cidal behavior (attempts), and/or SI (with or without intent
and/or a plan) across assessment types (see for example
Renteria et al. [110]). Another approach could involve stan-
dardization of scores across different instruments by devel-
oping a common metric [217]. Standardization of STB
assessment across future studies would significantly facilitate
the sharing of data, and thereby advance our understanding of
brain-based STB vulnerability.
Conclusions
More than 2 decades of neuroimaging studies on STBs
suggests a transdiagnostic model for STBs in which an
extended VPFC system may be important in the excessive
negative and blunted positive internal states that can sti-
mulate SI and a DPFC/IFG system that may facilitate SA
behaviors. Interactions between these systems are likely
important in the transition from ideation to attempt, perhaps
mediated by dACC and insula regions, but require further
investigation. With the exponential growth of research on
STBs, including the initiation of large global efforts, it is
hopeful that suicide prevention will soon be more effec-
tively targeted, reducing the tragic loss of life to suicide.
Acknowledgements This work was supported by the MQ Brighter
Futures Award MQBFC/2 (ALvH, HPB, and LS), by the National
Institute of Mental Health of the National Institutes of Health under
Award Number R01MH117601 (LS), RC1MH088366 (HPB),
R01MH113230 (HPB), R61MH111929 (HPB), T32MH014276
(ETCL), and T32DA022975 (ETCL). LS is supported by a NHMRC
Career Development Fellowship (1140764). ALvH is supported by a
Royal Society Dorothy Hodgkin Fellowship (DH15017), and an MRC
MRF emerging leaders award. LAA is supported by the American
Foundation for Suicide Prevention, Brain and Behavior Foundation/
NARSAD, Robert E. Leet and Clara M. Guthrie Patterson Trust, and
Department of Veterans Affairs National Center for PTSD and a
CSR&D CDA2. HPB is supported by the American Foundation for
Suicide Prevention, International Bipolar Foundation and For the Love
of Travis Foundation. CMM and HPB are supported by Women’s
Health Research at Yale and Women’s Health Access Matters.
Compliance with ethical standards
Conflict of interest HPB received an honorarium for a talk at Aetna.
The other authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons
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