Schizophrenia Research 157 (2014) 19–25

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Schizophrenia Research
journal homepage: www.elsevier.com/locate/schres

Frontal cortex control dysfunction related to long-term suicide risk in

recent-onset schizophrenia
Michael J. Minzenberg a,b,⁎, Tyler A. Lesh c, Tara A. Niendam c, Jong H. Yoon e,f,
Remy N. Rhoades a,b, Cameron S. Carter c,d
a
Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, CA, United States
b
Veterans Affairs Medical Center, San Francisco, CA, United States
c
Department of Psychiatry, University of California, Davis School of Medicine, Sacramento, CA, United States
d
Center for Neuroscience, University of California, Davis, CA, United States
e
Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Palo Alto, CA, United States
f
VA Palo Alto Health Care System, Palo Alto, CA, United States

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

Article history: Objective: Suicide is highly-prevalent and the most serious outcome in schizophrenia, yet the disturbances in
Received 25 March 2014 neural system functions that confer suicide risk remain obscure. Circuits operated by the prefrontal cortex
Received in revised form 23 May 2014 (PFC) are altered in psychotic disorders, and various PFC changes are observed in post-mortem studies of com-
Accepted 27 May 2014 pleted suicide. We tested whether PFC activity during goal-representation (an important component of cognitive
Available online 24 June 2014
control) relates to long-term suicide risk in recent-onset schizophrenia.
Method: 35 patients with recent-onset of DSM-IV-TR-defined schizophrenia (SZ) were evaluated for long-term
Keywords:
Schizophrenia
suicide risk (using the Columbia Suicide Severity Rating Scale) and functional MRI during cognitive control
Suicide task performance. Group-level regression models associating control-related brain activation with suicide risk
Cognitive control controlled for depression, psychosis and impulsivity.
fMRI Results: Within this group, past suicidal ideation was associated with lower activation with goal-representation
Frontal cortex demands in multiple PFC sectors. Among those with past suicidal ideation (n = 18), reported suicidal behavior
was associated with lower control-related activation in premotor cortex ipsilateral to the active primary motor
cortex.
Conclusions: This study provides unique evidence that suicide risk directly relates to PFC-based circuit dysfunction
during goal-representation, in a major mental illness with significant suicide rates. Among those with suicidal
ideation, the overt expression in suicidal behavior may stem from impairments in premotor cortex support of
action-planning as an expression of control. Further work should address how PFC-based control function changes
with risk over time, whether this brain–behavior relationship is specific to schizophrenia, and address its potential
utility as a biomarker for interventions to mitigate suicide risk.
Published by Elsevier B.V.

1. Introduction
Suicide is a major public health problem worldwide. It is a leading
cause of death, among the most common causes of death for young
people, including young adults (Nock et al., 2008; Hawton and van
Heeringen, 2009), and confers an enormous public health impact
(United States. Public Health Service: Office of the Surgeon General.,
1999; United States. Public Health Service, 2001; Goldsmith et al.,
⁎ Corresponding author at: Outpatient Mental Health, 116C, San Francisco Veterans
Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, United States.
Tel.: +1 415 221 4810x6554.
E-mail address: Michael.minzenberg@ucsf.edu (M.J. Minzenberg).
2002). In schizophrenia, the risk for suicidal ideation, behavior and com-
pleted suicide is particularly high early in the illness course (Dutta et al.,
2010; Pompili et al., 2011; Nielssen et al., 2012), though suicide risk
remains elevated for many years after a single suicide attempt (Dutta
et al., 2010).
Despite the increasing attention to clinical risk factors for suicide,
how brain dysfunction confers this risk remains unclear. Post-mortem
studies of suicide victims reveal many serotonergic disturbances in the
lateral and medial PFC (reviewed in Mann, 2003). These findings are
generally independent of co-morbid depression history, or psychiatric
diagnosis per se. These studies suggest that the lateral and medial PFC
are key loci of serotonergic dysfunction associated with suicide.
Nonetheless, it remains unclear how disrupted PFC-based circuit
operation contributes to suicide risk in at-risk populations. The major

http://dx.doi.org/10.1016/j.schres.2014.05.039
0920-9964/Published by Elsevier B.V.
20 M.J. Minzenberg et al. / Schizophrenia Research 157 (2014) 19–25
cognitive neuroscience models of PFC function generally posit superordi-
nate control processes, which support cognitive processes as diverse as
attention, behavior, decision-making, thought/language, and emotion-
regulation. These models include a role for lateral PFC subregions
(especially dorsolateral PFC, or DLPFC) in goal-representation via the
encoding and use of rules or strategies for decision-making, thereby
biasing processing of attention, perception and action, to influence
motor output via striato-thalamic circuits (Miller and Cohen, 2001;
Koechlin et al., 2003). In contrast, the posterior medial PFC monitors
conflict between goals and tasks (Botvinick et al., 2001) and other
mismatches between the individual's status and goals, such as negative
affect and pain (Schackman et al., 2011). In these conditions, the medial
PFC signals to the DLPFC the need to bolster control to optimize goal
attainment.
Other closely-linked frontal cortical regions represent goal-relevant
information, including rostral PFC, which represents hierarchical as-
pects of complex rules and actions (Badre, 2008); and rostral medial
PFC sectors (e.g. dorsomedial and ventromedial PFC), which represent
self-referential aspects and valuate environmental stimuli. Disturbances
in elements of these interacting networks may then manifest clinically
as disturbances of the control of thought, behavior or emotion, observed
as suicidal ideation or behavior. Considering that cognitive control per-
formance is associated with serotonergic gene variation (Strobel et al.,
2007), frontal-based control processes may link serotonergic dysfunc-
tion to suicide.
PFC-based cognitive control disturbances may therefore represent
an important mechanism underlying suicide risk. Cognitive control-
related medial and lateral PFC dysfunction is well-established in schizo-
phrenia (Minzenberg et al., 2009; Lesh et al., 2011, 2013), including in
the first-episode (Yoon et al., 2008). Schizophrenia outpatients with
past suicide attempts also have increased volumes of inferior PFC
white matter relative to those without suicide attempts (Rusch et al.,
2008), as well as decreased orbitofrontal gray matter density (Aguilar
et al., 2008), and relatively higher-risk schizophrenia patients exhibit
altered effective connectivity between the left-hemisphere posterior
cingulate cortex and medial PFC, relative to lower-risk patients
and healthy controls (Zhang et al., 2013). Schizophrenia patients
with past suicide attempts also have increased right amygdala
volume (Spoletini et al., 2011), which could in principle be associat-
ed with altered ascending influence on PFC circuit function. In addi-
tion, decreased fractional anisotropy in the cingulum bundle is
observed in suicidal traumatic brain-injured patients (Yurgelun-
Todd et al., 2011). More diagnostically-heterogeneous populations
with past suicide attempts show functional disturbances in medial
and lateral PFC sectors during varied cognitive tasks (Audenaert
et al., 2002; Amen et al., 2009; Jollant et al., 2010; Reisch et al.,
2010). These studies, while preliminary, suggest that patients with
suicidal behavior exhibit dysfunction of PFC-based circuits during
complex cognition, and may be impaired over and above those
patients who share other clinical features (e.g. diagnosis or other
symptoms).
We therefore tested the hypothesis that PFC-based circuit function
with explicit control demands directly relates to suicide risk, in schizo-
phrenia patients who are early in the illness course, when this risk is
particularly elevated. We employed an emerging clinical standard
for suicide risk assessment, the Columbia Suicide Severity Rating
Scale (Posner et al., 2011). Critically, in the analyses we accounted for
major symptom domains previously identified as clinical risk factors
for suicide in schizophrenia, including depression, psychosis and impul-
sivity. This allowed tests of the direct relationships of frontal circuit dys-
function to suicide risk, which are not simply accounted for by these
clinical risk factors. Additionally, in the model of past suicidal behavior
to brain dysfunction, we analyzed only those subjects who were posi-
tive for past suicidal ideation, allowing us to potentially disambiguate
brain function associated with overt behavior from that associated
with ideation.
2. Experimental/materials and methods
2.1. Subjects
The study was conducted at the Imaging Research Center at the
University of California — Davis Medical Center. All procedures were
approved by the UC Davis School of Medicine Institutional Review
Board. Inclusion criteria included age 18–50 years, right-handedness
(by Edinburgh Handedness Inventory), and diagnosis of 295.X (by
DSM-IV-TR). Exclusion criteria included neurological illness (including
head injury with loss of consciousness), uncorrectable visual problems
or peripheral motor disturbance, full-scale IQ b 80 (by Wechsler
Abbreviated Scale of Intelligence), active substance abuse or depen-
dence in the 6 months prior to study, significant uncontrolled medical
illness, and previously-known incompatibility with MRI procedures.
All included subjects tested negative for illicit drugs in the urine at all
study visits. After complete description of the study to the subjects,
written informed consent was obtained.
All patients were recruited from the UCD Early Diagnosis and Pre-
ventive Treatment (of Psychosis) research clinic, as clinically-stable out-
patients, with onset of psychotic symptoms within 2 years of study, and
no hospitalizations or changes in medication regimen for at least two
months prior to study. The frequencies of prescribed medications at
study were antipsychotics (n = 32), anticonvulsants (n = 4) and anti-
depressants (n = 6). None were receiving lithium or clozapine. Patients
were assessed with the Structured Clinical Interview for DSM-IV-TR.
Diagnosticians were masters/doctoral-level, SCID-trained clinicians,
with demonstrated reliability, defined by ≥ .80 intraclass correlation-
coefficient (ICC) for continuous measures and kappa ≥ .70 for categori-
cal measures. All diagnoses were confirmed via consensus conference,
and monthly reliability interviews to prevent drift. Based upon 10
sessions during the course of this study, diagnostic reliability for the
SCID was kappa ≥ 0.8, and for symptom total scores ICCs were ≥0.76.
A subset of the present sample was previously reported for AX-CPT
task-related fMRI effects compared to a healthy comparison group
(not focused on suicide risk), in Lesh et al. (2013). The present study
represents a secondary analysis drawn from a subset of that sample,
to specifically test relationships of brain function to suicide risk.
2.2. Clinical measures
2.2.1. Clinical measure of suicide risk — description and rationale
Suicide risk was rated with the Columbia Scale for the Rating of Sui-
cide Severity (C-SSRS), a relatively brief, yet comprehensive, structured
interview-based instrument with good validity and internal reliability
in 3 multi-site studies with diverse clinical populations (Posner et al.,
2011). This scale is comprised of three subscales. Suicidal Ideation (SI)
is an ordinal subscale containing items including the wish to be dead,
the specificity of these thoughts, including whether they are “active”,
with intent and plan. Intensity of Ideation (II) considers the frequency,
duration, controllability, deterrents and reasons for thoughts of suicide.
Suicidal Behavior (SB) is a nominal subscale that categorizes past actual,
interrupted and aborted attempts to die, and preparatory acts, and for
actual attempts, the potential or actual lethality or medical damage
sustained in the attempt(s). Items on each subscale are associated
with future suicidal behavior and/or completed suicide (Posner et al.,
2011). SI items are rated on a yes/no basis, II items on a 1–5 scale, and
SB as yes/no, with counts of actual, interrupted and aborted attempts.
We used the following criteria to stratify patients in each group on
each of the two non-continuous C-SSRS subscales (SI and SB): for SI,
the presence of any past suicidal ideation (i.e. positive on any SI item),
versus no past suicidal ideation; and for SB, the presence of any past be-
havior that can be considered the initiation of deliberate self-harm with
intent to die as the critical discrete threshold (i.e., a positive response to
actual attempt, interrupted attempt, or aborted attempt). For SB, we
considered positive responses that were restricted to Non-Suicidal
 M.J. Minzenberg et al. / Schizophrenia Research 157 (2014) 19–25 21

Self-Injurious Behavior and/or Preparatory Acts or Behavior, as not
meeting this criterion. The target subgroups in the SI and SB models
were then dummy-coded as e.g. “SI-positive” or “SI-negative”. In
contrast, the II subscale contains items that are rated in a continuous
manner and therefore were summed to establish a subscale total score
for neuroimaging analyses.
Both past overt suicidal behavior and lifetime “worst-point” suicidal
ideation were targeted on the basis of the following evidence. Overt
suicidal and self-injurious behavior represents a proximal risk factor
(or prelude to) eventual completed suicide for many individuals, as
those who survive a suicide attempt subsequently remain at elevated
risk for completion for many years (Owens et al., 2002). However,
many who complete suicide do so in a first attempt, and suicidal idea-
tion even in the absence of overt suicidal behavior is a strong risk factor
for eventual completion, especially at the “worst-point”, the time in the
patient's life in which they experienced the most intense desire to com-
mit suicide (Beck et al., 1999; Joiner et al., 2003). These observations
suggest that suicidal ideation in the absence of associated overt self-
injurious behavior is an important risk factor, as it may herald future
completed suicide without any interim suicide attempts prior to death.
We also evaluated the major symptom domains in schizophrenia
that contribute to suicide risk, including psychosis (Scale for the
Assessment of Positive Symptoms, SAPS), depression, with an instru-
ment validated for psychotic illness (Calgary Depression Scale, CDS),
and trait impulsivity (Barratt Impulsivity Scale, 11th version, BIS-11).
All symptom measures were obtained within two weeks of MRI.
2.3. AX version of the Continuous Performance Task (AX-CPT)
fMRI was conducted while subjects performed the AX version of the
Continuous Performance task (AX-CPT), a widely used cognitive control
task (Yoon et al., 2008). This task involves presentation of a “Cue” letter
that provides the rule which guides the subsequent stimulus-response
mapping to the Probe letter stimulus. The cue letter is presented for a
0.5 second duration, followed by a 3.5 second delay, and then the
Probe letter is shown for a duration of 0.5 s, and finally a 9.5 second
inter-trial interval (total trial duration 14 s). Subjects are instructed to
make a “target” response (two-choice button-press) to the probe letter
X, only when it follows the cue letter A. All other stimuli require a non-
target response, including trials with probe letter Y, and trials in which
the probe letter X is preceded by any letter other than A (collectively re-
ferred to as B Cues). Trials with target cue–probe pairings (e.g., AX)
occur with high frequency (70%) to establish the pre-potent tendency
for the subject to make a target response to the probe letter X. The
major goal-representation demand occurs with B-Cues, in which sub-
jects must represent and use the proper rule to overcome the trained
pre-potent tendency to make a “target” response to probe letter X.
Performance measures included accuracy and reaction time (RT) in
each task condition (cue–probe pairs), and the decrement (“cost”) in
accuracy and RT on BX trials compared to AX trials (see Table 1).
2.4. Functional neuroimaging
2.4.1. Acquisition and pre-processing
fMRI was conducted on a 1.5 T GE scanner and BOLD contrast was
acquired during single-shot, echo-planar imaging (EPI), using a T2*-
weighted sequence and whole-brain coverage. The parameters of
the EPI sequence were TR 2000 ms, TE 40 ms, flip angle 90°, FOV 220
× 220 mm, with 24 contiguous slices, each 4.0 mm isotropic voxel
size, matrix size 64 × 64 (from 80 mm above to 16 mm below the ante-
rior commissure–posterior commissure plane). Preprocessing was con-
ducted using SPM8, including 6-parameter linear motion correction
(spatial alignment to the first scan in each time-series), co-registration
to the subject's co-planar T2 image, normalization to the standard
MNI template (non-linear warping, using parameters derived from the
subject's co-planar T2 image), intensity normalization and smoothing
with an 8 mm kernel. All subjects had cumulative head movement
less than one voxel in each dimension.
2.4.2. Modeling of the BOLD signal and inferential statistics
We modeled task-related events by convolving the canonical hemo-
dynamic response function (HRF) with a series of delta functions, placed
at onset of each Cue and Probe event. Only correct trials were entered
into statistical contrasts, to emphasize on-task trials. Scan-to-scan

Table 1
Demographic and clinical characteristics, and task performance in schizophrenia group (n = 35).

Measure SI− (n = 17) SI+ (n = 18) SI+/SB− (n = 10) SI+/SB+ (n = 8)

Mean SD Mean SD Mean SD Mean SD

Age 21.5 3.2 21.6 4.0 20.6 2.1 23.8 6.0

Sex (% M) 14 (80%) 15 (83%) 7 (70%) 5 (63%)
IQ 99 10 105 14 106 15 104 11
Personal educ 12.3 1.7 13.3 2.1 12.4 1.3 15.2 2.4
Parental educ 14.1 4.2 15.6 3.1 16.6 3.2 13.6 1.7
C-SSRS: II total 0 0 13.4⁎⁎ 8.1 10.9 5.6 18.5⁎⁎⁎ 10.1
SAPS total 12.0 14.0 13.4 15.1 14.5 14.4 11.0 17.5
CDS total 0.5 1.0 2.3⁎ 3.2 1.9 2.2 3.2 4.8
BIS-11 total 51.2 10.1 52.9 9.1 54.5 9.3 50.0 8.4
AX accuracy (%) 94.8 4.9 94.1 7.1 93.1 8.4 96.0 3.0
AY accuracy (%) 86.4 15.6 83.7 19.5 85.5 21.5 80.0 15.9
BX accuracy (%) 80.1 20.8 86.4 14.2 86.8 16.3 85.5 10.2
BY accuracy (%) 97.3 5.6 95.0 8.9 97.1 4.3 91.0 14.0
Accuracy Cost (%) 14.7 16.8 7.7 12.7 6.3 14.6 10.5 8.2
AX RT (ms) 644 122 626 107 632 116 614 95
AY RT (ms) 822 119 795 149 781 146 823 165
BX RT (ms) 766 166 746 191 736 193 767 205
BY RT (ms) 674 120 693 154 677 142 726 187
RT Cost (ms) 123 92 120 105 104 102 152 113

IQ, Intelligence Quotient (WASI 2-scale), C-SSRS, Columbia Suicide Severity Rating Scale, SI, Suicidal Ideation subscale, II, Intensity of Ideation subscale, SB, Suicidal Behavior subscale, SAPS,
Scale for the Assessment of Positive Symptoms, CDS, Calgary Depression Scale, BIS-11, Barratt Impulsivity Scale, 11th version, AX-CPT, AX version of Continuous Performance Task. See
Experimental/materials and methods section for definition of individual task conditions.
⁎ p b 0.05.
⁎⁎ p b 0.005.
⁎⁎⁎ p b 0.10.
22 M.J. Minzenberg et al. / Schizophrenia Research 157 (2014) 19–25

movement (in 6 dimensions) was entered as nuisance regressors. To 3. Results

evaluate goal-representation, neural responses were contrasted be-
tween [High-control Cues (B Cues) minus Low-control Cues (A Cues)].
These were conducted as voxel-wise, fixed-effects analysis at the
subject-level, then random-effects analysis at the group-level. The
group-level regression model for each task contrast included total scores
on scales for Depression (Calgary Depression Scale), Impulsivity (Barratt
Impulsivity Scale, 11th version), and Psychosis (SAPS), and either A)
C-SSRS II subscale totals, B) SI+ vs. SI−, or C) SB+ vs. SB− variables,
in parallel analyses. Each reported contrast is for SI, II or SB, showing
brain regions where task-related BOLD signal change during goal-
representation is significantly related to SI, II or SB, each controlling for
depression, impulsivity and psychosis. The model that evaluated SB was
conducted on the 18-patient subsample who reported past suicidal
ideation, in order to evaluate how suicidal behavior relates to brain
dysfunction, beyond that of suicidal ideation alone. Eight of these
18 SI+ patients (44%) reported past suicidal behavior. For the determina-
tion of statistical significance at the group-level, we conducted a Monte
Carlo simulation, using the Alpha-Sim program in AFNI. Contrast maps
were first masked to the frontal cortex (derived from PickAtlas library)
and thresholded at p b 0.005, and the simulation then returned cluster
sizes that comprise the empirically-determined statistical threshold of
p b 0.05. The cluster-thresholds in the contrast maps were as follows
for each model: SI, 32 voxels (256 mm3), II, 31 voxels (248 mm3) and
SB, 30 voxels (240 mm3).
3.1. Clinical measures
Please see Table 1 for subject demographic and clinical characteristics.
3.2. Neuroimaging results
Table 2 and Figs. 1–3 show the results of group-level contrasts indi-
cating brain regions where the three subscales of suicide risk were sig-
nificantly associated with brain activity during goal-representation,
independent of depression, psychosis or impulsivity. Suicidal Ideation
(Table 2 and Fig. 1) was inversely related to neural activity during
goal-representation in three major clusters. The first was centered on
medial frontal sectors, including the pregenual anterior cingulate gyrus
and adjacent ventromedial PFC, extending to bilateral ventrolateral
PFC. A second cluster was centered on the left rostral pole, extending
into the ipsilateral left dorsomedial PFC. A third major cluster was ob-
served in the right dorsal anterior cingulate gyrus. The Intensity of Idea-
tion scores (Table 2 and Fig. 2) were significantly inversely associated
with an overlapping set of frontal regions, including a large, bilateral
midline PFC cluster which included dorsomedial and pregenual PFC.
However, in addition, several lateral PFC regions were observed, includ-
ing bilateral DLPFC and VLPFC, right rostrolateral PFC, and right supple-
mentary motor area. For each of these clusters, the test statistics were

Table 2
Frontal brain regions with a significant association of neural activity during goal-representation with long-term suicide risk in recent-onset schizophrenia.

Brain region Brodmann area Volume (mm3) Peak t score Peak coordinates

Suicidal Ideation
Left superior frontal gyrus 9 2200 3.84 −22, 40, 38
3.74 −16, 54, 40
Left medial frontal gyrus 9 3.73 −4, 40, 28
Right middle frontal gyrus 10 528 3.72 34, 54, 4
Left medial frontal gyrus 10 1152 3.48 −12, 44, 14
3.40 −2, 55, 12
3.36 −12, 48, 12
Right medial frontal gyrus 10 1624 3.40 6, 50, 10
3.32 15, 42, 15
Right dorsal anterior cingulate gyrus 24 440 3.38 10, 0, 44
32 3.37 15, 4, 42

Intensity of Ideation
Left superior frontal gyrus 9 6184 5.10 −26, 50, 40
4.53 −20, 42, 38
4.28 −20, 52, 38
4.10 −8, 54, 40
Left medial frontal gyrus 10 4.00 −12, 48, 12
Left middle frontal gyrus 6 968 4.57 −26, −12, 58
4.48 −30, −8, 50
Right dorsal anterior cingulate gyrus 32 920 4.52 16, 8, 40
4.29 15, 4, 42
Right middle frontal gyrus 10 712 4.21 36, 56, 4
Right dorsal anterior cingulate gyrus 32 2200 4.18 6, 46, 12
Right superior frontal gyrus 6 896 4.13 24, −6, 58
Left medial frontal gyrus 6 1448 4.04 −8, −14, 62
4.04 −8, 0, 50
32 3.74 −10, 10, 52
Right precentral gyrus 6 1224 3.80 38, −8, 38
3.57 48, −5, 32
Left inferior frontal gyrus 44 352 3.77 −42, 8, 10
Right superior frontal gyrus 8 256 3.59 24, 42, 52
Left middle frontal gyrus 9 456 3.55 −36, 8, 40
Right dorsal anterior cingulate gyrus 32 464 3.50 4, 32, 30
Right middle frontal gyrus 9 560 3.33 34, 26, 40
Right inferior frontal gyrus 45 248 3.09 48, 24, 8

Suicidal Behavior
Left middle frontal gyrus (dorsal premotor cortex) 6 280 4.58 −16, −10, 66
 M.J. Minzenberg et al. / Schizophrenia Research 157 (2014) 19–25
Fig. 1. SPM depicting frontal brain regions where lower activation during goal-representation is associated with lifetime worst-point suicidal ideation in recent-onset schizophrenia. Map
rendered at p b 0.005 and frontal clusters corrected to p b 0.05.
negative in sign, indicating that higher suicide risk scores were associat-
ed with relatively lower goal-related activity. With the Suicidal Behavior
scale (Table 2 and Fig. 3), among those subjects who reported past sui-
cidal ideation, additional positive past report of suicidal behavior was
inversely associated with brain activation during goal-representation
in the left dorsal premotor cortex, ipsilateral to primary motor cortex
that was active during task performance.
4. Discussion
This study represents a first effort to test a contemporary model of
prefrontal cortical function, derived from a cognitive neuroscience per-
spective, to understand how frontal dysfunction may underpin suicide
risk in patients with schizophrenia. We found several frontal sectors
that showed strong relationships between neural activity and measures
of suicide risk. Importantly, these associations were independent of the
major established clinical risk factors for suicide in these groups, includ-
ing depression, impulsivity and psychosis, which themselves are associ-
ated with disturbed brain function. It therefore appears that the present
findings identify brain dysfunction that directly relates to suicide risk in
these patients.
The schizophrenia group showed clear associations of suicidal
ideation with impaired goal-representation in several frontal regions
that have been implicated in both a meta-analysis of functional neuro-
imaging studies of PFC-dependent task performance by schizophrenia
patients (Minzenberg et al., 2009), as well as in a recent paper from
our group that reported a subset of the present sample, in comparison
to a matched healthy control group (Lesh et al., 2013). These results
suggest that the failure to maintain a proper context for action, with
23
the rule-representation that supports this function mediated by
frontal-based networks, may lead to repeated goal-failure as a contrib-
utor to suicidal thoughts in patients with schizophrenia.
In schizophrenia patients such as the sample under study, disrup-
tions in goal-representation may lead to failures to select the thoughts,
emotions, and behaviors necessary to attain these goals. These cognitive
failures could have a cumulative effect over time, leading to suicidal
thoughts and behaviors, perhaps in a manner analogous to how chronic
unremitting depression or physical pain culminates in suicidal thoughts
and behaviors in other clinical populations. In contrast, a more time-
independent scenario could be manifest as isolated “moments in time”
when the profound lack of experienced self-efficacy of thoughts, emo-
tions or behaviors (due to PFC dysfunction) triggers suicidal thoughts
or actions, perhaps in an automatic, associative manner. While these
might also occur with less severely ill populations (e.g. those with anx-
iety disorders) under certain (typically highly stressful) circumstances,
schizophrenia patients may be relatively less capable of “unselecting”
these thoughts or actions as an expression of intact self-regulation.
While this account is somewhat speculative, these various phenomena
(e.g. stress-response, self-regulation and agency) are also distinctly
related to control processes, and highly-dependent on the PFC
(Haggard, 2005; Maier et al., 2006; Arnsten, 2011). Heterogeneity in
the PFC regions/circuits subserving these psychological functions
could then form the basis for considerable clinical variation in suicide
phenomenology observed across disorders as diverse as psychotic
disorders, late-life depression, chronic pain, personality disorders and
impulse control disorders.
Interestingly, the analysis restricted to patients with past suicidal
ideation revealed that past suicidal behavior was specifically associated
24 M.J. Minzenberg et al. / Schizophrenia Research 157 (2014) 19–25
Fig. 2. SPM depicting frontal brain regions where lower activation during goal-representation is associated with lifetime worst-point intensity of suicidal ideation in recent-onset
schizophrenia. Map rendered at p b 0.005 and frontal clusters corrected to p b 0.05.
Fig. 3. SPM depicting region in left dorsal premotor cortex where lower activation during
goal-representation is associated with lifetime suicidal behavior in recent-onset
schizophrenia. Map rendered at p b 0.005 and frontal cluster corrected to p b 0.05.
with impaired control-related activity in dorsal premotor cortex, above
that of suicidal ideation alone. Premotor cortex subserves complex
aspects of action control, such as planning, selection and online control
of action (Scott, 2004; Chouinard and Paus, 2006; Hoshi and Tanji,
2007). This suggests that, among those who experience conscious
thoughts of suicide, an important threshold for conversion to overt
suicide-related behavior may be disturbances in premotor mediation
of these higher-order aspects of action control. Premotor function
could then constitute a specific anatomic target for the remediation
of overt suicidal behavior, as distinct from interventions that target
suicidal ideation.
The present results also demonstrate more generally that testing
sophisticated models of PFC function in severely ill clinical populations
at risk for suicide is tractable, with potential to develop candidate
biomarkers to study novel interventions to mitigate suicide risk. There
is preliminary evidence that suicide risk may be lower with lithium
treatment in bipolar disorder (Baldessarini and Tondo, 2008) and cloza-
pine treatment in schizophrenia (Meltzer et al., 2003); however, even
for promising pharmacological (or psychological (Brown et al., 2005))
treatments, it remains essentially unknown what the neurobiological
mechanism might be that confers protection against suicide, especially
at the level of neural system function. The present study is limited in
the capacity to evaluate potential psychotropic medication effects on
the brain–behavior relationships observed here, though it is worth
mentioning that none of the patients were taking either lithium or clo-
zapine (at or prior to study). The issue of how lithium and clozapine
might act to mitigate suicide risk and whether other medications
(such as other atypical antipsychotics, and antidepressants) affect sui-
cide risk are important questions that warrant further study. Knowledge
 M.J. Minzenberg et al. / Schizophrenia Research 157 (2014) 19–25
of the sites and mechanisms of brain circuit dysfunctions which confer
suicide risk is critical to advance the development of treatments, both
biological and psychological, to mitigate this tragic, prevalent outcome.
Role of funding source
This work was supported by an American Foundation for Suicide Prevention Young
Investigator Award, and the Doris Duke Charitable Foundation Grant # 2009045, both to
MJM, and MH059883 to CSC.
Contributors
MJM and CSC designed the study and wrote the protocol. TAL, TAN and RNR managed
the data acquisition. MJM managed the literature searches. MJM, JHY and RNR undertook
the statistical analysis, and MJM wrote the first draft of the manuscript. All authors
contributed to and have approved the final manuscript.
Conflicts of interest
The authors have no conflicts to declare.
Acknowledgments
We thank Madison Titone, BA, Sandra Garcia, BA, and Taylor Salo, BS for their
assistance with the study data acquisition and management.
References
Aguilar, E.J., Garcia-Marti, G., Marti-Bonmati, L., Lull, J.J., Moratal, D., Escarti, M.J., Robles,
M., Gonzalez, J.C., Guillamon, M.I., Sanjuan, J., 2008. Left orbitofrontal and superior
temporal gyrus structural changes associated to suicidal behavior in patients with
schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1673–1676.
Amen, D.G., Prunella, J.R., Fallon, J.H., Amen, B., Hanks, C., 2009. A comparative analysis of
completed suicide using high resolution brain SPECT imaging. J. Neuropsychiatry Clin.
Neurosci. 21 (4), 430–439.
Arnsten, A.F., 2011. Prefrontal cortical network connections: key site of vulnerability in
stress and schizophrenia. Int. J. Dev. Neurosci. 29 (3), 215–223.
Audenaert, K., Goethals, I., Van Laere, K., Lahorte, P., Brans, B., Versijpt, J., et al., 2002.
SPECT neuropsychological activation procedure with the Verbal Fluency Test in
attempted suicide patients. Nucl. Med. Commun. 23 (9), 907–916.
Badre, D., 2008. Cognitive control, hierarchy, and the rostro-caudal organization of the
frontal lobes. Trends Cogn. Sci. 12 (5), 193–200.
Baldessarini, R.J., Tondo, L., 2008. Lithium and suicidal risk. Bipolar Disord. 10 (1),
114–115.
Beck, A.T., Brown, G.K., Steer, R.A., Dahlsgaard, K.K., Grisham, J.R., 1999. Suicide ideation at
its worst point: a predictor of eventual suicide in psychiatric outpatients. Suicide Life
Threat. Behav. 29 (1), 1–9.
Botvinick, M.M., Braver, T.S., Barch, D.M., Carter, C.S., Cohen, J.D., 2001. Conflict monitoring
and cognitive control. Psychol. Rev. 108 (3), 624–652.
Brown, G.K., Ten Have, T., Henriques, G.R., Xie, S.X., Hollander, J.E., Beck, A.T., 2005.
Cognitive therapy for the prevention of suicide attempts: a randomized controlled
trial. JAMA 294 (5), 563–570.
Chouinard, P.A., Paus, T., 2006. The primary motor and premotor areas of the human
cerebral cortex. Neuroscientist 12, 143–152.
Dutta, R., Murray, R.M., Hotopf, M., Allardyce, J., Jones, P.B., Boydell, J., 2010. Reassessing
the long-term risk of suicide after a first episode of psychosis. Arch. Gen. Psychiatry
67 (12), 1230–1237.
Goldsmith, S.K., Institute of Medicine (U.S.), 2002. Committee on pathophysiology & preven-
tion of adolescent & adult suicide. Reducing Suicide: A National ImperativeNational
Academies Press, Washington, D.C.
Haggard, P., 2005. Conscious intention and motor cognition. Trends Cogn. Sci. 9 (6),
290–295.
Hawton, K., van Heeringen, K., 2009. Suicide. Lancet 373 (9672), 1372–1381.
Hoshi, E., Tanji, J., 2007. Distinctions between dorsal and ventral premotor areas: anatomical
connectivity and functional properties. Curr. Opin. Neurobiol. 17, 234–242.
Joiner Jr., T.E., Steer, R.A., Brown, G., Beck, A.T., Pettit, J.W., Rudd, M.D., 2003. Worst-point
suicidal plans: a dimension of suicidality predictive of past suicide attempts and
eventual death by suicide. Behav. Res. Ther. 41 (12), 1469–1480.
Jollant, F., Lawrence, N.S., Olie, E., O'Daly, O., Malafosse, A., Courtet, P., et al., 2010.
Decreased activation of lateral orbitofrontal cortex during risky choices under
25
uncertainty is associated with disadvantageous decision-making and suicidal
behavior. NeuroImage 51 (3), 1275–1281.
Koechlin, E., Ody, C., Kouneiher, F., 2003. The architecture of cognitive control in the
human prefrontal cortex. Science 302 (5648), 1181–1185.
Lesh, T.A., Niendam, T.A., Minzenberg, M.J., Carter, C.S., 2011. Cognitive control deficits in
schizophrenia: mechanisms and meaning. Neuropsychopharmacology 36 (1),
316–338.
Lesh, T.A., Westphal, A.J., Niendam, T.A., Yoon, J.H., Minzenberg, M.J., Ragland, J.D.,
Solomon, M., Carter, C.S., 2013. Proactive and reactive cognitive control and dorsolateral
prefrontal cortex dysfunction in first episode schizophrenia. Neuroimaging Clin. N. Am.
2, 590–599.
Maier, S.F., Amat, J., Baratta, M.V., Paul, E., Watkins, L.R., 2006. Behavioral control, the
medial prefrontal cortex, and resilience. Dialogues Clin. Neurosci. 8 (4), 397–406.
Mann, J.J., 2003. Neurobiology of suicidal behavior. Nat. Rev. 4, 819–828.
Meltzer, H.Y., Alphs, L., Green, A.I., Altamura, A.C., Anand, R., Bertoldi, A., et al., 2003.
Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention
Trial (InterSePT). Arch. Gen. Psychiatry 60 (1), 82–91.
Miller, E.K., Cohen, J.D., 2001. An integrative theory of prefrontal cortex function. Annu.
Rev. Neurosci. 24, 167–202.
Minzenberg, M.J., Laird, A.R., Thelen, S., Carter, C.S., Glahn, D.C., 2009. Meta-analysis of 41
functional neuroimaging studies of executive function in schizophrenia. Arch. Gen.
Psychiatry 66 (8), 811–822.
Nielssen, O.B., Malhi, G.S., McGorry, P.D., Large, M.M., 2012. Overview of violence to
self and others during the first episode of psychosis. J. Clin. Psychiatry 73 (5),
e580–e587.
Nock, M.K., Borges, G., Bromet, E.J., Cha, C.B., Kessler, R.C., Lee, S., 2008. Suicide and suicidal
behavior. Epidemiol. Rev. 30, 133–154.
Owens, D., Horrocks, J., House, A., 2002. Fatal and non-fatal repetition of self-harm.
Systematic review. Br. J. Psychiatry 181, 193–199.
Pompili, M., Serafini, G., Innamorati, M., Lester, D., Shrivastava, A., Girardi, P., et al., 2011.
Suicide risk in first episode psychosis: a selective review of the current literature.
Schizophr. Res. 129 (1), 1–11.
Posner, K., Brown, G.K., Stanley, B., Brent, D.A., Yershova, K.V., Oquendo, M.A., et al., 2011.
The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency
findings from three multisite studies with adolescents and adults. Am. J. Psychiatry
168 (12), 1266–1277.
Reisch, T., Seifritz, E., Esposito, F., Wiest, R., Valach, L., Michel, K., 2010. An fMRI study on
mental pain and suicidal behavior. J. Affect. Disord. 126 (1-2), 321–325.
Rusch, N., Spoletini, I., Wilke, M., Martinotti, G., Bria, P., Trequattrini, A., et al., 2008.
Inferior frontal white matter volume and suicidality in schizophrenia. Psychiatry
Res. 164 (3), 206–214.
Scott, S.H., 2004. Optimal feedback control and the neural basis of volitional motor
control. Nat. Rev. Neurosci. 5, 532–546.
Shackman, A.J., Salomons, T.V., Slagter, H.A., Fox, A.S., Winter, J.J., Davidson, R.J., 2011. The
integration of negative affect, pain and cognitive control in the cingulate cortex. Nat.
Rev. Neurosci. 12 (3), 154–167.
Spoletini, I., Piras, F., Fagioli, S., Rubino, I.A., Martinotti, G., Siracusano, A., Caltagirone, C.,
Spalletta, G., 2011. Suicidal attempts and increased right amygdala volume in
schizophrenia. Schizophr. Res. 125, 30–40.
Strobel, A., Dreisbach, G., Muller, J., Goschke, T., Brocke, B., Lesch, K.P., 2007. Genetic
variation of serotonin function and cognitive control. J. Cogn. Neurosci. 19 (12),
1923–1931.
United States. Public Health Service, 2001. National Strategy for Suicide Prevention: Goals
and Objectives for Action: Summary. U.S. Dept. of Health and Human Services, Public
Health Service, Rockville, MD.
United States. Public Health Service: Office of the Surgeon General., 1999. The Surgeon
General's Call to Action to Prevent Suicide, 1999. Dept. of Health and Human Services,
U.S. Public Health Service, Washington, D.C.
Yoon, J.H., Minzenberg, M.J., Ursu, S., Ryan Walter, B.S., Wendelken, C., Ragland, J.D., et al.,
2008. Association of dorsolateral prefrontal cortex dysfunction with disrupted
coordinated brain activity in schizophrenia: relationship with impaired cognition,
behavioral disorganization, and global function. Am. J. Psychiatry 165 (8),
1006–1014.
Yurgelun-Todd, D.A., Bueler, C.E., McGlade, E.C., Churchwell, J.C., Brenner, L.A., Lopez-
Larson, M.P., 2011. Neuroimaging correlates of traumatic brain injury and suicidal
behavior. J. Head Trauma Rehabil. 26 (4), 276–289.
Zhang, H., Wei, X., Tao, H., Mwansisya, T.E., Pu, W., He, Z., Hu, A., Xu, L., Liu, Z., Shan, B.,
Xue, Z., 2013. Opposite effective connectivity in the posterior cingulate and medial
prefrontal cortex between first-episode schizophrenic patients with suicide risk and
healthy controls. PLoS One 8 (5), e63477.