Journal of Affective Disorders 181 (2015) 9–17

Contents lists available at ScienceDirect

Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Research report

Suicidal ideation is associated with reduced prefrontal activation during a verbal fluency task in patients with major depressive disorder Shenghong Pu a,n, Kazuyuki Nakagome b, Takeshi Yamada a, Katsutoshi Yokoyama a, Hiroshi Matsumura a, Sayaka Yamada a, Takuya Sugie a, Akihiko Miura a, Hideaki Mitani c, Masaaki Iwata a, Izumi Nagata a, Koichi Kaneko a a

Division of Neuropsychiatry, Department of Brain and Neuroscience, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japan National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8551, Japan c Division of Technical Support, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japan b

art ic l e i nf o

a b s t r a c t

Article history: Received 31 March 2015 Accepted 2 April 2015 Available online 11 April 2015

Background: Despite the known relationship between prefrontal function and increased suicidality during major depressive episodes, the links between prefrontal function and suicidality remain unclear in major depressive disorder (MDD). Suicidal ideation usually precedes a suicide attempt. If prefrontal cortex (PFC) activity is a biomarker for suicidal ideation in depression, monitoring it could be useful for suicide prevention. Therefore, in this study, we assessed the association between prefrontal function and suicidal ideation in MDD. Methods: Prefrontal function in 67 patients with MDD (31 with suicidal ideation and 36 without) and 67 age-, gender-, and intelligence quotient-matched healthy controls (HCs) was evaluated using nearinfrared spectroscopy (NIRS) during a verbal fluency task (VFT). Suicidal ideation was assessed using item 3 of the Hamilton Depression Rating Scale (HAMD). Results: Regional hemodynamic changes were significantly smaller in patients with MDD than in HCs in prefrontal and temporal regions. Hemodynamic changes in the right dorsolateral PFC (DLPFC), orbitofrontal cortex (OFC), and right frontopolar cortex (FPC) regions in patients with MDD with suicidal ideation were significantly smaller than in those without suicidal ideation. In addition, hemodynamic changes correlated negatively with the severity of suicidal ideation in the DLPFC, OFC, and FPC in patients with MDD. Limitations: Further studies with a larger sample size are required to verify our findings. Conclusions: These results suggest that the DLPFC, OFC, and FPC are brain substrates of suicidal ideation in depressive states in patients with MDD, and that NIRS data can be employed as a clinically useful biomarker for the assessment of suicide risk. & 2015 Elsevier B.V. All rights reserved.

Keywords: Major depressive disorder Near-infrared spectroscopy Suicidal ideation Prefrontal cortex Verbal fluency task

1. Introduction Suicidality is a serious public health problem, and approximately one million suicides and ten million suicide attempts occur worldwide each year (Hawton and van Heeringen, 2009; Mann, 2003; World Health Organization, 2014; Zhang et al., 2014). An extensive body of research suggests that suicidal behavior results from the complex interaction of numerous cumulative factors (Dieserud et al., 2001; O'Connor and Sheehy, 2001; Owen et al., 2015; Panagioti et al., 2013; Taylor et al., 2010; Wasserman et al., 2007). Therefore, a biopsychosocial conceptualization of suicidal behavior is utilized in many clinical settings (Hoffman, 2000; King and Merchant, 2008; O'Connor and

n

Corresponding author. Tel.: þ 81 859 38 6547; fax: þ 81 859 38 6549. E-mail address: [email protected] (S. Pu).

http://dx.doi.org/10.1016/j.jad.2015.04.010 0165-0327/& 2015 Elsevier B.V. All rights reserved.

Nock, 2014). Despite decades of clinical, scientific, and policy efforts aimed at improving methods for predicting and preventing suicide, the rates of suicidal thoughts and attempts have remained virtually unchanged (Kessler et al., 2005). Improving our ability to predict and subsequently to prevent suicide has become an important priority. However, the current assessment of suicide risk is based on numerous socio-demographic and clinical risk factors, often yielding a high sensitivity but low specificity (Mann and Currier, 2007). A persistent barrier encountered by clinicians is that current clinical assessment methods rely almost exclusively on self-report of suicidal thoughts and intentions. Use of specific neurobiological markers in addition to the clinical assessment, might improve the evaluation of suicide risk (Ding et al., 2015). Suicide may be preceded by suicidal ideation, and suicidal behavior never occurs without contemplation. Although suicidal ideation is predictive of future suicide attempts and death, only a

10

S. Pu et al. / Journal of Affective Disorders 181 (2015) 9–17

minority of all individuals who think about suicide make the decision to attempt (Klonsky and May, 2014; Gliatto and Rai, 1999; ten Have et al., 2009). Thoughts of suicide (i.e., suicidal ideation) are related to, but distinct from, acting on those thoughts (i.e., suicide attempts or behavior) (Klonsky and May, 2014). Suicidal ideation is a frequent and potentially life-threatening indication for psychiatric emergency services (Ting et al., 2012) and can be considered a first step on the pathway to suicide (Kachur et al., 1995). Therefore, study of suicidal ideation is important for gaining an understanding of the development of risk for attempt (Ballard et al., 2015). Marzuk et al. (2005) reported on the neuropsychological correlates of suicidality in MDD. They found that patients with current suicidal ideation performed significantly worse than patients without suicidal ideation on several executive tasks such as the Wisconsin Card Sorting Test. Marzuk et al. (2005) suggested that current suicidal ideation, regardless of history of suicide attempt, is associated with impaired executive function. Subsequently, Westheide et al. (2008) discovered that current suicidal ideation might be a stronger predictor of executive function deficits than the history of suicidal behavior in patients with MDD. Recently, Gujral et al. (2014) have suggested that among depressed older persons, those who have attempted suicide and those with no history of suicide attempt but with current suicidal ideation are similarly impaired in executive function. Thus, the presence of suicidal ideation could play an important role in the phenomenon of suicidality-associated executive dysfunction in patients with MDD (Westheide et al., 2008). Suicidal ideation is a common, core symptom of MDD (Iosifescu et al., 2008). In addition, many studies have demonstrated neuropsychological deficits in patients with MDD, with executive dysfunction being the most prominent (Austin et al., 2001; Hammar and Ardal, 2009). Executive dysfunction was related to both structural and functional changes in the prefrontal cortex (PFC) (Rogers et al., 2004). Considering the significant risk of suicidality in patients with MDD (Harris and Barraclough, 1997; Lekka et al., 2006; Nock et al., 2010; Schneider et al., 2006), elucidation of the relationship between the neural activity in the PFC that underlies executive function and suicidal ideation in patients with MDD is a worthwhile focus of study. A functional neuroimaging study showed blunted regional cerebral blood flow (rCBF) responses in the PFC during a verbal fluency task (VFT) in patients with MDD who had attempted suicide (Audenaert et al., 2002), consistent with the findings of structural neuroimaging studies (Cox Lippard et al., 2014). Moreover, impaired frontal rCBF responsiveness was found to predict attempts in a prospective assessment of suicide decedents (Willeumier et al., 2011). However, the suicide neuroimaging literature has predominately focused on individuals who have made prior suicide attempts but who may or may not have current suicidal ideation (Oquendo et al., 2003). Although this research is valuable for understanding individuals who engage in suicidal behavior, investigation of the neural correlates of active suicidal thought is also needed; understanding the biological pathways of suicidal ideation will accelerate the development of targeted treatments (Ballard et al., 2015). The primary objective of the present study was to investigate more precisely the relationship between the activity in the PFC associated with executive function and suicidal ideation in patients with MDD, using a multi-channel near-infrared spectroscopic (NIRS) imaging methodology. We hypothesized that patients with current suicidal ideation would have greater dysfunction in specific PFC regions than patients without suicidal thoughts. Furthermore, we hypothesized that the degree of dysfunction in those regions would correlate with the severity of current suicidal ideation.

2. Materials and methods 2.1. Subjects (Table 1) The participants were 67 patients (29 male, 38 female) diagnosed with MDD based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV, American Psychiatric Association, 1994) using the Mini-International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998). The patients were recruited from among the outpatients at Tottori University Hospital. None of the participants had clinical evidence of other major psychiatric, neurological, or medical disorders based on history and medical examination. Patients with previous head trauma, stroke, electroconvulsive therapy, or current or previous history of alcohol or drug abuse were excluded from the study. On the day of the NIRS experiment, patients with MDD were assessed for depression severity by two trained psychiatrists (TY, IN) using the Hamilton Rating Scale for Depression (HAMD) (Hamilton, 1960). All the patients with MDD were in a depressed mood state (17-item HAM-D score4 7). Daily doses of all antidepressants were converted to an equivalent dose of imipramine (Inagaki and Inada, 2006). Healthy individuals who were appropriate matches for the patients with MDD with respect to age, gender, and premorbid intelligence quotient (IQ) participated in the present study as controls. Premorbid IQ was estimated using the Japanese version of the National Adult Reading Test (Matsuoka et al., 2006). Inclusion criteria for controls were similar to those for the patient sample, although controls were also required to have no previous or current psychiatric illnesses. Sixty-seven individuals (29 male, 38 female) meeting these criteria were selected to participate in the study. All participants were right-handed by the criterion of scoring above 80% on the Edinburgh Inventory Index (Oldfield, 1991) and were native speakers of Japanese. All participants gave their consent on a written form after receiving a comprehensive explanation of the study protocol. The study was approved by the Ethics Committee of Tottori University Faculty of Medicine and the investigation was carried out in accordance with the latest version of the Declaration of Helsinki. 2.2. Suicidal ideation Suicidal ideation was measured on a scale of 0  4 using the suicide item (item 3) from the HAMD. Individuals receiving a score of 0 were considered to have “no suicidal ideation.” Scores of 1 or above were taken to indicate its presence. This cutoff value has been commonly used in previous studies (Ballard et al., 2015; Park et al., 2014). Participants with MDD were subdivided into two groups according to the presence or absence of suicidal ideation. 2.3. NIRS methodology The 52-channel NIRS (ETG-4000, Hitachi Medical Co.) machine measures relative changes in oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) at two wavelengths (695 and 830 nm) of infrared light based on the modified Beer–Lambert law (Yamashita et al., 1996). In this system, the Hb values include a differential path length factor (DPF). The DPF variation in the forehead region of adult humans is roughly homogeneous (Zhao et al., 2002; by Monte Carlo simulation). The distance between source and detector in source–detector pairs of probes was set at 3 cm, and each measuring area located between the source and detector of one pair was defined as a “channel” (ch). The machine measures points at a depth of 2–3 cm below the scalp, which corresponds to the surface of the cerebral cortex (Okada and Delpy,

S. Pu et al. / Journal of Affective Disorders 181 (2015) 9–17

2003; Toronov et al., 2001). The probes of the NIRS machine were placed on the frontotemporal region of each participant, with the midcolumn of the probe located over Fpz and the lowest probes located along the T3-Fp1-Fpz-Fp2-T4 line, in accordance with the International 10–20 System used in electroencephalography. The probe arrangement enabled the measurement of Hb values from the surface regions of both the PFC (dorsolateral PFC, DLPFC; ventrolateral PFC, VLPFC; orbitofrontal cortex, OFC; and frontopolar cortex, FPC) and temporal cortex. The correspondence between the NIRS channels and cortical anatomy has been confirmed in a multisubject study of anatomical craniocerebral correlations (Okamoto et al., 2004). The spatial information from each channel was estimated using functions from the Functional Brain Science Laboratory at Jichi Medical University in Japan (http://www.jichi. ac.jp/brainlab/virtual_reg.html) (Tsuzuki et al., 2007). The sampling frequency was 10 Hz. To examine VFT-related activation, data were analyzed using the “integral mode” installed on the NIRS machine, in which the pre-task baseline was determined as the mean over the 10-s period just prior to the task period, and the post-task baseline was determined as the mean over the 5-s period after the 50-s post-task period. Linear fitting was applied to the data recorded between these two baselines. A moving-average method, using a 5-s window, was applied to remove any short-term motion artifacts. In addition, we rejected noise related to body-movement artifacts (no signal, high frequency, and low frequency) using the algorithm published in Takizawa et al. (2008). 2.4. The activation task The task procedure in the present study was similar to that of Takizawa et al. (2008). Hb changes were measured during the VFT (letter version). The VFT was chosen because it has often been used for cognitive activation in NIRS studies, and because previous reports described measurable prefrontal activation in healthy participants during the letter fluency task (Herrmann et al., 2003, 2006; Kameyama et al., 2004). Each subject sat in a comfortable chair during the NIRS measurements, and to avoid artifacts was instructed to minimize movement such as head movements, strong biting, and eye blinking. The 160-s blockdesign VFT contained three different periods: a 30-s pre-task period, a 60-s task period, and a 70-s post-task period (Fig. 1). For the pre- and post-task baseline periods, participants were instructed to repeat consecutively the five Japanese vowels (“a”, “i”, “u”, “e”, and “o”) aloud. The contrast between the verbal fluency condition and the vocalization condition was used to increase the specificity for verbal fluency of the readout from the NIRS. During the task period, participants were instructed to generate as many Japanese words beginning with a designated syllable as possible. The three sets of initial syllables (A; /to/, /se/, /o/, B; /a/, /ki/, /ha/, C; /na/, /i/, /ta/) were presented in counterbalanced order among the participants and each syllable changed every 20s during the 60-s task. The total number of correct words generated during the VFT was adopted as the measure of task

11

performance. Simultaneously, we measured changes in oxy-Hb and deoxy-Hb. We used the mean changes in oxy-Hb (as opposed to deoxy-Hb) measured during the VFT as an index of cortical activity because oxyHb better reflects this activity and because it demonstrates stronger correlations with blood oxygenation level-dependent (BOLD) signals as measured by fMRI (Hoshi et al., 2001; Strangman et al., 2002). 2.5. Statistical analysis Statistical analyses were performed using SPSS 19.0 software (Tokyo, Japan). Categorical variables were compared using the chisquare test. In all groups, the clinical variables that fit the normal distribution were compared using t-tests and one-way analysis of variance (ANOVA), while the Mann-Whitney U-test and Kruskal  Wallis nonparametric ANOVA were used for clinical variables that were not normally distributed. Mean oxy-Hb changes were compared using one-way ANOVA for each channel. Post hoc Gams–Howell tests were performed on channels showing responses to the task condition that reached significance. To examine the relationships between mean oxy-Hb changes and suicidal ideation (item 3 of the HAMD) in the MDD group, we calculated Spearman’s rho correlation coefficients. We adopted a false discovery rate (FDR)-based procedure for correcting for multiple testing in the between-groups comparisons and in the correlational analyses of the 52 channels, and identified channels for which the rho values reached an FDR-corrected significance level of p o0.05. We set the value of q specifying the maximum FDR to 0.05 so that no more than 5% of channels were false positive on average (Benjamini and Yekutieli, 2001; Singh and Dan, 2006; Tomioka et al., 2015).

3. Results 3.1. Demographic and clinical characteristics of the study groups Table 1 summarizes the demographic and clinical characteristics of the study groups. There were no differences among the groups with respect to any demographic or clinical characteristic (p 40.05). In addition, there was no difference between groups in the average number of words generated during the VFT (F ¼0.759, p¼ 0.470). 3.2. Mean oxy-Hb changes during the VFT in patients with MDD Patients with MDD exhibited significantly smaller increases in oxyHb during the task than did HCs in fifty of fifty-two channels (ch1, ch3, ch4, and ch6 to ch52; FDR-corrected po0.05), which were predominantly in the prefrontal and temporal regions (Fig. 2). 3.3. Demographic and clinical characteristics of patients with MDD with and without suicidal ideation Table 2 summarizes the demographic and clinical characteristics of the patients with MDD, with and without suicidal ideation. No differences were found between groups with respect to any demographic variable (p4 0.05). 3.4. Mean oxy-Hb changes during the VFT in patients with MDD with and without suicidal ideation

Fig. 1. The task design of the verbal fluency task (VFT).

In 48 channels, ANOVA revealed significant differences among the three study groups in changes in mean oxy-Hb induced by the VFT (ch2, ch4, ch6, ch8 to ch10, and

12

S. Pu et al. / Journal of Affective Disorders 181 (2015) 9–17

Table 1 Demograpshics and clinical characteristics of participants. Demographics

Major depressive disorder (n ¼67) (mean7 SD)

Healthy controls (n¼67) (mean 7SD)

Statistics

P value

Age (years) Gender, women/men Education, years Estimated premorbid IQ Edinburg handedness inventory (%) Duration of illness (months) HAMD Task performancea Antidepressant dose (mg/day)b

58.17 16.0 38/29 12.4 7 2.7 98.9 7 13.0 96.6 7 11.4 31.9 7 52.8 18.2 7 6.0 12.2 7 4.3 42.17 58.3

58.1 717.8 38/29 13.0 7 2.9 101.5 79.8 97.9 7 6.3 – – 13.17 4.6 –

U ¼2199 X2 ¼0 U ¼1981 U ¼2036 U ¼2213 – – t (df ¼132) ¼-1.132 –

0.839 1.000 0.227 0.353 0.795 – – 0.260 –

HAMD, 17-item Hamilton Depression Rating Scale. a b

The number of words generated in the verbal fluency task. Imipramine-equivalent dose.

Fig. 2. Task-related prefrontal cortex activation. Above: Brain area in yellow corresponds to the near-infrared spectroscopy (NIRS) channels with significantly lower levels of activation in the major depressive disorder (MDD) than in the healthy controls (HCs) (false discovery rate [FDR]-corrected p o 0.05). The locations of NIRS channels were probabilistically estimated and anatomically labeled in the standard Montreal Neurological Institute brain space in accordance with Tsuzuki et al. (2007). Below: Grandaveraged waveforms of oxygenated hemoglobin (oxy-Hb) changes during the VFT (the period between the two dotted vertical lines in each graph) in 52 channels over prefrontal and temporal regions as measured by NIRS. Red and blue lines represent MDD and HCs, respectively. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

ch12  ch52; FDR-corrected p: 0.001  0.045). The channels were in the PFC (DLPFC, VLPFC, OFC, and FPC) and in temporal regions. The details of post-hoc analysis are shown in Fig. 3. This analysis indicated that in 42 channels (ch2, ch6, ch8 to ch10, ch12 to ch21, ch24 to ch29, ch31, ch32, and ch34  52) in the PFC (all sub regions mentioned above) and temporal regions, the increase in mean oxy-Hb changes induced by the VFT was significantly smaller in patients with MDD with suicidal ideation than in HCs (Fig. 3A). The post-hoc analysis

also showed that in 25 channels (ch14, ch15, ch19 to ch21, ch24, ch25, ch28, ch29, ch31, ch32, ch34 to ch36, ch39  ch42, ch44  ch46, ch48  ch50, and ch52) in the PFC (all sub regions but only in right FPC) and temporal regions, the increase in mean oxy-Hb changes induced by the VFT was significantly smaller in patients with MDD without suicidal ideation than in HCs (Fig. 3B). Moreover, in six channels (ch25, ch35, ch36, ch46, ch48, and ch49) in the PFC (right DLPFC, OFC, and right FPC) the increase in mean oxy-Hb changes was significantly

S. Pu et al. / Journal of Affective Disorders 181 (2015) 9–17

13

Table 2 Demographic and clinical characteristics of patients with MDD with and without suicidal ideation. Demographics

MDD with suicidal ideation (n¼ 31) (mean7 SD) MDD without suicidal ideation (n¼ 36) (mean 7 SD) Statistics

P value

Age (years) Gender, women/men Education, years Estimated premorbid IQ Edinburg handedness inventory (%) Duration of illness (months) HAMD Task performancea

57.3 7 15.7 20/11 12.17 2.5 99.4 7 12.5 93.8 7 15.6 27.3 740.1 19.7 75.2 11.9 7 4.5

58.7 7 16.5 18/18 12.6 7 2.9 98.4 7 13.6 98.9 7 4.6 35.97 62.0 16.9 76.4 12.5 7 4.1

0.855 0.232 0.448 0.757 0.081 0.772 0.062 0.611

Antidepressant dose (mg/day)b

44.0 7 75.3

40.5 7 49.4

U¼ 543 X2 ¼ 1.43 U¼ 500 t (df ¼65) ¼ 0.310 U¼ 480 U¼ 535 t (df ¼65) ¼ 1.899 t (df ¼65) ¼  0.512 U¼ 482

0.294

MDD, Major Depressive Disorder; HAMD, 17-item Hamilton Depression Rating Scale. a b

The number of words generated in the verbal fluency task. Imipramine-equivalent dose.

Fig. 3. 3D topographic maps of mean oxy-Hb changes in prefrontal cortex sub-regions Study groups were patients with MDD with and without suicidal ideation, and healthy controls (HCs). The brain area in yellow corresponds to the NIRS channels with significantly smaller mean oxy-Hb changes in the patients with MDD with suicidal ideation than the HCs (A), those in the patients with MDD without suicidal ideation vs. HCs (B), and those in patients with MDD with vs. without suicidal ideation (C). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

smaller in patients with MDD with suicidal ideation than in those without suicidal ideation (Fig. 3C). 3.5. Correlation between mean oxy-Hb changes and suicidal ideation in MDD In patients with MDD, the mean oxy-Hb changes showed a significant negative correlation with suicide ideation (item 3 of the

HAMD) scores in 11 channels (ch17, ch26, ch27, ch35, ch36, ch38, ch39, ch47  49, and ch51; FDR-corrected p o0.05; rho:  0.42 to  0.31), with the highest correlations located approximately in the DLPFC, OFC, and FPC regions (Fig. 4). The mean oxy-Hb changes did not show any significant correlation with task performance during VFT or with other clinical variables, such as age, education, estimated premorbid IQ, duration of illness, dose of antidepressant, or the HAMD scores of patients with MDD.

14

S. Pu et al. / Journal of Affective Disorders 181 (2015) 9–17

Fig. 4. Cortical distribution of the areas of significant correlation between mean oxy-Hb changes and suicidal ideation (item 3 of the HAMD). Above: Brain area in yellow corresponds to the NIRS channels in which mean oxy-Hb changes show significant correlation with suicidal ideation scores (item 3 of the HAMD; Spearman’s correlation coefficient; FDR-corrected p o 0.05). Below: Scatter diagrams showing the relationship item 3 of the HMAD scores and mean oxy-Hb changes in channels 35 (right DLPFC), 36 (right FPC), and 49 (left OFC). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

4. Discussion In this study, we measured Hb concentration changes in the PFC and temporal cortex during a VFT using 52-channel NIRS imaging. Our results showed that changes in mean oxy-Hb levels induced by the VFT were significantly smaller in patients with MDD than in age-, gender-, and IQ-matched HCs in the PFC and temporal regions. These results are in agreement with other NIRS studies (Herrmann et al., 2004; Kameyama et al., 2006; Noda et al., 2012; Ohta et al., 2008; Pu. et al., 2012; Suto et al., 2004; Tsujii et al., 2014; Akashi et al., 2015) and with other neuroimaging studies (Mayberg et al., 1994; Okada et al., 2003). Our study also found significant differences in changes in mean oxy-Hb levels among patients with MDD with and without suicidal ideation in the right DLPFC, OFC, and right FPC regions, where differences had also been observed between the patients with MDD and HCs. Furthermore, in the patients with MDD in our study, significant negative correlations were observed between changes in mean oxy-Hb levels induced by the VFT and the scores for the items on suicidal ideation in the HAMD, in the DLPFC, OFC, and FPC regions. These results suggest that the functions of the DLPFC, OFC, and FPC regions are associated with suicidal ideation in patients with MDD and that NIRS is an efficient medical tool for monitoring these characteristics. To our knowledge, this is the first study to report an association between NIRS imaging and suicidal ideation in patients with MDD. The majority of articles on suicidal risk in depressive patients have noted a close relationship between deficits in executive function and MDD. For example, a preliminary study revealed deficits in executive functions linked to the PFC in depressed patients with suicidal behavior (Keilp et al., 2001), and poor performance on tests of executive function, attention, and memory was associated with suicidal behavior in late-life depression

(Nordentoft, 2007). Raust et al. (2007) demonstrated significant executive function deficits in patients with suicidal risk, which were consistent with prefrontal dysfunction. Marzuk et al. (2005) suggested that current suicidal ideation, regardless of history of suicide attempt, may be associated with impaired executive function. The presence of suicidal ideation could reflect a cognitive rigidity underlying executive impairment (Westheide et al., 2008). The present study demonstrated an interesting relationship among neural activities in the DLPFC, OFC, and FPC regions, and suicidal ideation. The PFC governs the executive control of information processing and behavioral expression, including the ability to selectively attend to and maintain information, inhibit irrelevant stimuli, and evaluate and select the appropriate response (Knight et al., 1995; Miller and Cohen, 2001). In addition, evidence indicates that the DLPFC is associated with complex cognition such as controlled attention, working memory, cognitive flexibility, strategic memory, conceptual reasoning, anticipation, goal selection, planning, sequencing, monitoring, and use of feedback in task performance (Bonelli and Cummings, 2007; Rankin, 2007; Royall et al., 2002). The OFC participates in the executive control of information processing and behavioral expression by inhibiting neural activity associated with irrelevant, unwanted, or uncomfortable (e.g. painful) information, sensations, or actions (Shimamura, 2000), and plays a main role in decision-making and predicting expected outcomes (Monkul et al., 2007). Recent developments point towards the FPC as an area of interest in the integration of executive control functions (Stuss, 2007), which plays a key role in coordinating and integrating information from other PFC sub regions (Koechlin et al., 1999; Ramnani and Owen, 2004). A SPECT study found blunted PFC rCBF responses during VFT in attempters with MDD (Audenaert et al., 2002), which is consistent with frontal findings in structural neuroimaging studies (Cox Lippard et al., 2014). Studies using structural MRI converge in

S. Pu et al. / Journal of Affective Disorders 181 (2015) 9–17

showing OFC gray matter decreases in attempters with MDD (Monkul et al., 2007). Additionally, a regional cerebral metabolic rate of glucose (rCMRglu) PET study reported right DLPFC hypometabolism in MDD attempters and in association with suicidal ideation (Sublette et al., 2013). Moreover, an fMRI study in men showed decreased left OFC activation associated with risky gambling task choices (Jollant et al., 2010). In one of the few studies examining internal states and thoughts of suicide, fMRI showed frontal (DLPFC and FPC) decreases during autobiographic recall of mental pain associated with previous attempts, and fronto-temporal (medial PFC, anterior cingulate cortex, and hippocampus) increases during recall of suicide actions (Reisch et al., 2010). These findings taken together suggest that reduced PFC (in particular, DLPFC, OFC, and FPC) activity may be associated with suicidal ideation in patients with MDD in depressive states. Our findings need to be interpreted within the context of the study limitations. First, multichannel NIRS has limited spatial resolution compared with fMRI and PET. However, a recent MRI– NIRS combination study, which used a probabilistic method for the registration of NIRS data into the Montreal Neurological Institute (MNI) coordinate space, suggested that the errors of spatial estimation, expressed as standard deviations, were approximately 10 mm (Okamoto and Dan, 2005; Tsuzuki et al., 2007). These results suggest that multichannel NIRS can roughly detect sub-regionspecific activation in the PFC. Second, because the present study is cross-sectional, these results may not be generalizable to all patients with MDD. Although longitudinal investigations are necessary to replicate these findings, this study should assist patients with MDD who may be at risk for suicidal ideation by underscoring the importance of regular assessment and treatment. Third, although we did not find any relationships between oxy-Hb signals and duration of illness or dosages of medication in the patients with MDD, most of them were chronic and medicated. Thus, to fully rule out medication effects, future studies are warranted using firstepisode and/or drug-naïve patients with MDD. Fourth, suicidal ideation was examined only with item 3 of the HAMD instead of with psychometric instruments specifically dealing with it. This item is not a well-validated or in-depth assessment of suicidality. Further findings might have emerged had we conducted a more indepth assessment of the three hypothesized domains of suicidality (i.e., cognitive, emotional, and behavioral) (Range and Antonelli, 1990). On the other hand, this nonintrusive, easily administered measure of suicidal ideation is useful in an initial screening (Ballard et al., 2015; Park et al., 2014).

5. Conclusion Despite these limitations, our study indicated that the patients with MDD had dysfunction in the prefrontal and temporal regions, and that patients with MDD with and without suicidal ideation can be distinguished by oxy-Hb activation in the right DLPFC, OFC, and right FPC regions. Moreover, hypofunction in the DLPFC, OFC, and FPC regions was associated with the severity suicidal ideation. Our findings suggest that the DLPFC, OFC, and FPC are brain substrates of suicidal ideation in patients with MDD. Further studies with a larger sample size are required to verify our findings. If confirmed, our work may allow investigators to evaluate the potential of NIRS as a neuroimaging biomarker for the assessment of suicide risk in patients with MDD.

Conflict of interest All the authors declare that they have no conflicts of interest with respect to this study or its publication.

15

Role of Funding source Funding agencies had no role in study delineation, data collection and analysis, decision to submit the paper to the present journal, or preparation of the manuscript.

Acknowledgement The authors thank all the participants in this study. The authors also thank the Hitachi Medical Corporation for providing us with technical advice. This study was supported by Intramural Research Grant (23-10 and 26-3) for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry (NCNP); and the Takeda Science Foundation (SP).

References Akashi, H., Tsujii, N., Mikawa, W., Adachi, T., Kirime, E., Shirakawa, O., 2015. Prefrontal cortex activation is associated with a discrepancy between selfand observer-rated depression severities of major depressive disorder: A multichannel near-infrared spectroscopy study. J. Affect. Disord. 174, 165–172. Audenaert, K., Goethals, I., VanLaere, K., Lahorte, P., Brans, B., Versijpt, J., Vervaet, M., Beelaert, L., VanHeeringen, K., Dierckx, R., 2002. SPECT neuropsychological activation procedure with the Verbal Fluency Test in attempted suicide patients. Nucl. Med. Commun. 23 (9), 907–916. American Psychiatric Association, 1994. Diagnostic and statistical manual of mental disorders (4th ed.). American Psychiatric Association, Washington DC (1994). Austin, M.P., Mitchell, P., Goodwin, G.M., 2001. Cognitive deficits in depression: possible implications for functional neuropathology. Br. J. Psychiatry 178, 200–206. Ballard, E.D., Lally, N., Nugent, A.C., Furey, M.L., Luckenbaugh, D.A., Zarate Jr., C.A., 2015. Neural correlates of suicidal ideation and its reduction in depression. Int. J. Neuropsychopharmacol. 18 (1), 1–6. Benjamini, Y., Yekutieli, D., 2001. The control of the false discovery rate in multiple testing under dependency. Ann. Stat. 29, 1165–1188. Bonelli, R.M., Cummings, J.L., 2007. Frontal-subcortical circuitry and behavior. Dialogues Clin. Neurosci. 9 (2), 141–151. Cox Lippard, E.T, Johnston, J.A, Blumberg, H.P., 2014. Neurobiological risk factors for suicide: insights from brain imaging. Am. J. Prev. Med 47 (3 Suppl. 2), S152–S162. Dieserud, G., Røysamb, E., Ekeberg, O., Kraft, P., 2001. Toward an integrative model of suicide attempt: a cognitive psychological approach. Suicide Life Threat Behav. 31 (2), 153–168. Ding, Y., Lawrence, N., Olié, E., Cyprien, F., le Bars, E., Bonafé, A., Phillips, M.L., Courtet, P., Jollant, F., 2015. Prefrontal cortex markers of suicidal vulnerability in mood disorders: a model-based structural neuroimaging study with a translational perspective. Transl. Psychiatry 24 (5), e516. http://dx.doi.org/10.1038/ tp.2015.1. Gliatto, M.F., Rai, A.K., 1999. Evaluation and treatment of patients with suicidal ideation. Am. Fam. Physician 59 (6), 1500–1506. Gujral, S., Dombrovski, A.Y., Butters, M., Clark, L., Reynolds 3rd, C.F., Szanto, K., 2014. Impaired executive function in contemplated and attempted suicide in late life. Am. J. Geriatr. Psychiatry 22, 811–819. Hamilton, M., 1960. A rating scale for depression. J. Nurol. Neurosurg. Psychiatry 23, 56–62. Hammar, A., Ardal, G., 2009. Cognitive functioning in major depression—a summary. Front. Hum. Neurosci 3, 26. Harris, E.C., Barraclough, B., 1997. Suicide as an outcome for mental disorders. A meta-analysis. Br. J. Psychiatry 170, 205–228. Hawton, K., van Heeringen, K., 2009. Suicide. Lancet 373 (9672), 1372–1381. Herrmann, M.J., Ehlis, A.C., Fallgatter, A.J., 2003. Frontal activation during a verbalfluency task as measured by near-infrared spectroscopy. Brain Res. Bull. 61 (1), 51–56. Herrmann, M.J., Ehlis, A.C., Fallgatter, A.J., 2004. Bilaterally reduced frontal activation during a verbal fluency task in depressed patients as measured by nearinfrared spectroscopy. J. Neuropsychiatry Clin. Neurosci. 16 (2), 170–175. Herrmann, M.J, Walter, A., Ehlis, A.C., Fallgatter, A.J., 2006. Cerebral oxygenation changes in the prefrontal cortex: effects of age and gender. Neurobiol. Aging 27 (6), 888–894. Hoshi, Y., Kobayashi, N., Tamura, M., 2001. Interpretation of near-infrared spectroscopy signals: a study with a newly developed perfused rat brain model. J. Appl. Physiol. 90 (5), 1657–1662. Hoffman, M.A., 2000. Suicide and hastened death: a biopsychosocial perspective. Couns. Psychol. 28, 561–572. Inagaki, A., Inada, T., 2006. Dose equivalence of psychotropic drugs: 2006-version. Jpn. J. Clin. Psychopharmacol. 9, 1443–1447 (in Japanese with English abstracts). Iosifescu, D.V., Greenwald, S., Devlin, P., Perlis, R.H., Denninger, J.W., Alpert, J.E., Fava, M., 2008. Pretreatment frontal EEG and changes in suicidal ideation during SSRI treatment in major depressive disorder. Acta. Psychiatr. Scand. 117 (4), 271–276. Jollant, F., Lawrence, N.S., Olie, E., O’Daly, O., Malafosse, A., Courtet, P., Phillips, M.L., 2010. Decreased activation of lateral orbitofrontal cortex during risky choices

16

S. Pu et al. / Journal of Affective Disorders 181 (2015) 9–17

under uncertainty is associated with disadvantageous decision-making and suicidal behavior. Neuroimage 51 (3), 1275–1281. Kachur, S.P., Potter, L.B., Powell, K.E., Rosenberg, M.L., 1995. Suicide: epidemiology, prevention, and treatment. Adolesc. Med. 6 (2), 171–182. Kameyama, M., Fukuda, M., Yamagishi, Y., Sato, T., Uehara, T., Ito, M., Suto, T., Mikuni, M., 2006. Frontal lobefunction in bipolar disorder: a multichannel nearinfrared spectroscopy study. Neuroimage 29, 172–184. Kameyama, M., Fukuda, M., Uehara, T., Mikuni, M., 2004. Sex and age dependencies of cerebral blood volume changes during cognitive activation: a multichannel near-infrared spectroscopy study. Neuroimage 22 (4), 1715–1721. Kessler, R.C., Berglund, P., Borges, G., Nock, M., Wang, P.S., 2005. Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990  1992 to 2001  2003. JAMA 293 (20), 2487–2495. Keilp, J.G., Sackeim, H.A., Brodsky, B.S., Oquendo, M.A., Malone, K.M., Mann, J.J., 2001. Neuropsychological dysfunction in depressed suicide attempters. Am. J. Psychiatry 158 (5), 735–741. King, C.A., Merchant, C.R., 2008. Social and interpersonal factors relating to adolescent suicidality: a review of the literature. Arch. Suicide. Res. 12 (3), 181–196. Klonsky, E.D., May, A.M., 2014. Differentiating suicide attempters from suicide ideators: a critical frontier for suicidology research. Suicide Life Threat Behav. 44 (1), 1–5. Knight, R.T., Grabowecky, M.F., Scabini, D., 1995. Role of human prefrontal cortex in attention control. Adv. Neurol. 66, 21–34. Koechlin, E., Basso, G., Pietrini, P., Panzer, S., Grafman, J., 1999. The role of the anterior prefrontal cortex in human cognition. Nature 399, 148–151. Lekka, N.P., Argyriou, A.A., Beratis, S., 2006. Suicidal ideation in prisoners: risk factors and relevance to suicidal behaviour. A prospective case-control study. Eur. Arch. Psychiatry Clin. Neurosci. 256 (2), 87–92. Mann, J.J., Currier, D., 2007. A review of prospective studies of biologic predictors of suicidal behavior in mood disorders. Arch. Suicide Res. 11 (1), 3–16. Mann, J.J., 2003. Neurobiology of suicidal behaviour. Nat. Rev. Neurosci. 4 (10), 819–828. Marzuk, P.M., Hartwell, N., Leon, A.C., Portera, L., 2005. Executive functioning in depressed patients with suicidal ideation. Acta Psychiatr. Scand. 112 (4), 294–301. Matsuoka, K., Uno, M., Kasai, K., Koyama, K., Kim, Y., 2006. Estimation of premorbid IQ in individuals with Alzheimer’s disease using Japanese ideographic script (Kanji) compound words: Japanese version of National Adult Reading Test. Psychiatry Clin. Neurosci. 60 (3), 332–339. Mayberg, H.S., Lewis, P.J., Regenold, W., Wagner Jr., H.N., 1994. Paralimbic hypoperfusion in unipolar depression. J. Nucl. Med. 35 (6), 929–934. Miller, E.K., Cohen, J.D., 2001. An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci. 24, 167–202. Monkul, E.S., Hatch, J.P., Nicoletti, M.A., Spence, S., Brambilla, P., Lacerda, A.L., Sassi, R.B., Mallinger, A.G., Keshavan, M.S., Soares, J.C., 2007. Fronto-limbic brain structures in suicidal and non-suicidal female patients with major depressive disorder. Mol. Psychiatry 12 (4), 360–366. Nock, M.K., Hwang, I., Sampson, N.A., Kessler, R.C., 2010. Mental disorders, comorbidity and suicidal behavior: results from the National Comorbidity Survey Replication. Mol. Psychiatry. 15 (8), 868–876. Noda, T., Yohida, S., Matsuda, T., Okamoto, N., Sakamoto, K., Koseki, S., Numachi, Y., Matsushima, E., Kunugi, H., Higuchi, T., 2012. Frontal and right temporal activations correlate negatively with depression severity during verbal fluency task: a multi-channel near-infrared spectroscopy study. J. Psychiatr. Res. 46 (7), 905–912. Nordentoft, M., 2007. Prevention of suicide and attempted suicide in Denmark. Epidemiological studies of suicide and intervention studies in selected risk groups. Dan. Med. Bull. 54 (4), 306–369. O'Connor, R., Nock, M.K., 2014. The psychology of suicidal behavior. Lancet Psychiatry 1, 73–85. O'Connor, R.C., Sheehy, N.P., 2001. State of the art: suicidal behavior. Psychology 14, 20–24 (BPS). Ohta, H., Yamagata, B., Tomioka, H., Takahashi, T., Yano, M., Nakagome, K., Mimura, M., 2008. Hypofrontality in panic disorder and major depressive disorder assessed by multi-channel near-infrared spectroscopy. Depress. Anxiety 25 (12), 1053–1059. Okada, E., Delpy, D.T., 2003. Near-infrared light propagation in an adult head model. II. Effect of superficial tissue thickness on the sensitivity of the near-infrared spectroscopy signal. Appl. Opt. 42, 2915–2922. Okada, G., Okamoto, Y., Morinobu, S., Yamawaki, S., Yokota, N., 2003. Attenuated left prefrontal activation during a verbal fluency task in patients with depression. Neuropsychobiology 47 (1), 21–26. Okamoto, M., Dan, H., Sakamoto, K., Takeo, K., Shimizu, K., Kohno, S., Oda, I., Isobe, S., Suzuki, T., Kohyama, K., Dan, I., 2004. Three-dimensional probabilistic anatomical cranio-cerebral correlation via the international 10 20 system oriented for transcranial functional brain mapping. Neuroimage 21, 99–111. Okamoto, M., Dan, I., 2005. Automated cortical projection of head-surface locations for transcranial functional brain mapping. Neuroimage 26, 18–28. Oldfield, R.C., 1991. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97–113. Oquendo, M.A., Placidi, G.P., Malone, K.M., Campbell, C., Keilp, J., Brodsky, B., Kegeles, L.S., Cooper, T.B., Parsey, R.V., van Heertum, R.L., Mann, J.J., 2003. Positron emission tomography of regional brain metabolic responses to a serotonergic challenge and lethality of suicide attempts in major depression. Arch. Gen. Psychiatry 60 (1), 14–22.

Owen, R., Gooding, P., Dempsey, R., Jones, S., 2015. A qualitative investigation into the relationships between social factors and suicidal thoughts and acts experienced by people with a bipolar disorder diagnosis. J. Affect. Disord. 176C, 133–140. Panagioti, M., Gooding, P., Taylor, P.J., Tarrier, N., 2013. A model of suicidal behavior in posttraumatic stress disorder (PTSD): the mediating role of defeat and entrapment. Psychiatry Res. 209 (1), 55–59. Park, Y.M., Lee, B.H., Lee, S.H., 2014. The association between serum lipid levels, suicide ideation, and central serotonergic activity in patients with major depressive disorder. J. Affect. Disord. 159, 62–65. Pu, S., Nakagome, K., Yamada, T., Yokoyama, K., Matsumura, H., Mitani, H., Adachi, A., Nagata, I., Kaneko, K., 2012. The relationship between the prefrontal activation during a verbal fluency task and stress-coping style in major depressive disorder: a near-infrared spectroscopy study. J. Psychiatr. Res. 46 (11), 1427–1434. Ramnani, N., Owen, A.M., 2004. Anterior prefrontal cortex: insights into function from anatomy and neuroimaging. Nat. Rev. Neurosci. 5, 184–194. Rankin, K.P., 2007. Social cognition in frontal injury. In: Miller, B.L., Cummings, J.L. (Eds.), The Human Frontal Lobes. Functions and Disorders. The Guilford Press, New York, pp. 345–360. Range, L.M., Antonelli, K.B., 1990. A factor analysis of six commonly used instruments associated with suicide suing college students. J. Pers. Assess. 55, 804–811. Raust, A., Slama, F., Mathieu, F., Roy, I., Chenu, A., Koncke, D., Fouques, D., Jollant, F., Jouvent, E., Courtet, P., Leboyer, M., Bellivier, F., 2007. Prefrontal cortex dysfunction in patients with suicidal behavior. Psychol. Med. 37 (3), 411–419. 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. Rogers, M.A., Kasai, K., Koji, M., Fukuda, R., Iwanami, A., Nakagome, K., Fukuda, M., Kato, N., 2004. Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence. Neurosci. Res. 50 (1), 1–11. Royall, D.R., Lauterbach, E.C., Cummings, J.L., Reeve, A., Rummans, T.A., Kaufer, D.I., LaFrance Jr, W.C., Coffey, C.E., 2002. Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association. J. Neuropsychiatry Clin. Neurosci. 14 (4), 377–405. Schneider, B., Wetterling, T., Sargk, D., Schneider, F., Schnabel, A., Maurer, K., Fritze, J., 2006. Axis I disorders and personality disorders as risk factors for suicide. Eur. Arch. Psychiatry Clin. Neurosci. 256 (1), 17–27. Shimamura, A.P., 2000. Toward a cognitive neuroscience of metacognition. Conscious Cogn. 9 (2 Pt 1), 313–323. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatic Interview M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59, 22–33. Singh, A.K., Dan, I., 2006. Exploring the false discovery rate in multichannel NIRS. Neuroimage 33, 542–549. Strangman, S., Culver, J.P., Thompson, J.H., Boas, D.A., 2002. A quantitative comparison of simultaneous BOLD fMRI and NIRS recording during functional brain activation. Neuroimage 17, 719–731. Stuss, D.T., 2007. New approaches to frontal lobe testing. In: Miller, B.L., Cummings, J.L. (Eds.), The Human Frontal Lobes. Functions and Disorders. The Guilford Press, New York, pp. 292–305. Sublette, M.E., Milak, M.S., Galfalvy, H.C., Oquendo, M.A., Malone, K.M., Mann, J.J., 2013. Regional brain glucose uptake distinguishes suicide attempters from nonattempters in major depression. Arch. Suicide Res. 17 (4), 434–447. Suto, T., Fukuda, M., Ito, M., Uehara, T., Mikuni, M., 2004. Multichannel nearinfrared spectroscopy in depression and schizophrenia: cognitive activation study. Biol. Psychiatry 55, 501–511. Takizawa, R., Kasai, K., Kawakubo, Y., Marumo, K., Kawasaki, S., Yamasue, H., Fukuda, M., 2008. Reduced frontopolar activation during verbal fluency task in schizophrenia: a multi-channel near-infrared spectroscopy study. Schizophr. Res. 99, 250–262. Taylor, P.J., Gooding, P.A., Wood, A.M., Johnson, J., Pratt, D., Tarrier, N., 2010. Defeat and entrapment in schizophrenia: the relationship with suicidal ideation and positive psychotic symptoms. Psychiatry Res. 178 (2), 244–248. Ting, S.A., Sullivan, A.F., Miller, I., Espinola, J.A., Allen, M.H., Camargo Jr., C.A., Boudreaux, E.D, Emergency Department Safety and Follow-up Evaluation (ED-SAFE) Investigators, 2012. Multicenter study of predictors of suicide screening in emergency departments. Acad. Emerg. Med. 19 (2), 239–243. ten Have, M., de Graaf, R., van Dorsselaer, S., Verdurmen, J., van ‘t Land, H., Vollebergh, W., Beekman, A., 2009. Incidence and course of suicidal ideation and suicide attempts in the general population. Can. J. Psychiatry 54 (12), 824–833. Tomioka, H., Yamagata, B., Kawasaki, S., Pu., S., Iwanami, A., Hirano, J., Nakagome, K., Mimura, M., 2015. A longitudinal functional neuroimaging study in medicationnaïve depression after antidepressant treatment. PLoS One 10 (3), e0120828. http://dx.doi.org/10.1371/journal.pone.0120828, eCollection 2015. Toronov, V., Webb, A., Choi, J.H., Wolf, M., Michalos, A., Gratton, E., Hueber, D., 2001. Investigation of human brain hemodynamics by simultaneous near-infrared spectroscopy and functional magnetic resonance imaging. Med. Phys. 28, 521–527. Tsujii, N., Akashi, H., Mikawa, W., Tsujimoto, E., Niwa, A., Adachi, T., Shirakawa, O., 2014. Discrepancy between self- and observer-rated depression severities as a

S. Pu et al. / Journal of Affective Disorders 181 (2015) 9–17

predictor of vulnerability to suicide in patients with mild depression. J. Affect. Disord. 161, 144–149. Tsuzuki, D., Jurcak, V., Singh, A.K., Okamoto, M., Watanabe, E., Dan, I., 2007. Virtual spatial registration of stand-alone fNIRS data to MNI space. Neuroimage 34, 1506–1518. Wasserman, D., Geijer, T., Sokolowski, M., Rozanov, V., Wasserman, J., 2007. Nature and nurture in suicidal behavior, the role of genetics: some novel findings concerning personality traits and neural conduction. Physiol. Behav. 92 (1  2), 245–249. Westheide, J., Quednow, B.B., Kuhn, K.U., Hoppe, C., Cooper-Mahkorn, D., Hawellek, B., Eichler, P., Maier, W., Wagner, M., 2008. Executive performance of depressed suicide attempters: the role of suicidal ideation. Eur. Arch. Psychiatry Clin. Neurosci. 258 (7), 414–421. Willeumier, K., Taylor, D.V., Amen, D.G., 2011. Decreased cerebral blood flow in the limbic and prefrontal cortex using SPECT imaging in a cohort of completed suicides. Transl. Psychiatry 1, e28.

17

World Health Organization, 2014. Suicide Prevention: The Mondial Emergency. Yamashita, Y., Maki, A., Ito, Y., Watanabe, E., Koizumi, H., 1996. Noninvasive nearinfraredtopography of human brain activity using intensity modulation spectroscopy. Opt. Eng. 35, 1046–1049. Zhang, H., Chen, Z., Jia, Z., Gong, Q., 2014. Dysfunction of neural circuitry in depressive patients with suicidal behaviors: a review of structural and functional neuroimaging studies. Prog. Neuropsychopharmacol. Biol. Psychiatry 53, 61–66. Zhao, H., Tanikawa, Y., Gao, F., Onodera, Y., Sassaroli, A., Tanaka, K., Yamada, Y., 2002. Maps of optical differential pathlength factor of human adult forehead, somatosensory motor and occipital regions at multi-wavelengths in NIR. Phys. Med. Biol. 47, 2075–2093.