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Diminished responses to bodily threat and blunted interoception in suicide attempters

  1. Danielle C DeVille
  2. Rayus Kuplicki
  3. Jennifer L Stewart
  4. Tulsa 1000 Investigators
  5. Martin P Paulus
  6. Sahib S Khalsa  Is a corresponding author
  1. Laureate Institute for Brain Research, United States
  2. Department of Psychology, The University of Tulsa, United States
  3. Oxley College of Health Sciences, The University of Tulsa, United States
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Cite this article as: eLife 2020;9:e51593 doi: 10.7554/eLife.51593

Abstract

Psychological theories of suicide suggest that certain traits may reduce aversion to physical threat and increase the probability of transitioning from suicidal ideation to action. Here, we investigated whether blunted sensitivity to bodily signals is associated with suicidal action by comparing individuals with a history of attempted suicide to a matched psychiatric reference sample without suicide attempts. We examined interoceptive processing across a panel of tasks: breath-hold challenge, cold-pressor challenge, and heartbeat perception during and outside of functional magnetic resonance imaging. Suicide attempters tolerated the breath-hold and cold-pressor challenges for significantly longer and displayed lower heartbeat perception accuracy than non-attempters. These differences were mirrored by reduced activation of the mid/posterior insula during attention to heartbeat sensations. Our findings suggest that suicide attempters exhibit an ‘interoceptive numbing’ characterized by increased tolerance for aversive sensations and decreased awareness of non-aversive sensations. We conclude that blunted interoception may be implicated in suicidal behavior.

eLife digest

The human brain closely monitors body signals essential for our survival, including our heartbeat, our breathing and even the temperature of our skin. This mostly unconscious process is called interoception. It helps people perceive potential or actual threats and helps them to respond appropriately. For example, a person charged by a wild animal will act instinctively to run, fight or freeze. Unlike most creatures, humans show an ability to counteract these survival instincts, and are capable of intentionally engaging in behaviors that result in physical harm. Recent increases in the rate of suicide have made it more urgent to try to understand what leads to this behavior in humans.

Now, DeVille et al. show that people with psychiatric disorders who have survived a suicide attempt have blunted interoception. In four experiments, people with a history of suicide attempts were compared to another group of individuals without a history of suicide attempts. The groups were carefully matched such that there were no significant differences in the demographic and clinical characteristics of the two groups, including in terms of their age, sex, body mass index and psychiatric symptoms.

Both groups completed uncomfortable tasks like holding their breath or keeping their hand in icy cold water. The participants also completed two tasks that required them to focus on their own heartbeat, one of which was paired with functional magnetic resonance imaging. Those with a history of suicide attempts held their breath and kept their hand in cold water for longer, and also were less in tune with their heart rate. This “interoceptive numbing” was associated with less activity in part of the brain called the insular cortex. These differences could not be explained by the individuals having a psychiatric disorder or a history of considering suicide, or by them taking psychiatric medications. Instead, the interoceptive numbing was most often seen in individuals who made an attempt on their own life.

The experiments identify physical characteristics that may differentiate people who attempt suicide from those who do not. This lays the groundwork for future research aimed at identifying biological indicators of suicide risk. More studies are needed to verify the results. If the results are verified, the next step would be prospective studies to determine whether measuring interoception can help clinicians predict who is at risk of a suicide attempt. If it does, it might give clinicians a new tool to try to prevent suicide by ensuring those at greatest risk receive appropriate care.

Introduction

Suicide ranks among the leading causes of death worldwide (World Health Organization, 2014). In the US alone, suicide increased by nearly 30 percent between 2000 and 2016 (World Health Organization, 2014; Hedegaard et al., 2018). For every death by suicide, it is estimated that there are 25 additional suicide attempts (Hedegaard et al., 2018), each associated with significant social, emotional, and financial consequences. Experts have strived to understand and prevent death by suicide for decades, and yet, our current scientific grasp of the factors that contribute to suicidal behavior is lacking. Moreover, epidemiological data suggest that we are no better at preventing death by suicide than we were 100 years ago (Hedegaard et al., 2018; United States Department of Commerce Bureau of the Census, 1920; Kessler et al., 2005; Nock et al., 2008), with suicide rates rising despite the application of prevention and intervention efforts (Linehan, 2008; Nock, 2016; Paris, 2006).

Theoretical models of suicide have invoked the concept of ‘suicidal capacity’ to differentiate the small subset of individuals who attempt suicide from the much larger group of individuals who experience suicidal ideation but never resort to suicidal action (Ribeiro and Joiner, 2009; Smith and Cukrowicz, 2010). A basic tenet of this concept is the notion that most human beings are ‘hard-wired’ for survival and thus driven to avoid physical pain and threats to bodily homeostasis. Psychological theories of suicide suggest that in an individual with heightened suicidal capacity, certain dispositional (Klonsky and May, 2015) and acquired (Van Orden et al., 2010; Van Orden et al., 2008) traits result in a lower aversion to physical threat and a higher likelihood of transitioning from suicidal ideation to action. Consistent with this line of thinking, non-suicidal self-injury (Klonsky and May, 2014; Franklin et al., 2011) and high levels of fearlessness of the pain involved in dying (May et al., 2012) are behavioral and clinical factors that have been reported to predict suicide attempts. Thus it seems possible that suicidal behavior might be influenced by one’s ability to access and respond adaptively to homeostatic information regarding the internal state of the body, but few studies have directly investigated this topic.

Interoception describes the nervous system’s process of sensing, interpreting, and integrating signals originating from inside the body (Craig, 2002; Khalsa et al., 2018). Emerging evidence suggests that dysfunctions of interoception may contribute to certain mental illnesses (Khalsa et al., 2018; Khalsa and Lapidus, 2016), including mood and anxiety disorders (Paulus and Stein, 2010; Avery et al., 2014; Barrett et al., 2016; Wiebking et al., 2015; Harshaw, 2015; Domschke et al., 2010), substance use disorders (Paulus and Stewart, 2014; Verdejo-Garcia et al., 2012), eating disorders (Kerr et al., 2016; Berner et al., 2018; Khalsa et al., 2015), and nonsuicidal self-injury (Muehlenkamp, 2012), all of which are associated with an elevated risk of suicide (Nock et al., 2010; Harris and Barraclough, 1997; Smith et al., 2018a). Interoception is thought to be substantially supported by the insular cortex, with the primary representation of visceral sensations occurring in the mid-to-posterior insula, and the integration of interoceptive information with cognition, emotion, and other higher order processes occurring in more anterior regions (Barrett and Simmons, 2015; Critchley and Harrison, 2013; Hassanpour et al., 2018).

To test the hypothesis that abnormalities of interoception are associated with suicidal capacity in individuals with psychiatric disorders, we evaluated interoceptive processing in participants with a history of suicide attempts as compared to a matched psychiatric reference sample of participants with no history of suicide attempts. We measured aversive interoceptive processing across the respiratory and nociceptive domains, via an inspiratory breath-hold challenge and a cold-pressor challenge. We assessed cardiac interoception during a heartbeat perception task as well as during a functional magnetic resonance imaging (fMRI) task involving focused attention to heartbeat sensations. We predicted that relative to non-attempters, suicide attempters would 1) tolerate aversive interoceptive sensations to a greater extent, 2) demonstrate lower interoceptive accuracy, and 3) exhibit differences in brain activity in the insular cortex when attending to interoceptive sensations.

Results

Demographic and clinical characteristics

We found that both participant groups were well-matched in terms of demographic and clinical characteristics, showing no significant differences in age, BMI, sex, diagnosis, or levels of self-reported depression, anxiety, substance use, or eating disorder symptoms (Table 1). We noticed that the groups showed a significant difference in their usage of psychotropic medication, with a greater proportion of the suicide attempters reporting taking such medications. We provide further details regarding our participants, including psychiatric diagnoses, use of psychotropic medications, missing data values, and scores on self-report measures in Appendix 1.

Table 1
Participant demographics and clinical characteristics.
Suicide attempters
(n = 34)
Non-attempters
(n = 68)
p
Demographics
Age, years31 (11)33 (10)0.40
BMI27.1 (6.3)28.6 (5.0)0.20
% Female56 (n = 19)70 (n = 47)0.27
Clinical Features
PHQ-912.1 (5.4)11.2 (5.7)0.42
PHQ-9 SI question0.5 (0.8)0.3 (0.5)0.12
OASIS9.2 (4.6)8.5 (4.2)0.47
DAST3.7 (4.2)3.5 (4.0)0.89
SCOFF1.7 (1.6)1.3 (1.4)0.16
% Medicated85 (n = 29)59 (n = 40)0.01
  1. Note: All values reported are in the format of Mean (SD) unless otherwise indicated.

    BMI = Body Mass Index; PHQ-9 = Patient Health Questionnaire; SI = Suicidal Ideation; OASIS = Overall Anxiety Severity and Impairment Scale; DAST = Drug Abuse Screening Test; SCOFF = Eating Disorders Screening Tool. All scores on clinical measures reflect total scores unless otherwise specified. For all clinical measures, higher numbers indicate greater endorsement of the construct assessed.

Breath-hold challenge

We found that suicide attempters held their breath for significantly longer than non-attempters, approximately 10 s longer on average across both trials (F (1, 121.84) = 4.48, p = 0.036, R2 = 0.042) (see Figure 1). We also observed a repetition effect, such that all participants held their breath longer during the second trial (F(1,97.01) = 20.18, p < 0.001, R2 = 0.173), replicating previous results with this task (Willem Van der Does, 1997). We did not find a significant interaction between group and trial. We report a summary of the Linear Mixed Effects (LME) output for the model examining breath-hold duration, including fixed effects estimates and standardized regression coefficients in Supplementary file 1.

Figure 1 with 1 supplement see all
Suicide attempters held their breath significantly longer than non-attempters during the inspiratory breath-hold challenge (approximately 10 s on average).

They also exhibited greater increases in carbon dioxide (CO2) and decreases in oxygen (O2). The mean breath-hold duration across the two trials is displayed below. Error bars indicate + / - 1 standard error, *p < 0.05.

Concordant with the increased breath-hold duration in suicide attempters, we found that suicide attempters had higher concentrations of exhaled carbon dioxide (CO2) than non-attempters after the breath-hold trials (F(1,120.33) = 5.52, p < 0.001, R2 = 0.043). However, we did not find an effect of trial or interaction between group and trial. We also found that suicide attempters had lower concentrations of exhaled oxygen (O2) following the breath-hold trials relative to non-attempters (F(1,132.27) = 5.00, p = 0.027, R2 = 0.036). We observed a significant main effect of trial (F(1,91.09) = 6.16, p = 0.015, R2 = 0.020), such that reductions in O2 were greater after the second breath-hold across both groups. We report summaries of the LME outputs for the O2 and CO2 models, including fixed effects estimates and standardized regression coefficients in Supplementary file 1.

Despite the prolonged breath-hold duration and elevations in CO2, we found that suicide attempters did not report any differences in perceived breathlessness (p = 0.70), feelings of suffocation (p = 0.95), fear of suffocation (p = 0.97), urge to breathe (p = 0.76), breathing sensation intensity (p = 0.53), unpleasantness (p = 0.63), task difficulty (p = 0.48), or effort expended during the breath-hold (p = 0.27) relative to non-attempters (Figure 1—figure supplement 1 ).

Cold-pressor challenge

We found that the cold-pressor challenge elicited increased pain ratings over time in both groups (F(3,276.16) = 86.78, p < 0.001, R2 = 0.589). However, this effect was qualified by a significant interaction between timepoint and group (F(3,277.39) = 2.89, p = 0.036, R2 = 0.030). On closer examination of the LME fixed effects, we observed that suicide attempters kept their hands submerged in the cold water for significantly longer than non-attempters after reaching their peak pain level (t(278.56) = 2.78, p = 0.006, β = 0.13), without any significant differences in the amount of time taken to reach mild, moderate, and peak pain levels (Figure 2). Overall, suicide attempters kept their hands submerged in the icy water for approximately 18 s longer than the non-attempters. We report fixed effects and model summary values in Supplementary file 2. Additionally, although suicide attempters provided slightly lower average ratings of unpleasantness, pain, difficulty, and stress than non-attempters, these differences were not statistically significant (unpleasantness: U = 1107, p = 0.117, FDR-p = 0.144, r = 0.16; pain: U = 1067, p = 0.122, FDR-p = 0.144, r = 0.15; difficulty: U = 1123, p = 0.090, FDR-p = 0.144, r = 0.17; stress: U = 1095, p = 0.144, FDR-p = 0.144, r = 0.15).

Suicide attempters exhibited significantly greater pain tolerance than non-attempters during the cold-pressor challenge.

However, they did not significantly differ in their retrospective ratings of overall pain, unpleasantness, difficulty, or stress experienced during the task. Error bars indicate + / - 1 standard error; *p < 0.05.

Heartbeat perception task

Our initial LME model examining heartbeat perception accuracy as a function of group, condition (i.e. guess, no-guess, and perturbation), and their interaction, showed a significant effect of condition (F(2,195.08) = 12.72, p < 0.001, R2 = 0.200). However, there was no significant effect of group and no group by condition interaction. By examining the fixed effects we noticed that, relative to guessing trials, accuracies on the no-guess (t(195.08) = −4.61, p < 0.001, β = −0.33) and breath-hold perturbation trials (t(195.07) = −4.013, p < 0.001, β = −0.29) were significantly lower.

We made a post-hoc decision to apply a second model that omitted the guessing score from the analysis, based on a recent study indicating that heartbeat perception accuracy scores are potentially confounded by guessing (Desmedt et al., 2018). For the second heartbeat perception model, we examined accuracy as a function of group and condition across the no-guess and breath-hold perturbation trials only (i.e. after omitting the ‘guess’ trial), and found a significant difference between groups (F(1,97.04) = 8.64, p = 0.004, R2 = 0.048) (Figure 3) and a significant interaction between group and trial (F(1,144.47) = 4.37, p = 0.04, R2 = 0.043). In particular, we found that suicide attempters exhibited lower heartbeat perception accuracy during the no-guess condition relative to non-attempters, t(144.46) = −2.94, p = 0.003, β = −0.29), and that the difference in accuracy between attempters and non-attempters was attenuated during the perturbation trial (t(97.73) = 2.09, p = 0.04, β = 0.14). We did not observe group differences in ratings of task confidence or difficulty across the no-guess and perturbation trials (Confidence: U = 1153.5, p = 0.453, FDR-p = 0.67, r = 0.08; Difficulty: U = 1014.5, p = 0.766, FDR-p = 0.767, r = 0.03). Suicide attempters displayed a tendency to rate their heartbeat sensations as less intense (U = 1345, p = 0.028), although this was non-significant after applying a Benjamini-Hochberg correction across contrasts (FDR-p = 0.084, r = 0.22) (Figure 3). We report fixed effects and model summary values in Supplementary file 3.

Suicide attempters exhibited significantly lower heartbeat perception accuracy than non-attempters during the no-guess and breath-hold perturbation conditions.

There were no perceived differences in reported in task difficulty or confidence in performance across the no-guess and perturbation conditions. Suicide attempters also provided lower ratings of heartbeat intensity across these conditions, although this was no longer significant after correction for multiple comparisons. Error bars indicate + / - 1 standard error; *p < 0.05, +p < 0.10.

Interoceptive attention task during fMRI

We also found that, relative to non-attempters, suicide attempters exhibited reduced BOLD activation in the right dorsal mid-insula and right posterior insula during interoceptive attention to the heartbeat versus the exteroceptive attention condition (p < 0.005, corrected at α <0.05; Figure 4). There was also a cluster of reduced BOLD activation within the left dorsal mid-insula, but this did not survive correction. The whole-brain analysis revealed four additional clusters with significantly reduced BOLD activation during attention to heart sensations among suicide attempters: one cluster within the right precuneus, one within the right superior temporal gyrus, one within the right posterior cingulate cortex, and one within the right dorsomedial prefrontal cortex (p < 0.0005, ACF corrected at α < 0.05; Table 2).

Suicide attempters exhibited lower blood oxygen level-dependent (BOLD) signal in the right posterior and mid insula than non-attempters during attention to heartbeat sensations (relative to the exteroceptive condition; p < 0.005, ACF corrected at α < 0.05).

Error bars indicate + / - 1 standard error.

Table 2
Brain regions exhibiting significantly decreased blood oxygen level-dependent (BOLD) signal during attention to heartbeat sensations relative to exteroceptive sensations in suicide attempters relative to non-attempters
LocationMNI CoordinatesPeak tVolume (mm3)
xyz
Right Dorsal Posterior Insula31−1915−3.7469
Right Dorsal Mid-Insula39-113−3.4352
Right Precuneus and Posterior Cingulate5−6127−4.81568
Right Superior Temporal Gyrus65−295−5.2784
Right Middle Cingulate Cortex11-745−5.0712
Right Superior Medial Gyrus15717−5.2544
  1. Note: A voxel-wise threshold of p < 0.005 was set for the insula, and a voxel-wise threshold of p < 0.0005 for the rest of the brain; all significant activations passed a cluster-size correction for multiple comparisons of α < . 05.

Correlations across interoceptive tasks and measures

We report exploratory correlations across all behavioral and neuroimaging variables in Appendix 1—figure 1.

Role of psychotropic medication status

We conducted additional analyses to examine potential confounding effects of medication status on our primary interoception variables of interest, due to the statistically significant difference observed in the proportion of individuals taking psychotropic medications in each group. Our results remained largely unchanged after accounting for medication status, as detailed in Appendix 2.

Role of suicidal ideation

We did not initially account for the role of suicidal ideation in the current study, focusing instead on interoceptive processing differences between individuals with a history of suicide attempts within the last 5 years and individuals with no suicide attempt history. To rectify this issue, we conducted additional analyses examining whether suicidal ideation history might explain the observed abnormalities of interoception across subjective, behavioral, and neural levels. Our observation of diminished interoception in suicide attempters was largely unchanged after accounting for lifetime suicidal ideation intensity, as detailed in Appendix 2 and displayed in Appendix 2—figure 1.

Discussion

We investigated whether attenuated interoceptive processing is associated with self-reported suicide attempts in individuals with a range of psychiatric disorders including depression, anxiety, post-traumatic stress disorder, eating disorders, and/or substance use disorders. We found that suicide attempters show reduced responses to homeostatic threats to the body, including increased tolerance for sensations of air hunger and increased tolerance of cold pain relative to non-attempters. Additionally, we found that suicide attempters exhibit decreased heartbeat perception accuracy and decreased mid and posterior insula activity when attending to sensations from the heart, an interoceptive organ that is vital for maintaining survival. Taken together, these findings provide initial support for the hypothesis that an increased capacity to engage in self-destructive and life-threatening behaviors is associated, behaviorally and neurobiologically, with a blunted sensitivity to internal bodily signals.

Prior to the current investigation, only a few empirical studies have examined the relationship between suicidality and interoception. These studies also suggested a role for interoceptive deficits in suicidal behavior, although the measurement of interoception was restricted solely to self-report questionnaires (Forrest et al., 2015; Dodd et al., 2018; Smith et al., 2018b; Rogers et al., 2018). Here, using a battery of behavioral measures of interoceptive processing, we demonstrate that interoceptive dysfunction in suicide attempters extends beyond symptom measures and includes abnormalities across behavioral, physiological, and neural indices. Furthermore, we observed these differences in a well-characterized sample of participants with similar levels of psychiatric symptoms, increasing the likelihood that the history of suicidal behavior was the driving force behind the differences observed in interoception rather than a varying expression of psychopathology between groups.

Our use of the cold-pressor and inspiratory breath-hold challenges enabled us to examine interoceptive responses to homeostatic threat, revealing that suicide attempters were able to sustain both tasks for a longer period of time than non-attempters. There are several potential explanations for these findings. Suicide attempters may be less sensitive to the physiological cascade that typically follows a homeostatic threat to bodily integrity, allowing them to persist at the task for longer before noticing and responding to internal physiological cues to withdraw. Indeed, the suicide attempters demonstrated an ability to continue the breath-hold task for longer time periods than non-attempters, even in the face of greater reductions in O2 and increases in CO2 (i.e. physiological indicators of potential bodily harm). Suicide attempters may also appraise signals of homeostatic threat (e.g. pain, breathlessness) as less salient, resulting in slower withdrawal from aversive homeostatic perturbations. For example, while the suicide attempters sustained breath-hold and cold-pressor perturbations longer than to non-attempters, they did not demonstrate the expected corresponding increases in unpleasantness, stress, difficulty, and other ratings of task aversiveness. Rather, in the cold-pressor challenge, the suicide attempters’ ratings of stress and difficulty were marginally lower than that of non-attempters, even though they continued the cold-pressor challenge for an average of 18 s longer. Based on the current findings, we speculate that a disconnection between the physiological and affective experiences of pain may enable such individuals to engage in self-injurious behaviors and to fail to withdraw from painful stimuli, possibly to the point of inflicting physical harm.

Suicide attempters, relative to non-attempters, also displayed reduced interoceptive accuracy for heartbeat sensations and decreased hemodynamic responses in the right dorsal mid and posterior insula during interoceptive attention to naturally-occurring heart sensations. In terms of the importance of these regions, the mid/posterior insula is often presumed to be the primary recipient of thermal, nociceptive, tactile, and cardiovascular inputs from the ventromedial thalamic nuclei (Craig, 2002; Critchley and Harrison, 2013), supporting the subsequent representation of conscious awareness of internal bodily states. Prior research suggests that the dorsal mid-insula is sensitive to homeostatic signals (Simmons et al., 2013b) and critical to the brain’s representation of visceral stimulation (Hassanpour et al., 2018), visceral attention (Farb et al., 2013; Simmons et al., 2013a), and interoceptive memory (DeVille et al., 2018). From a clinical perspective, dysfunction in the dorsal mid-insula has been linked to somatic symptoms (Avery et al., 2014) and failure to meet energy needs (Simmons et al., 2016) among individuals with depression, suggesting that functional abnormalities within this region may be associated with the inability to effectively attend to and use homeostatically relevant information from the body. Additionally, the posterior insula has been conclusively linked to the detection of aversive sensory stimuli and associated shifts in behavioral response strategies in mice (Gehrlach et al., 2019), and it is a brain region that is closely tied to the amygdala and threat processing (Berret et al., 2019; Livneh et al., 2017). Meta-analytic functional neuroimaging findings in humans have specifically implicated the mid/posterior insula in cardiac interoception, with a particular role in attending to and accurately perceiving naturally occurring cardiac sensations (Schulz, 2016). Collectively, these studies illustrate that the observed blunting of insular cortex activation in suicide attempters is precisely located within subregions that are closely relevant for aversive threat processing, conscious awareness of the heartbeat signal, and homeostatic regulation.

Prior theoretical work has suggested that a low signal-to-noise ratio of visceral input to the insula may influence interoception among individuals with certain psychiatric illnesses, who are thought to be less capable of discriminating random signal fluctuations from biologically relevant signals (Paulus and Stein, 2010; Barrett et al., 2016; Barrett and Simmons, 2015). As a result, it is thought that these individuals tend to erroneously evaluate benign signal changes as significant, and plan and act on these signals accordingly (Paulus et al., 2019). In this view, the suicide attempters’ reduced mid and posterior insula activation during heartbeat interoception could reflect a ‘noisier’ or weaker processing of interoceptive afferents, potentially interfering with the ability to accurately detect signals from their bodies. To extend this line of thought, it is also possible that difficulty distinguishing signal from noise manifests as a reduced ability to adaptively detect homeostatically-relevant signals (e.g. those related to pain and/or suffocation, as in the cold-pressor and breath-hold tasks), which could help to explain the group differences in homeostatic threat response observed in the current study. However, these notions remain tentative until further research can replicate and extend the findings across other measures of response to aversive and/or painful interoceptive stimuli.

We found that suicide attempters exhibited reduced activation within cortical midline structures during cardiac interoceptive attention (i.e. dorsomedial prefrontal cortex, posterior cingulate, and precuneus) that have been previously implicated as core brain regions underlying human self-referential processing (Northoff and Bermpohl, 2004; Northoff et al., 2006; Lemogne et al., 2011). Our finding is consistent with prior research linking abnormal self-referential processing to suicidal ideation and behavior (Marchand et al., 2012) and suggests that further exploration for a role of interoception in the relationship between interoception and self-referential processing in suicide may be worthwhile. Suicide attempters also exhibited reduced activation within the superior temporal gyrus during interoceptive attention. Prior studies have linked suicide attempts with structural and functional abnormalities within the superior temporal gyrus (Soloff et al., 2012; Pan et al., 2015; Aguilar et al., 2008; van Heeringen et al., 2014), arguing for a role in socio-emotional threat evaluation, but further investigation would be necessary to pinpoint the role of interoception in this relationship.

Our findings provide some key empirical support for modern theoretical models of suicide that are built upon desire-capability frameworks (Klonsky et al., 2017), such as the motivational-volitional model (O'Connor and Kirtley, 2018), the interpersonal-psychological theory of suicide (Ribeiro and Joiner, 2009; Van Orden et al., 2010), and the three-step theory (Klonsky and May, 2015). One assertion shared by each of these models is that, for suicide attempts and/or death by suicide to occur, the suicidal individual must express the capacity to approach (rather than avoid) bodily harm. According to these theories, individuals who engage in suicidal behavior demonstrate an ability to ignore—or override—the natural aversion to bodily harm that protects humans against physical injury. Our observations are consistent with these theories and provide early experimental evidence for the role of blunted interoception and heightened tolerance for homeostatic threat in suicidal attempts.

Limitations and future directions

Although our study represents the most comprehensive investigation related to interoception and suicide to date, we must acknowledge certain limitations. We evaluated evidence for interoceptive processing focusing on individuals with a history of suicide attempts within the last 5 years, based on the report that self-reported interoceptive deficits may be greater among individuals with more recent suicide attempts (Forrest et al., 2015). An alternative approach for future research might be to compare performance on neural and behavioral constructs related to interoception in individuals with more recent suicide attempts. Another limitation is that, while our findings suggest that individuals with suicide attempts exhibit abnormal interoception, we did not fully examine whether a history of suicidal ideation—versus a suicide attempt—has an independent impact on interoception. To begin to address this point, we conducted additional analyses which suggested that the observation of diminished interoception in suicide attempters was largely unchanged after accounting for lifetime suicidal ideation. But prospective studies are needed to conclusively discern whether the relationship between interoception and suicide attempt history can be attributed to group differences in suicidal ideation. Additionally, after matching our suicide attempter and non-attempter samples on measures of psychopathology, we found that the proportion of participants taking psychotropic medications at the time of data collection was significantly greater in the suicide attempters. Accounting for these differences in subsequent analyses did not substantially affect our results. One possibility is that the greater psychotropic medication usage in this group might reflect an effort by clinicians to reduce further suicide attempts.

From our cross-sectional study, it is difficult to judge whether the observed differences in interoception represent predispositions (i.e. innate characteristics), whether they reflect an emerging response at some point during the development of suicidal ideation, or occur as a response to suicidal behavior. Addressing these questions via longitudinal task-based assessments of interoception and/or pain processing would provide valuable insight into the impact of blunted interoception on the emergence of suicidal ideation and the conversion to suicidal behavior (Millner et al., 2017). Although not the primary intent of our investigation, we observed several interrelationships within and across levels of analysis raising the possibility of a latent interoceptive awareness trait factor. However, these relationships were inconsistent and were not pre-specified in our hypotheses. Identification of such a latent factor would likely require additional investigation using larger samples and inclusion of individuals not meeting criteria for psychiatric disorders.

We also used an imprecise, albeit commonly employed, measure of pain perception in the cold-pressor challenge. It would be advantageous to clarify whether suicidal action is differentially linked to impaired processing of other pain signals. Examples include visceral pain, which tends to be poorly localized, often referred to somatic structures and produces strong autonomic and affective responses, as well as other somatic pain signals (e.g. thermal or mechanical pain), which tend to be discretely localized to somatic structures and produce more variable autonomic and affective responses (Sikandar and Dickenson, 2012). Beyond stimulating visceral and somatic pain processing via different neuroanatomical pathways, it would be helpful to evaluate the degree to which altered pain responding is directly driven by differences in nociception per se as opposed to indirectly modulated by differences in interoceptive processing (Pollatos et al., 2012). Additionally, it is increasingly understood that cardiac interoception is rather difficult to assess (Khalsa and Lapidus, 2016). Heartbeat perception tasks such as the one employed in the current study are widely used, but have been the subject of criticism (Desmedt et al., 2018), and there is evidence to suggest that performance on this type of task can be influenced by one’s a priori knowledge about their heartbeat (Murphy et al., 2018). We addressed some of these potential confounds in our heartbeat perception task by including a no-guess trial condition, and a trial in which an inspiratory perturbation was used to putatively increase the intensity of heartbeat sensations. We also conducted analyses with and without the inclusion of the guessing trial. Overall, it appeared that suicide attempters had lower heartbeat perception accuracy across all three trials, with the strongest differences occurring during the least confounded condition (i.e. the no-guess trial). We did not investigate cardiac interoception using a more rigorous and ecologically valid form of perturbation, such as double-blinded infusions of isoproterenol (Khalsa et al., 2009), but would expect that blunted interoception in suicide attempters in a similar context would constitute robust evidence replicating the present findings. Lastly, we should note that none of the interoceptive tasks applied in this study have demonstrated sufficient reliability to be considered appropriate for implementation in prognostic assessments of suicidality in clinical settings.

Conclusion

We find that suicide attempters exhibit evidence of ‘interoceptive numbing’ characterized by increased tolerance for aversive respiratory and nociceptive sensations, reduced awareness of the heartbeat, and blunted activity in the dorsal mid and posterior insular cortex, a region of the brain associated with the primary representation of visceral afferent signals. The presence of these specific interoceptive deficits among individuals with prior suicide attempts reveals a possible role of interoceptive dysfunction in distinguishing individuals at risk of suicide.

Materials and methods

Participants

We performed a retrospective analysis from a pre-existing dataset containing the first 500 participants of the Tulsa-1000 (T-1000) cohort, a naturalistic longitudinal study of 1000 individuals with mood, anxiety, substance use, and/or eating disorders (Victor et al., 2018). Participants were considered eligible for T-1000 study entry if they fulfilled any of the following symptom criteria: Patient Health Questionnaire (PHQ-9; Kroenke et al., 2001)≥10 and/or Overall Anxiety Severity and Impairment Scale (OASIS; Campbell-Sills et al., 2009)≥8, and/or Drug Abuse Screening Test (DAST-10; McCabe et al., 2006) score >3, and/or Eating Disorder Screen (SCOFF; Morgan et al., 2000) score ≥2. Please refer to Victor et al. (2018) for a detailed description of the T-1000 inclusion criteria and study procedures. All participants provided written informed consent and received financial compensation for their involvement, and all procedures were approved by the Western Institutional Review Board.

Participants were included in the suicide attempter group (n = 34) if they endorsed making a suicide attempt at any point during the previous five years as documented in the Columbia Suicide Severity Rating Scale (CSSRS; Posner et al., 2011) and/or life-chart interviews (Aupperle et al., 2020), which were conducted during the baseline data collection period, and used to gather information about each participant’s lifetime psychosocial, medical, educational, occupational, and treatment history (Victor et al., 2018). We used a propensity score matching algorithm for psychiatric reference sample identification (MatchIt package in R De et al., 2011, 1:2 nearest neighbor method without replacement), resulting in a group of non-attempter participants who denied having ever made a suicide attempt, and who exhibited similar screening symptoms on the PHQ-9, SCOFF, DAST, and OASIS scales (Table 1). To maximize the amount of data available for analysis, non-attempter participants (N = 239) were only matched to suicide attempters if their data had been manually checked and they had complete observations of the behavioral and psychophysiological variables examined. Further information regarding participant inclusion and exclusion criteria, matching procedures, and suicide attempt method are provided in Appendix 1.

Procedures

For a detailed description of general study procedures, please see Appendix 1.

Breath-hold challenge

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Each participant completed two inspiratory breath-hold trials, providing a brief measure of sensitivity to respiratory perturbation (i.e. air hunger). Participants were seated in front of a computer screen, fitted with a respiration belt (Biopac Systems, Inc), provided with a nose clip, and a tube-like breathing apparatus was placed into the mouth. During normal breathing, concentrations of O2 and carbon dioxide CO2 were analyzed from exhaled air, providing a baseline measurement. Participants were then instructed to inhale maximally and, at the end of inhalation, to begin holding their breath for as long as they were able to tolerate. Trial duration was limited to 2 min, with a 2-min rest period between each trial; participants were instructed to stop and breathe if they reached the time limit, but they were not informed of how long the time limit would be beforehand. Participants were instructed to exhale into the breathing apparatus when they were no longer able to tolerate the breath-hold. Following each breath-hold, participants provided ratings of the task (i.e. respiratory sensation intensity, unpleasantness, and difficulty) as well as ratings of associated psychological experiences (i.e., stress, required effort, breathlessness, urge to breathe, breathlessness, sensations of suffocation, fear of suffocation) on a visual analogue scale (VAS) ranging from 0 (‘Not at all’) to 100 (‘Extremely’).

Cold-pressor challenge

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Participants immersed their dominant hand in a circulating pool of water cooled to six degrees Celsius. They were asked to keep their hand submerged for as long as they could tolerate. Maximum trial duration was limited to 2 min, although, as in the breath-hold task, this was not disclosed beforehand. Throughout the task, participants made continuous real-time pain intensity ratings with their dominant hand on a scale ranging from 0 (‘No pain’) to 100 (‘Worst pain imaginable’). These ratings were used to calculate each participant’s peak pain rating, as well as the time elapsed prior to the ratings of mild (25 out of 100), moderate (50 out of 100), and peak pain (100 out of 100 or the participant’s maximum pain rating). Afterwards each participant provided ratings of task unpleasantness, difficulty, and stress on a visual analogue scale (VAS) ranging from 0 (‘Not at all’) to 100 (‘Extremely’).

Heartbeat perception task

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To assess cardiac interoception, participants performed three trials of a heartbeat tapping task. Participants were instructed to tap a key on a keyboard every time they felt their heartbeat, without taking their pulse. Each trial was 60 s in duration. In the first trial (‘guess’), subjects were instructed to tap every time they felt their heartbeat without taking their pulse. Guessing was encouraged if they felt unsure. In the next trial (‘no guess’), guessing was discouraged and participants were asked to tap only when they felt confident in feeling their heartbeat. In the final trial (‘perturbation’), participants were instructed to inhale deeply, hold their breath, and tap along with their perceived heartbeats while sustaining the breath-hold. The breath-hold perturbation was expected to amplify cardiac sensations and presumably increase heartbeat perception accuracy. Guessing was also discouraged in this trial. Heartbeat perception accuracy was calculated using a common accuracy metric (Schandry, 1981). Afterwards, participants provided VAS ratings ranging from ‘Not at all’ (0) to ‘Extremely’ (100) to indicate their perceived heartbeat intensity, confidence in their ability to accurately estimate their heartbeat, and their assessment of task-related difficulty.

Interoceptive attention task during fMRI

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The interoceptive attention task engages selective attention toward naturally-occurring interoceptive sensations in order to amplify activity in brain regions underlying interoceptive processing. We and others have previously demonstrated that this task is effective at mapping the neural basis of interoceptive attention in healthy individuals and those with, depression, substance use disorders, or eating disorders (Avery et al., 2014; Kerr et al., 2016; Simmons et al., 2013a; Avery et al., 2017; Stewart et al., 2019). The task consisted of two types of trials: interoceptive trials and exteroceptive trials. During the interoceptive trials, the words ‘HEART’ or ‘STOMACH’ were presented in a black font against a white background with each trial lasting 10 s. During the interoceptive trials, participants were instructed to focus on the sensations in their heart or stomach. Trials involving stomach interoception were not examined in the current study. Each interoceptive and exteroceptive stimulus was presented 12 times. During the exteroceptive trials, the word ‘TARGET’ was presented on the screen in black text against a white background. The color of the word periodically changed from black to various lighter shades of gray; throughout the duration of the 10 s trial, participants were instructed to focus on the intensity of the color change. To ensure that participants remained attentive during the task, following one-half of the trials, participants were asked to rate the intensity of the sensations from their heart or stomach or the intensity of the color change, on a scale from 0 to 6, with 0 indicating ‘No sensation’ (interoceptive) or ‘No change in color’ (exteroceptive) and six indicating an ‘Extremely’ intense sensation (interoceptive) or an ‘Extremely’ intense color change (exteroceptive). Participants performed this task over two scanning runs, each lasting 360 s.

Analysis of demographic, behavioral, and physiological data

We conducted analyses of demographic, clinical, behavioral, and physiological data using the R base statistical software package version 3.5.1 (R Development Core Team, 2013). The ‘TableOne’ package (version 0.9.3; Yoshida et al., 2019) was used to display summaries of clinical characteristics between groups. LME analyses were conducted using the ‘lmerTest’ package version 3.1.1 (Kuznetsova et al., 2017). A marginal ANOVA was used on each LME model to examine F-tests for interactions and main effects. In the event of significant interactions, the summaries of LME fixed effects were examined to clarify which factors were driving the effect. The Kenward-Roger approximation of degrees of freedom was used for all LME analyses. R-squared estimates for fixed-effects were computed using the ‘r2glmm’ package in R (Jaeger, 2017) as described in Edwards et al. (2008). Tables depicting model output were generated using the ‘sjPlot’ package (version 2.6.2; Lüdecke, 2018) and figures were created using the ‘ggplot2’ package (version 3.0.0; Wickham, 2011). VAS ratings for each task were also compared between groups. Since a proportion of the VAS ratings were not normally distributed, Mann-Whitney tests, which are robust to deviations from normality, were used to compare ratings between groups. Where applicable, a Benjamini-Hochberg correction was applied to minimize the false discovery rate (FDR) associated with repeated testing. We provide specific details for the analysis of each task below. The source code for our primary analyses and figures has also been provided.

Breath-hold challenge

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Three LME models were used to examine the relationship between group, trial repetition, the interaction between group and trial, and three outcome variables: breath-hold duration, post breath-hold CO2 concentration, and post breath-hold O2 concentration. For each model, group, timepoint, and their interaction were included as fixed effects. A participant identifier was included as a random effect, and hold duration, post-hold CO2 concentration, or post-hold O2 concentration were specified as dependent measures. A Benjamini-Hochberg correction was applied across these three models. Additionally, Benjamini-Hochberg corrected Mann-Whitney tests were used to examine group differences in VAS ratings of intensity, unpleasantness, difficulty, stress, required effort, breathlessness, urge to breathe, breathlessness, sensations of suffocation, and fear of suffocation following the breath-hold tasks.

Cold-pressor challenge

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We used a LME model to examine the relationship between group and the amount of time (seconds) elapsed from the start of the cold-pressor challenge until the participant reached four markers of pain intensity: mild pain, moderate pain, peak pain, and task discontinuation (i.e. hand removal from the water). Group, timepoint, and the interaction between group and timepoint were included as fixed effects. A participant identifier was included as a random effect, and duration in seconds was the specified dependent measure. VAS ratings of pain intensity, unpleasantness, difficulty, and stress were also compared between groups using Benjamini-Hochberg corrected Mann-Whitney tests.

Heartbeat perception task

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We used a LME model to examine the relationship between group and heartbeat tapping accuracy across the three task conditions (i.e. guess, no-guess and breath-hold). Heartbeat tapping accuracy was included as the dependent measure, the interaction between group and condition was modeled as a fixed effect, and a participant identifier was specified as a random effect. Additionally, based on a recent study indicating that heartbeat perception accuracy scores are potentially confounded by guessing (Desmedt et al., 2018), a post-hoc decision was made to apply a second model that omitted the guessing score from the analysis, focusing only on the no-guess and breath-hold perturbation trials. Benjamini-Hochberg corrected Mann-Whitney tests were used to examine group differences in mean VAS ratings of heartbeat perception confidence, task difficulty, and heartbeat intensity across the no-guess and breath-hold trials.

Analysis of interoceptive attention task during fMRI

Data acquisition and imaging parameters

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Structural and functional magnetic resonance images were acquired using a General Electric (GE) Discovery MR750 3 Tesla MRI scanner. A 3D MPRAGE sequence obtained high-resolution anatomical images (FOV = 240 mm x 192 mm, slices/volume (axial) = 186, slice thickness = 0.9 mm, image matrix = 256×256, voxel volume = 0.938×0.938 × 0.9 mm, TR/TE = 5/2.012 ms, acceleration factor R = 2, flip angle = 8°, inversion/delay time TI/TD = 725/1400 ms, scan time = 340377 ms) using an 8-channel receive-only head coil (GE). Functional data were collected as echo-planar image (EPI) volumes depicting BOLD contrast (180 EPI volumes per run, slice thickness = 2.9 mm, voxel volume = 1.875×1.875 × 2.9 mm, acquisition matrix = 96×96, TR = 2000 ms, TE = 27 ms, flip angle = 78°, axial-oblique slices, 39 slices per volume, scan time = 360 s) using an eight-channel head array coil (GE), with a sensitivity encoding (SENSE) factor of 2 to minimize EPI distortions while also increasing the number of slices collected per TR.

Preprocessing, and subject-level analysis

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Data preprocessing was conducted using afni_proc.py (Cox, 1996). The first three volumes of the functional scans were discarded to allow the signal to reach T1 equilibrium, and a despiking algorithm was used to remove any transient signal spikes from the data. For each participant, the remaining volumes were corrected for differences in slice acquisition time; head motion was corrected by rigid body translation and rotation; the first volume of the functional run (before discarding three volumes) was coregistered to the anatomical coordinates of the participant’s structural scan by linear warping, then normalized to the Montreal Neurological Institute (MNI) template and resampled to 2 × 2 × 2 mm3 voxels. The EPI data were then smoothed using a 4 mm full-width at half-maximum Gaussian kernel, and the value for each EPI volume was normalized to percent signal change using each voxel’s average signal across the time course.

The imaging data were analyzed at the subject level using a multiple linear regression model, with regressors for each task condition (i.e. cardiac attention, stomach attention, exteroceptive attention, and response periods). To adjust the model for the shape and delay of the BOLD function, task regressors were constructed by convolution of a block function having a 5- or 10 s width (depending on the trial duration) beginning at the onset of occurrence of each condition. Nuisance regressors included each run mean, linear, quadratic, and cubic signal trends, as well as six head motion variables (three translations, three rotations).

Group analysis

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We identified the insular cortex as an a priori region of interest due to its well-documented involvement in interoceptive attention (Avery et al., 2014; Kerr et al., 2016; Simmons et al., 2013a; Avery et al., 2017; Stewart et al., 2019), and focused our analysis on cardiac interoception. A mask of the left and right insula was defined using the N27 anatomical atlas within AFNI. The AFNI program 3dttest++ was used to examine group differences in interoceptive attention. For the interoceptive attention condition, all subject-level beta coefficients represented signal change relative to the exteroceptive condition. A small volume correction of p<0.005 was applied within the insula, and a voxel-wise threshold of p<0.0005 was set for the rest of the brain. Results were then corrected using a cluster-size threshold of α <0.05. To accurately estimate the cluster sizes necessary to achieve familywise error correction, we applied the --Clustsim correction in 3dttest++, which employs randomization and permutation simulation to produce cluster-level threshold values that adequately control the false positive rate (Cox et al., 2017).

Appendix 1

General procedures

The data used in the current study were collected over three to four visits to the Laureate Institute for Brain Research facility. The initial visits involved completion of the following clinical assessment measures: Patient Health Questionnaire (PHQ-9), Overall Anxiety Severity and Impairment Scale (OASIS), Drug Abuse Screening Test (DAST), Eating Disorder Screen (SCOFF), an assessment of medication status and medical history, a demographics questionnaire, the Mini International Neuropsychiatric Interview (Sheehan et al., 1998), and the Columbia Suicide Severity Rating Scale (C-SSRS)(Posner et al., 2011). There were no differences in diagnosis or medication status between groups, as illustrated in Appendix 1—tables 12. During the initial visit, participants completed an additional battery of self-report scales, from which the Multidimensional Assessment of Interoceptive Awareness (Mehling et al., 2012), the Anxiety Sensitivity Index (Taylor et al., 2007), and the Toronto Alexithymia Scale Bagby et al., 1994) were selected and included in current analyses (see Appendix 1—table 3; no significant group differences were observed on these measures after correcting for multiple comparisons). The latter visits involved completion of a fMRI scan and, on a separate date, completion of psychophysiological tasks including the breath-hold challenge, cold pressor challenge, and heartbeat perception tasks. An experimenter remained in the room with each participant but out of sight during the psychophysiological tasks, and video recordings of each participant were obtained to ensure compliance with instructions.

Appendix 1—table 1
Percent of individuals meeting diagnostic criteria for psychiatric disorders per the Mini International Neuropsychiatric Interview (MINI) at the time of data collection.
Suicide attempters
(n = 34)
Non-attempters
(n = 68)
Major depressive disorder74% (n = 25)74% (n = 50)
Anxiety disorders62% (n = 21)65% (n = 44)
Post-traumatic stress disorder32% (n = 11)28% (n = 19)
Substance use disorder (excluding alcohol)35% (n = 11)41% (n = 28)
Alcohol use disorder26% (n = 9)24% (n = 16)
Eating disorders9% (n = 3)3% (n = 2)
Mean (SD) number of diagnoses per individual3.2 (1.9)3.1 (1.9)
  1. Note: There were no significant differences in the proportion of diagnoses between suicide attempter and non-attempter groups. ‘Anxiety disorder’ includes any of the following: social anxiety disorder, general anxiety disorder, and/or panic disorder with or without agoraphobia. ‘Eating disorder’ includes a diagnosis of anorexia nervosa, bulimia nervosa, or binge eating disorder. Total percentages will not add up to 100% as several patients met criteria for more than one disorder.

Appendix 1—table 2
Percent of individuals taking psychotropic medications by drug class.
Suicide attempters
(n = 34)
Non-attempters
(n = 68)
SSRIs38% (n = 13)29% (n = 20)
SNRIs14.7% (n = 5)7.4% (n = 5)
Bupropion17.6% (n = 6)8.8% (n = 6)
Tricyclic Antidepressants8.8% (n = 3)0
Tetracyclic Antidepressants14.7% (n = 5)1.5% (n = 1)
Atypical antipsychotics23.5% (n = 8)7.4% (n = 5)
Anticonvulsants26.5% (n = 9)10.3% (n = 7)
Benzodiazepines26.5% (n = 9)13.2% (n = 9)
Stimulants5.8% (n = 2)13% (n = 9)
Narcotics (e.g., Suboxone)11.8% (n = 4)11.8% (n = 8)
Opioid Antagonists5.8% (n = 2)1.5% (n = 1)
Lithium5.8% (n = 2)0
  1. Note: ‘SSRI’=selective serotonin reuptake inhibitor; ‘SNRI’=serotonin and norepinephrine reuptake inhibitor

Appendix 1—table 3
Self-report measures by group.
Attempter
(n = 34)
Non-attempter
(n = 68)
Mean (SD)pAdjusted p
Multidimensional Assessment of Interoceptive Awareness (MAIA)
Attention Regulation2.7 (1.2)2.9 (1.0)0.230.37
Body Listening2.0 (1.3)2.4 (1.1)0.100.37
Emotional Awareness3.4 (1.2)3.7 (0.9)0.210.37
Not Distracting1.8 (0.9)1.5 (0.9)0.230.37
Noticing3.5 (0.8)3.6 (1.0)0.760.87
Not Worrying2.7 (1.0)2.5 (1.1)0.440.59
Self-Regulation2.4 (1.2)2.8 (1.1)0.900.90
Body Trust2.7 (1.3)3.2 (1.0)0.020.16
Anxiety Sensitivity Index (ASI)
Cognitive Concerns6.9 (6.7)6.1 (6.7)0.520.88
Physical Concerns5.8 (5.7)6.3 (5.7)0.650.88
Social Concerns11.6 (6.8)11.4 (6.8)0.880.88
Total ASI24.3 (17.1)23.8 (12.9)0.860.88
Toronto Alexithymia Index (TAS-20)
Difficulty Identifying Feelings18.8 (6.5)18.1 (5.0)0.540.72
Difficulty Describing Feelings14.7 (3.2)14.7 (3.2)0.650.72
Externally Oriented Thinking25.3 (3.2)26.4 (3.0)0.090.36
Total TAS58.8 (10.2)59.5 (8.2)0.720.72
  1. Note: The adjusted p-values are corrected using the Benjamini-Hochberg adjustment.

Appendix 1—figure 1
Pearson correlation coefficients across measures.

‘CP’ = cold-pressor, ‘BH’ = breath-hold (computed using participants’ mean duration and VAS ratings across trial 1 and trial 2, ‘HB’ = heartbeat perception task (computed using the mean of the no-guess and perturbation conditions). IA-fMRI = interoceptive attention to heartbeat sensations during fMRI.

Matching procedures and participant selection

Several individuals from the first 500 participants of the Tulsa 1000 dataset were not included in the current analysis. These included: 1) participants reporting suicide attempts occurring more than 5 years prior to entry into the study (n = 51), 2) participants with missing or incomplete C-SSRS data (n = 44), 3) participants who reported a history of aborted suicide attempts only (n = 7), defined as having made a suicide plan with intent but never taking any action towards it, and 4) participants who were initially categorized as non-attempters but made subsequent attempts after data collection (n = 3). Our decision to only include suicide attempters who had made attempts within the past 5 years was implemented in response to literature finding that individuals who have made suicide attempts in the previous 5 years exhibit more self-reported interoceptive deficits than those who made attempts more than 5 years ago (Forrest et al., 2015). Following the matching procedure, there were no statistically or clinically significant differences between non-attempters and attempters on the PHQ-9, DAST, SCOFF, or OASIS, with each group’s mean on these measures matched within < 1 point of the other group. While a group of psychiatrically healthy individuals participated in the T1000 study, they were not incorporated into the current study.

Missing data values

The data from 2 to 5 suicide attempters were not eligible for inclusion in each of the breath-hold analyses, either due to missing or unusable physiological data. For the breath hold duration analysis, the sample was reduced to 32 participants in the suicide attempter group. All 68 participants in the non-attempter group had usable data for calculation of breath-hold duration. In the analyses comparing oxygen (O2) and carbon dioxide (CO2) concentrations following the breath-hold, there were 29 suicide attempters with complete post breath-hold measures of O2, and 28 with complete post breath-hold measures of CO2. There were seven individuals from the suicide attempter group with missing cold-pressor data; as such, the analyses reported here reflect a comparison of 27 attempter and 68 non-attempter participants. There were two suicide attempters with missing data from the heartbeat perception task. Additionally, a total of 7 participants (four non-attempters and two attempters) were not included in the fMRI analysis, for the following reasons: two participants were not scanned, one participant had significant slice artifacts, three participants had poor anatomical-functional image alignment, and one participant had an average head motion greater than 0.3 millimeters.

Suicide attempt methods and recency of attempts

Within the attempter group, 26% (n = 9) attempted suicide via asphyxiation, 11% (n = 3) by injury involving cutting the wrists or other areas, 15% (n = 5) by other injuries, such as jumping into traffic, intentional car accidents, or attempting to fire a gun, and 50% (n = 17) by self-poisoning (e.g., overdose). A total of 62% (n = 24) of individuals in the attempter group endorsed one previous suicide attempt, 24% (n = 8) reported two previous attempts, 6% (n = 2) reported three previous attempts, and 9% (n = 3) reported four or more previous suicide attempts. For participants with multiple attempts, the attempt method reported here reflects their most recent attempt. Of all attempter participants identified, a total of 11 had identified as having made their most recent suicide attempt within 1 year of data collection, six reported making a suicide attempt within 2 years of data collection, and 11 participants reported attempting suicide between 2 and 5 years prior to data collection.

Appendix 2

Assessing effects of psychotropic medication status

To address the potential concern that our results might be attributed to the effects of psychotropic medication rather than suicide attempt history, we re-examined our primary outcome variables after covarying for medication status.

Heartbeat perception accuracy

To examine whether the observed group difference between suicide attempters’ and non-attempters on heartbeat tapping accuracy remained after covarying for the effects of psychotropic medication status, we included psychotropic medication status (i.e., medicated or unmedicated) as a fixed effect covariate in our linear mixed effects (LME) model and re-analyzed the model, again using analysis of variance (ANOVA). After adjusting the model for medication, the main effect of suicide group (attempter vs. non-attempter) remained significant (F(1,140.32) = 9.3, p = 0.003) as did the significant interaction between group and condition (F(1,97.72) = 4.37, p = 0.039). There was no significant effect of medication status (F(1,96.7) = 0.74, p = 0.392).

Appendix 2—figure 1
Performance on interoceptive measures across three groups: suicide attempters, suicide ideators, and non-ideators.

(A) During attention to interoceptive sensations (vs. exteroceptive sensations) suicide attempters exhibited lower blood oxygen level-dependent (BOLD) signal in the right dorsal mid insula compared to ideators (p = 0.004) and non-ideators (p < 0.001). Suicide attempters also exhibited lower BOLD activation in the posterior insula relative to ideators (p = 0.001) and non-ideators (p = 0.002) during interoceptive attention. (B) Suicide attempters exhibited lower levels of heartbeat perception accuracy relative to that of ideators (p = 0.012) and non-ideators (p = 0.007) during the no-guess and perturbation trials of the heartbeat perception task. The mean of the no-guess and perturbation trials is illustrated. (C) There was no significant difference between attempters and ideators (p = 0.062), nor between attempters and non-ideators (p = 0.110) in breath hold duration across trials. (D) Relative to ideators, suicide attempters sustained the cold pressor longer after reaching peak pain (p = 0.001); no significant differences were observed between attempters and non-ideators (p = 0.074). Error bars indicate + / - 1 standard error.

Blunted insula signal during interoceptive attention

To examine whether the observed group difference between suicide attempters’ and non-attempters’ signal in the mid and posterior insula during cardiac attention could be attributed to psychotropic medication status, we extracted the subject-level beta values from each insula cluster corresponding to the contrast between the cardiac and exteroceptive attention. We then built a linear model with the subject-level beta values as the dependent measure, suicide attempt history (attempter vs. non-attempter) and medication status as predictor variables. We did not use LME for this analysis as no repeated measures were involved. The effect of suicide attempt history was still significant in both regions (mid insula: F(1,92) = 13.63, p = 0.0004; posterior insula: F(1,92) = 12.62, p = 0.0006). Moreover, there was no effect of medication status on the right mid insula or posterior insula beta values during cardiac (vs. exteroceptive) attention (mid insula: F(1,92) = 2.36, p = 0.13; posterior insula: F(1,92) = 3.22, p = 0.08).

Breath-hold task

To assess the role of medication status, we included psychotropic medication status as a covariate in the LME models used to assess for group differences in breath hold task performance. Specifically, three models were built to examine the relationship between suicide attempt history, breath hold trial, and the following outcome variables 1) breath-hold duration, 2) post breath-hold expired oxygen concentrations, and 3) post breath-hold expired carbon dioxide concentrations, after covarying for medication status. For the model examining breath-hold duration, medication status was a non-significant predictor of duration (F(1,96.8) = 2.62, p = 0.109). However, the group difference in breath-hold was no longer statistically significant when medication status was included as a covariate (F(1,119.38) = 2.8, p = 0.095). For the models examining oxygen and carbon dioxide concentrations, the group differences between suicide attempters’ and non-attempters’ post breath-hold oxygen and carbon dioxide concentrations remained statistically significant even after covarying for medication status, (oxygen: F(1,91.08) = 4.13 p = 0.044; carbon dioxide: F(1,91.04) = 5.55, p = 0.020). No effects of medication status on post breath-hold concentrations of oxygen (F(1,94.12) = 0.266, p = 0.61) or carbon dioxide (F(1,93.84) = 0.127, p = 0.722) were observed.

Cold-pressor challenge

To examine whether suicide attempters exhibited an increased tolerance for cold-pressor pain after covarying for the effects of medication status, we re-analyzed our LME models with medication status included as a covariate. After adjusting the model for the effects of medication status, the interaction between time and suicide attempt group remained statistically significant (F(3,277.36) = 2.9, p = 0.036). Examination of fixed effects revealed that, while suicide attempters exhibited no differences in the amount of time elapsed prior to their ratings of mild, moderate, or peak pain, they kept their hands submerged in the water for a longer period of time (t(278.56) = 2.79, p = 0.006). There was no effect of medication status (F(1,91.37) = 0.039, p = 0.84).

Discussion of psychotropic medication status

After re-examining the data to evaluate a potential influence of differences in psychotropic medication status between suicide attempters and non-attempters, we found a similar overall pattern of results. Specifically, across all tasks we continued to see evidence suggestive of ‘interoceptive numbing’ characterized by a heightened tolerance for aversive interoceptive sensations (pain tolerance via the cold-pressor challenge, elevated carbon dioxide during breath hold) and reduced awareness of non-aversive sensations (decreased heartbeat perception accuracy and reduced activation of posterior insula during interoceptive attention to heartbeat sensations). These findings further reinforce the notion that blunted awareness of interoceptive sensations and attenuated responses to bodily threat may distinguish individuals at risk for suicide.

Assessing for potential effects of suicidal ideation

In the current study we evaluated evidence for interoceptive processing differences between individuals with a history of suicide attempts within the last 5 years and individuals with no suicide attempt history. We did not specifically address the role of suicidal ideation. Our primary rationale for not focusing on ideation history in the current study was twofold: 1) suicide attempt history has a stronger theoretical link to blunted interoceptive processing than suicidal ideation, as individuals who have made a prior suicide attempt have demonstrated an ability to override homeostatic signals through their suicidal actions; and 2) we had a limited assessment of suicide ideation history as the scale we used to assess this, the Columbia Suicide Severity Rating Scale (C-SSRS), accounts only for the worst lifetime presence of ideation and does not prompt the interviewer to collect dates of ideation. Recognizing that readers may seek more information regarding suicidal ideation within our sample, we sought to determine whether the observed relationship between interoception and suicidal behavior could be simply attributed to differences in ideation. We addressed this to the best of our ability by 1) re-analyzing our four primary findings after including the intensity of suicidal ideation as a covariate, and 2) dividing our non-attempter group on the basis of lifetime ideation and examining differences between suicide attempters, lifetime ideators without suicide attempts, and non-ideators. We report these analyses below.

Approximately 54% of non-attempters in our sample (n = 34) endorsed a lifetime history of suicidal ideation. Individuals completing the C-SSRS are also graded with an ‘Intensity of Ideation’ (IOI) score, which is calculated from the participants’ responses to items regarding the frequency, duration, controllability, deterrents, and reasons associated with their suicidal ideation. On the IOI scale, a score of 0 is obtained for individuals with no ideation, whereas ideators have a possible score ranging from 2 to 25. In our sample, the mean IOI score obtained from non-attempters was approximately 5.2 (SD = 7.1), whereas the suicide attempter group had a mean IOI of 15.2 (SD = 7.0); the difference in IOI between groups was statistically significant (t(87) = −6.04, p < 0.001).

Blunted insula signal during interoceptive attention

Using the subject-level beta coefficient values from the insula clusters corresponding to the contrast between cardiac and exteroceptive attention, we constructed a linear model to examine the relationship between suicide attempt status and insula BOLD signal in each cluster after covarying for each participant’s IOI score. Examination of this model revealed that IOI was not significantly associated with BOLD signal differences in the dorsal mid insula (t(81) = −5.82, p = 0.018, β = −0.07) or the posterior insula (t(81) = −1.31, p = 0.18, β = −0.16) and that after including IOI in the models, attempt history remained significant (Mid Insula: t(81) = −2.80, p = 0.006, β = −0.34; Posterior Insula: t(81) = −2.74, p = 0.008, β = −0.32).

To examine differences between attempters’, ideators’, and non-ideators’ signal in the insula during cardiac attention, we conducted a linear model using the subject-level betas in each cluster as the outcome measure and group (i.e., attempter, ideator, or non-ideator). For the right dorsal mid-insula, the attempters’ BOLD signal was significantly lower relative to that of ideators and non-ideators (attempters vs. ideators: t(88) = 2.98, p = 0.004, β = 0.34; attempters vs. non-ideators: t(88) = 3.72, p < 0.0001, β = 0.42). The findings were similar for the posterior insula cluster, such that the attempters’ exhibited significantly lower BOLD signal relative to that of ideators (t(88) = 3.35, p = 0.001, β = 0.38) and non-ideators (t(88) = 3.21, p = 0.002, β = 0.36).

Heartbeat perception accuracy

We re-analyzed the linear mixed effects model to examine differences in heartbeat perception accuracy during the no-guess and breath-hold conditions between attempters and non-attempters after covarying for the effects of IOI. Examination of fixed effects revealed that when IOI and suicide attempt history were considered together, IOI was non-significant (t(85.23) = −0.011, p = 0.991, β = 0.00). After covarying for IOI, the effect of attempt history remained statistically significant, (t(115.1) = −2.45, p = 0.016, β = −0.30).

After dividing the non-attempter group on the basis of lifetime ideation, a linear mixed model was constructed to examine differences between attempters, lifetime ideators, and non-ideators. Examination of fixed effects revealed that both ideators and non-ideators were more accurate than attempters (ideators vs. attempters: t(138.14) = 2.54, p 0.012, β = 0.25; non-Ideators vs. attempters: t(138.14) = 2.78, p = 0.007, β = 0. 32).

Breath-hold challenge duration

A linear mixed effects model was used to examine the effect of attempt history on overall breath hold duration after covarying for IOI. Examination of fixed effects in the model containing IOI and attempt history revealed no significant effect of IOI (t(83.8) = −1.31, p = 0.195, β = −0.16). With IOI included as a covariate, the effect of attempt history remained significant (t(96.6) = 2.32, p 0.022, β = 0.29).

After dividing the non-attempters on the basis of lifetime ideation, a LME model was used to examine differences in breath hold duration between attempters, lifetime ideators, and non-ideators. It was observed that attempters sustained the breath hold for approximately 11 s longer than ideators, and 10 s longer than non-ideators. However, the group differences were no longer statistically significant (attempters vs. ideators: t(113.18) = −1.88, p = 0.062); attempters vs. non-ideators: t(113.12) = −1.61, p = 0.109).

Cold-pressor challenge duration

We re-analyzed the LME model to examine the effect of attempt history on cold-pressor challenge duration after covarying for IOI. Examination of fixed effects revealed a significant effect of IOI (t(78.48) = −2.36, p 0.02, β = −0.18). When IOI was included as a covariate, the interaction between attempt history and timepoint remained significant (t(239) = 2.19, p 0.030, β = 0.12).

After dividing the non-attempters on the basis of lifetime ideation, a linear mixed effects model was used to examine the relationship between cold-pressor challenge duration and group among attempters, lifetime ideators, and non-ideators. It was noted that suicide attempters sustained the cold-pressor challenge for approximately 24 s longer than ideators, and 12 s longer than non-ideators. Examination of fixed effects revealed that attempters sustained the significantly longer than ideators after reaching peak pain (t(259.9)=−3.39, p < 0.001, β = −0.21), but not significantly longer than non-ideators (t(92) = −1.80, p = 0.08. β = −0.11) after reaching peak pain.

Discussion of suicidal ideation

After re-examining the data to evaluate the influence of suicidal ideation, the overall pattern of results suggests that our primary findings are likely attributed to suicidal behavior, not the effects of suicidal ideation. When intensity of suicidal ideation was included as a covariate, the group differences we previously reported were unchanged across all tasks. Additionally, when we analyzed differences between attempters, ideators, and non-ideators, we found that that the suicide attempters, relative to ideators and non-ideators, exhibited heightened pain tolerance in the cold-pressor challenge, reduced heartbeat perception accuracy, and reduced activation of the mid and posterior insula during interoceptive attention (Appendix 2—figure 1). Although further research on the distinction between ideation and attempts is warranted, our initial findings support the notion that the interoceptive deficits observed among suicide attempters are not explained by the presence of suicidal ideation alone.

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Decision letter

  1. Christian Büchel
    Senior Editor; University Medical Center Hamburg-Eppendorf, Germany
  2. Alexander Shackman
    Reviewing Editor; University of Maryland, United States

In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.

Acceptance summary:

The authors examine whether individuals with a history of suicide attempt differ in interoceptive processing, relative to a matched psychiatric reference sample. The study includes a battery of interoceptive tasks (breath-hold, cold-pressor, heartbeat perception, and fMRI). The results indicate that suicide attempters show increased tolerance for aversive respiratory/nociceptive signals, reduced cardiac interoceptive accuracy, and a decreased insula signal during interoception. The findings suggest that blunted awareness of interoceptive sensations and attenuated responses to bodily threat may help to distinguish individuals at risk of suicide. The reviewers and I are enthusiastic about the work.

Decision letter after peer review:

Thank you for submitting your article "Diminished responses to bodily threat and blunted cardiac interoception in suicide attempters" for consideration by eLife. Your article has been reviewed by two peer reviewers, and the evaluation has been overseen by a Reviewing Editor (Alexander Shackman) and a Senior Editor (Christian Büchel). The following individual involved in review of your submission has agreed to reveal their identity: Nils Kroemer (Reviewer #2).

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.

The two reviewers were enthusiastic about the work:

• I think this is a very strong and important paper. Its key strength is the convergence of multiple methods. This helps address critiques that might be levelled at individual measures. I am impressed by how well the groups are matched in terms of key variables. Some would view differences in psychotropic medication between the groups to be a major flaw, but I think the approach the authors have taken is sensible. Overall, this paper is well guided by theory, methodologically strong, and potentially important clinically.

• This is a very important topic that is notoriously difficult to investigate well so I would like to commend the authors. This is arguably one of the best studies on this topic that I am aware of.

Essential Revisions:

1) Stats.

a) The description of the statistical analysis in the manuscript is currently not sufficient. I was happy to look at the code, but it should not be necessary to know R to understand what exactly the authors did. Therefore, more details on the models should be provided in the Materials and methods or the supporting information.

b) Relatedly, it was not obvious to me why the authors used the lme function for some analyses but not others (although it was even passed to a _gls variable) and sometimes the summary function or the anova function was used, not both.

c) In the manuscript, it was not clear to me which results were reported. Thus, it would be preferable to be a bit more precise in terms of the statistical descriptions and to include the output of the estimated models in the supporting information.

2) Cold pressor challenge.

a) The authors write: "Examination of fixed effects revealed that, while there were no significant group differences in the amount of time elapsed prior to reaching mild, moderate, and peak pain, suicide attempters kept their hands submerged in the cold water for significantly longer (18 seconds on average, SD = 25) than non-attempters after reaching peak pain (t(276)=2.8, p = 0.006, Cohen's d = .34)."

b) First, does the average refer to the group difference in duration and the SD to the pooled SD across groups?

c) Second, if it only refers to this category, why are the degrees of freedom so high that it appears as if a fixed effect across all repeated measurements was taken for the comparison?

d) Third, how was Cohen's d calculated because the study would not be large enough to find significant group differences of this magnitude if the degrees of freedom are calculated correctly (1-β = .36 for d = .34, n1 = 34, n2 = 68). This indicates that a formula was used to estimate d from t, which is only valid for non-nested t-contrasts ("simple" two-sample t-tests).

3) Relations amongst measures.

a) At the moment, DeVille et al. are not fully capitalizing on the strength of the design provided by the complementary measures of interoceptive awareness because the correlations between the interoceptive measures are not reported.

b) The authors report associations between percent signal change in the insula and their behavioral measures of interoceptive awareness, but not between the behavioral measures only.

c) However, the associations between insular signal changes and interoceptive measures are weak and inconsistent. Why would the signal related to the heartbeat detection task show a stronger correlation with the breath-hold duration than with behavioral measures on the same task?

d) The selective report of the significant difference in the manuscript is misleading and should be rephrased. Without a conclusive indication of behavioral loadings on a latent awareness factor, I would be very cautious to interpret such correlations at all. Moreover, the absence of loadings on a shared factor should also be reflected in the Discussion which emphasizes the relevance of interoceptive awareness for the risk of suicide attempts.

https://doi.org/10.7554/eLife.51593.sa1

Author response

Essential Revisions:

1) Stats.

a) The description of the statistical analysis in the manuscript is currently not sufficient. I was happy to look at the code, but it should not be necessary to know R to understand what exactly the authors did. Therefore, more details on the models should be provided in the Materials and methods or the supporting information.

We agree that more information describing each statistical analysis would improve the manuscript. In response to the reviewers’ questions we sought additional consultation with a statistician regarding the best way to clearly present our analyses and results. During this process, we opted to make two additional changes to our analysis approach that should increase the accuracy and methodological rigor of our study. First, we realized that by not specifying “type = marginal” in our ANOVA, R defaulted to a sequential approach, which is not the best approach for our models and can result in inconsistency between ANOVA output and LME fixed effects summary tables. We have made the appropriate correction. All ANOVA findings reported in this revision are calculated using marginal sums of squares. Additionally, we have adopted the Kenward-Roger approximation of degrees of freedom for all tests conducted using the LME. Despite having made this revision to our analysis approach, our findings are consistent with those described in our initial submission, with the minor exception of the heartbeat perception task.

We have rewritten the Materials and methods and Results sections to reflect these changes and to include more details regarding our model specifications, each analysis conducted, and the associated results. We feel that these revisions should substantially increase the clarity for readers regarding our statistical approach.

b) Relatedly, it was not obvious to me why the authors used the lme function for some analyses but not others (although it was even passed to a _gls variable) and sometimes the summary function or the anova function was used, not both.

We had initially made the decision to use a GLS for the breath-hold analyses. Although our breath-hold task consists of two trials, when we planned our analyses we decided the most parsimonious approach would be to take the mean duration of both trials and test for overall group differences, since the two trials were identical and we were not necessarily interested in performance differences from trial to trial. However, after consideration of the reviewers’ comments, we agreed that switching between analysis approaches could cause unnecessary confusion. Additionally, while a between-groups comparison may be a simpler test overall, the examination of each trial is likely more appropriate given the task design. Therefore, we have re-analyzed data from the breath-hold task using a linear mixed effects model. Our updated findings are consistent with the initial results. The linear mixed effects analyses for breath hold duration, O2 concentration, and CO2 concentration are reported in Results subsection “Breath-Hold Challenge”, and displayed in Supplementary file 1.

The reviewers note that sometimes the summary function was used without the anova function. The ANOVA function in R provides F tests for each coefficient, while “summary(model)” displays post-hoc tests describing contrasts between all levels of each factor. When only two groups are being compared (i.e., in the absence of potential interactions), the output of the fixed effects model summary and the output of the ANOVA should be identical. Additionally, when the only significant effect is a main effect of a factor with < 2 levels (e.g., a main effect of group, or a main effect of trial where there are 2 trials), the estimates of fixed effects will not provide additional information. Thus in our case it would be redundant to report both the ANOVA F-statistics and the fixed effects t-statistics. In our revised manuscript, we report overall F-statistics in the text, except for cases in which the fixed effects needed to be examined to clarify interactions or main effects involving three or more levels. To provide more detail on the results obtained with the models, we have also added the output of the LME summary tables to the revised manuscript supporting information section (Supplementary Files 1-3).

We have rewritten our Materials and methods and Results section with clearer language describing our analyses. Please note that in the Results section of the updated manuscript we have followed eLife’s guidelines to use an active voice and more engaging style. Additionally, we provide the following statement that describes our overall statistical approach (in addition to more specific details provided throughout the Materials and methods and Results section for each model):

“A marginal analysis of variance (ANOVA) was used on each LME model to examine F-tests for interactions and main effects. In the event of significant interactions, the summaries of LME fixed effects were examined to clarify which factors were driving the effect. The Kenward-Roger approximation of degrees of freedom was used for all LME analyses.”

We have submitted the revised code and statistical output in the form of an R Markdown HTML file.

c) In the manuscript, it was not clear to me which results were reported. Thus, it would be preferable to be a bit more precise in terms of the statistical descriptions and to include the output of the estimated models in the supporting information.

We agreed with the reviewers that the manuscript could be improved by providing more precision in our Materials and methods and Results sections. In making these changes in the revised manuscript, we have rewritten both sections. We have now added a paragraph in the Materials and methods section providing a description of our overall statistical approach (under the subheading “Analysis of Demographic, Behavioral, and Physiological Data”).Additionally, we have revised the language throughout the Materials and methods and Results section for each task to provide more specific details about the statistical modeling approach. To further enhance clarity, we have also added Tables displaying the exact model specification (e.g., Duration ~ Group x Trial + 1|id) and model outputs (i.e., fixed effects estimates with p-values, random effects estimates, and model fit indices). Please see Supplementary files 1-3 in our revised submission for these details.

2) Cold pressor challenge.

a) The authors write: "Examination of fixed effects revealed that, while there were no significant group differences in the amount of time elapsed prior to reaching mild, moderate, and peak pain, suicide attempters kept their hands submerged in the cold water for significantly longer (18 seconds on average, SD = 25) than non-attempters after reaching peak pain (t(276)=2.8, p = 0.006, Cohen's d = .34)."

b) First, does the average refer to the group difference in duration and the SD to the pooled SD across groups?

The average refers to the difference between the mean of attempters and non-attempters, and the SD is the pooled SD across groups. After giving this more consideration, we have decided that it does not make sense to report the SD here. The decision to report the group difference in duration in number of seconds is to provide a metric that is straightforward and accessible to all readers, and reporting the pooled SD here adds unnecessary confusion. Additionally, we report clearer measures of variability elsewhere (i.e., as illustrated by the error bars in Figure 2).

c) Second, if it only refers to this category, why are the degrees of freedom so high that it appears as if a fixed effect across all repeated measurements was taken for the comparison?

After receiving these reviews, we consulted with a statistician regarding our overall statistical approach, which revealed there is a debate surrounding the best approach for calculating degrees of freedom for the fixed effects in linear mixed effects models. In the revised submission, we use the Kenward-Roger approximation. This approach provides a more conservative estimate of statistical significance of fixed effects. We have clarified this in the manuscript in the paragraph that follows the subheading “Analysis of Demographic, Behavioral, and Physiological Data”.

d) Third, how was Cohen's d calculated because the study would not be large enough to find significant group differences of this magnitude if the degrees of freedom are calculated correctly (1-β = .36 for d = .34, n1 = 34, n2 = 68). This indicates that a formula was used to estimate d from t, which is only valid for non-nested t-contrasts ("simple" two-sample t-tests).

Cohen’s d was calculated using the “lme.dscore” function from the R package “EMAtools.” This function does use a formula to estimate Cohen’s d from the t-statistic [i.e., (2*t)/sqrt(df)]. In this revised submission, in lieu of Cohen’s d, we have decided to take a simpler approach and report the standardized β coefficients (i.e., slope differences in units of standard deviation of our dependent variable) in our LME summary tables. Additionally, we report Marginal R2 and Conditional R2 for the overall model. However, if the reviewers or Editors prefer that we use an alternative metric for reporting effect size, we would be happy to do so.

3) Relations amongst measures.

a) At the moment, DeVille et al. are not fully capitalizing on the strength of the design provided by the complementary measures of interoceptive awareness because the correlations between the interoceptive measures are not reported.

b) The authors report associations between percent signal change in the insula and their behavioral measures of interoceptive awareness, but not between the behavioral measures only.

c) However, the associations between insular signal changes and interoceptive measures are weak and inconsistent. Why would the signal related to the heartbeat detection task show a stronger correlation with the breath-hold duration than with behavioral measures on the same task?

d) The selective report of the significant difference in the manuscript is misleading and should be rephrased. Without a conclusive indication of behavioral loadings on a latent awareness factor, I would be very cautious to interpret such correlations at all. Moreover, the absence of loadings on a shared factor should also be reflected in the Discussion which emphasizes the relevance of interoceptive awareness for the risk of suicide attempts.

The reviewers’ concerns related to the selective reporting of the correlations in our initial submission of the manuscript was well-received. We did not intend to mislead our audience, and we agree that the practice of reporting noteworthy correlations in the main manuscript while relegating other correlations to the supplemental materials can be problematic. Therefore, we removed all text that selectively described some correlations but not others from the manuscript. Although by removing discussion of the correlations throughout the manuscript addresses the concerns described by the reviewers in point (d), it does not address the initial concern described in (a)-(c). Thus, we have added a Figure to Appendix 1 that displays the correlations across all measures from the behavioral and neuroimaging tasks, and include a brief comment at the end of the Results section indicating that “Exploratory correlations across behavioral and neuroimaging variables are reported in Appendix 1—figure 1.” Although this approach may not fully capitalize on the strength of the design, given the length of the manuscript, the breadth of the findings we are already reporting, and our lack of specific hypotheses regarding the strength and direction of the correlations across tasks, we believe that any additional focus on the correlations would detract from rather than enhance our manuscript. Additionally, given that our data is a subsample of a larger study, it may be better to analyze the relationships across interoception measures using the larger dataset that includes healthy subjects. We have added the following comment to the “Limitations and Future Directions” section:

“Although not the primary intent of our investigation, we observed several interrelationships within and across levels of analysis raising the possibility of a latent interoceptive awareness trait factor. However, these relationships were inconsistent and were not pre-specified in our hypotheses. Identification of such a latent factor would likely require additional investigation using larger samples and inclusion of individuals not meeting criteria for psychiatric disorders.”

Regarding the comment on the weak relationship between insular signal change and interoceptive measures described in (c), the reviewers raise an excellent question about the unexpected differences between the within-task and across-task correlations. It is possible that we were better able to capture variability (and therefore stronger correlations) in the measure of intensity obtained during the heartbeat detection task due to the fact a) the heartbeat perception task involved modulation of the heartbeat, and b) required subjects to provide ratings on a 0-100 scale instead of 0-6 scale (that is, more variability in the dependent variable). The relationships between these two tasks may also be worth exploring in an analysis that includes the full sample of 500 individuals, rather than a subsample of suicide attempters and matched non-attempters.

[Editors' note: we also include below the reviews that the authors received from another journal prior to submission to eLife, along with the authors’ responses.]

Reviewer #1:

Comments to authors:

The manuscript “Diminished responses to bodily threat and blunted cardiac interoception in suicide Attempters" is an excellent, novel, and well-written contribution that reports physiological and self-report data that is in line with theories suggesting that suicide may root in blunted interoceptive processing or in other words increased tolerance to (impending) physiological damage. This is currently the most comprehensive study on this topic. Being a sub-study of a larger study has allowed recruiting a particularly well described sample and has offered the opportunity for individual matching of patients between suicide-attempters and non-attempters. The findings have important implications for research and clinical practice.

The manuscript is well structured; language and grammar are clear and precise. The Introduction is sound, methods, sample selection as well as sample size appear appropriate and the Discussion is well balanced.

We thank the reviewer for this kind assessment of our study and manuscript.

Major issues:

The only major point I did not really understand was, why the authors have chosen to match 34 suicide-attempters with 68 non-attempters, which is a sample exactly twice the size and creates un-even cell-sizes (which is associated with statistical problems).

We chose to increase the number of individuals in our reference group by using a 1:2 matching ratio in order to increase our confidence in the between-groups comparisons due to the relatively low number of suicide attempters available to us. Although unequal cell sizes can be problematic for certain statistical analyses, the analysis methods we selected are tolerant to the issues associated with unequal cell sizes (e.g., heterogeneous variances between groups).

In the sample description, I missed an overview of diagnoses and comorbidities. In addition, a bit more information on type of and reason for medication would be helpful (maybe in the appendix).

Information about medication usage and diagnostic comorbidities has been added to the Supplement. See Supplemental Table S1 for an overview of the diagnostics between groups and Supplemental Table S2 for an overview of the types of medications participants were taking.

In the main manuscript, a little more information regarding missing data would make it easier for the reader to appreciate what is reported in detail in the appendix. I would suggest shifting the sentence "non-attempter subjects (n=239) were only included for matching to suicide attempters if their data had been manually checked and they had complete observations on the behavioral and psychophysiological variables examined" to the Materials and methods section.

The relevant information has been moved to the main text of the manuscript.

I also missed a-priori power considerations.

We did not conduct or report an a-priori power analyses in the current study, due to the fact that we conducted all analyses retrospectively using a dataset that had previously been collected as part of a longitudinal naturalistic study. Additionally, given the lack of literature on behavioral and neuroimaging assessments of interoception and suicide, expected effect sizes would have been difficult to estimate beforehand. A comment on this has been added to the manuscript (subsection “Participants”) to clarify that our findings are from a retrospective analysis of a pre-existing dataset.

In the Discussion, maybe a brief remark regarding the problem of relatively low reliability of physiological measures might be useful. In particular, it should be made clear that none of the tasks applied in the study could serve for (individual) diagnosis or prognosis.

This is an important point and we have added this comment to the Discussion (“it should be noted that none of the interoceptive tasks applied in the current study have demonstrated sufficient reliability to be considered appropriate for implementation in prognostic assessments of suicidality in clinical settings.”).

Minor issues:

Please add version/build no. of R package 'nlme'.

In the sentence "Suicide attempters held their breath longer (10 seconds on average)" I'd suggest adding SD.

In the figure captions, I would suggest to explain the meaning of the asterisk and report the associated significance level.

We thank the reviewer for pointing these issues out. These changes have been made in the text and in the figure captions.

Reviewer #2:

Comments to authors: The paper by Khalsa and colleagues reports on the findings of an interesting study examining the topic of diminished interoception to orthostatic threats in suicide attempters. With rising numbers of suicide deaths, identifying indices specific to attempters versus non-attempters is highly relevant and timely. The paper is well written and presents strong and interesting findings.

We appreciate the reviewer for their kind assessment of our manuscript.

I only have a few suggestions:

Did the authors assess for current suicidal ideation in their sample? It seems important not only to ensure that there were no group differences but whether there is a difference between non-ideators versus ideators versus past attempters. My understanding is that research on indices between ideators versus attempters is greatly needed to better predict and target the group at greatest risk. What about current or past NSSI, particularly given that NSSI is thought to decrease pain perceptions.

Suicidal ideation was assessed in two ways, using 1) the Patient Health Questionnaire (PHQ-9) during screening, and 2) using the Columbia Suicide Severity Rating Scale (CSSR) upon entry to the Tulsa 1000 longitudinal study. Participants in the study were excluded from the study if they reported active suicidal ideation on the PHQ-9. During the study, administration of the CSSR focused on assessing lifetime suicidal ideation, not current suicidal ideation at that time. As a result, we were unable to examine current and/or recent suicidal ideation in our sample, and we recognize that this is a limitation in the Discussion. We agree that research on indices that distinguish ideators from attempters is greatly needed. To assess this limitation to the best of our ability, we have re-run our analyses after a) covarying for lifetime ideation intensity and b) dividing our non-attempter group on the basis of presence or absence of lifetime ideation. These analyses are reported in the supplement. We acknowledge that this is not a perfect way of addressing this and that further research will be needed to effectively parse out the contribution of ideation to the differences in interoception between ideators and non- ideators.

Regarding the relationship between non-suicidal self-injury (NSSI) and pain perception:

In our sample, 47% (n=16) of suicide attempters reported a history of NSSI, and 50% (n=17) of suicide attempters denied a history of NSSI. We re-analyzed the four primary interoceptive domains examined in the current study with the inclusion of an interaction term between attempt history and NSSI. We found no significant interaction between attempt history and NSSI affecting overall heartbeat perception accuracy (t(90) = 1.6, p = .12), breath hold duration (t(90) = 1.15, p = .26), cold pressor duration (t(85) = .16, p = .87), or signal in the right posterior insula during cardiac attention (t(90) = 1.9, p = .06). We have added this analysis of the role of non- suicidal self-injury and some interpretive comments to the supplement.

It would be helpful to provide a bit more support for the chosen tasks. For example, how is the sensation elicited by breath holding (suffocation) or pain using the CPT thought to relate to suicide behaviors? Why would people who can tolerate shortness of breath better be more willing to take their life? It seems a plausible pathway in NSSI were repeated cutting leads to habituation and this in terms of less pain avoidance, but the importance of the sensory perception is less clear in attempters.

Our decision to examine interoception and suicide attempt history was motivated primarily by existing theories of suicide (Klonsky and May, 2015; Van Orden et al., 2010) and the small body of experimental work on suicide attempt history and interoception (Dodd et al., 2018; Forrest, Smith, White, and Joiner, 2015; Smith, Forrest, and Velkoff, 2018). We selected available tests of interoception from our study database that had a clear relationship to vital organ systems (i.e., cardiac, respiratory) or threats to bodily integrity (i.e., pain). The ability to tolerate aversive respiratory sensations is particularly relevant, as methods involving asphyxiation account for a large and increasing proportion of death by suicide (Yau and Paschall, 2018). Although the cold pressor task may not readily resemble a specific method of suicidal behavior, it is a strong assessor of pain tolerance and has been shown to correlate well with assessments of interoceptive sensitivity (Pollatos, Füstös, and Critchley, 2012) and other modalities of pain processing (Harris and Rollman, 1983).

Regarding the comment that “It seems a plausible pathway in NSSI were repeated cutting leads to habituation and this in terms of less pain avoidance, but the importance of the sensory perception is less clear in attempters,” theoretical work on suicide has previously argued that there is are two plausible pathways between pain perception and suicide attempts, one in which pain tolerance increases over time due to repeated exposure to pain (e.g., NSSI), and one in which the individual, regardless of pain exposure, has a heightened pain threshold and/or pain tolerance (i.e., “dispositional” contributors to suicidal capability as described in the model proposed by Klonsky and May (Klonsky and May, 2015)). While it is true that repeated cutting may lead to pain habituation which, in turn, might increase one’s suicidal capacity (as described in Joiner’s theory of suicide (Van Orden et al., 2010)), a trait-level dispositional degree of pain insensitivity could also predispose individuals to engage in life-threatening and/or physically harmful behaviors (Klonsky and May, 2015). In the current study we do not attempt to dissociate whether the interoceptive differences observed in our suicide attempters is due to a dispositional or acquired factors. Our primary aim was to establish whether evidence for such interoceptive differences exists, which would lay a foundation for future studies to distinguishing the role of dispositional or acquired factors.

Since one cannot rule out that the attempt itself (e.g., via hanging) caused the diminished interoception, additionally comparing non-attempters/non-ideators to non- attempters/ideators could further elucidate interoceptive differences in suicidal versus non-suicidal individuals.

As the reviewer points out, there are two possible interpretations to our findings. The first interpretation is that individuals who possess heightened tolerance for aversive interoceptive sensations are predisposed to engage in suicidal behavior in the presence of suicidal ideation, whereas individuals who lack tolerance for aversive interoceptive sensations will be less likely to engage in suicidal behavior, even in the presence of severe ideation. Another interpretation is that there are no interoceptive differences distinguishing those with the capacity to engage in suicidal behaviors from those who lack this capacity, but that suicide attempts themselves result in diminished interoception. While we believe that the former interpretation makes the most sense given the theoretical literature on suicidal capacity (Klonsky and May, 2015; Van Orden et al., 2010), we agree with the reviewer that we cannot rule out the possibility that the act of having previously engaged in suicidal behavior caused the diminished interoception in our sample. Additionally, it will be interesting to examine whether diminished interoception at baseline predicts the later emergence of suicidal behavior from a longitudinal perspective. Since the findings we are reporting are from an ongoing naturalistic longitudinal study we plan to explore this question in the future.

The reviewer also raises the issue of comparing of attempters, ideating non-attempters, and non-ideators. We agree that the ability to distinguish between these three groups is important. We have conducted additional analyses within our current sample in an attempt to provide clarification on this issue. In these additional analyses, we re-examined our four primary interoception variables after covarying for ideation intensity, and we examined group differences after splitting our sample into three groups: suicide attempters, ideators without a history of attempts, and non-ideators (See supplement). We have also added to the Discussion of this limitation in the main body of the manuscript.

Why was the breath-holding test repeated?

The breath holding test was repeated and averaged in order to increase our confidence in the measure through multiple observations, matching the approach of previous studies utilizing this test (Asmundson and Stein, 1994).

"greater expired O2 following breath hold" – should this say "lesser"?

This typo was corrected.

It is not clear why the authors report the findings on CO2 and O2. Of course, one would expect that breath holding time goes along with higher CO2 and (a small but non-clinical) decrease in O2 – in my mind that is not a result but just a manipulation check.

This is more than a manipulation check. Measurement of CO2 levels provided physiological evidence of suicide attempters’ greater ability to tolerate acute hypercapnic body states. Of course, based on gas exchange laws the O2 and CO2 levels were expected to be reciprocally related, and in that regard, including both could be viewed as a form of manipulation check. Leaving both results allows readers to assess both possibilities.

Reviewer #3:

Comments to authors: This interesting and potential important paper further strengthens previous studies suggesting a link between interoceptive processes and suicidality. Its strengths are twofold, firstly replicating previous findings of an association between self report interoceptive measures and recent (last 5 years) suicide plans, but more importantly substantiating these with more objective experimental measures of interception and their linked brain regions i.e. insula.

We thank the reviewer for this assessment.

I only have minor comments:

1) Many of the interception measures have either an implicit or explicit visceral pain component – it would be nice to be able to dissociate visceral pain (e.g. cold water immersion) from more somatic types of pain (e.g. Von Frey hairs) or alternately somatic sensory sensitivity to try and clarify whether suicidality is linked to impaired pain or somatic perception per se (nociception) or more specifically to interoceptive processes. It would be useful to at least raise this issue in the Discussion. e.g. [1]

[1] Pollatos O, Füstös J, and Critchley HD (2012). On the generalised embodiment of pain: how interoceptive sensitivity modulates cutaneous pain perception. Pain, 153 (8), 1680-6

We agree with the reviewer and have added a comment to the Discussion and is replicated below:

“The current study employed an imprecise, albeit commonly employed, measure of pain perception. It would be advantageous to be able to clarify whether suicidal action is differentially linked to impaired processing of visceral pain signals, which tend to be poorly localized, often referred to somatic structures, and produce strong autonomic and affective responses, as opposed to somatic pain signals, which tend to be discretely localized to somatic structures and produce more variable autonomic and affective responses (Sikandar and Dickenson, 2012). Beyond stimulating visceral and somatic pain processing via different neuroanatomical pathways, it would be helpful to evaluate the degree to which altered pain responding was directly driven by differences in nociception per se as opposed to indirectly modulated by differences in interoceptive processing (Pollatos et al., 2012).”

2) Previous authors have shown/ not shown an association between interception and personality features particularly emotionally unstable PD [2]. Do personality features mediate moderate link between interoception and suicidality in this cohort where personality measures were recorded?

[2] Hart N, McGowan J, Minati L, Critchley HD. Emotional regulation and bodily sensation: interoceptive awareness is intact in borderline personality disorder. J Personal Disord. 2013;27(4):506-18.

[3] Müller LE, Schulz A, Andermann M, Gäbel A, Gescher DM, Spohn A, et al. Cortical representation of afferent bodily signals in borderline personality disorder: neural correlates and relationship to emotional dysregulation. JAMA psychiatry. 2015;72(11):1077-86.

We unfortunately do not have personality measures related to emotional stability/instability assessed in the current study. However, this raises an interesting question, and we have discussed the possibility further in the Supplement.

Reviewer #4:

This study examines several indices of interoceptive awareness in psychiatric patients with histories of suicide attempts (n=34) and a psychiatric comparison group with similar levels of psychopathology (n=68). The topic of the study is timely, as the field knows little about what factors facilitate transition from suicidal thoughts to acts, and interoceptive awareness may be one of them. However, problems with sample size and design I think greatly limit what information can be gleaned from this study's results.

Sample size.

It seems sample size is insufficient for accurate estimation of population parameters, which not only means that real effects can be missed, but that seemingly 'significant' effects can be false positives. I worry this is a substantial rather than small problem when it comes to interpreting results: there are so many different statistical comparisons reported between the two groups, but by my calculation power for even a *single* statistical test is at most around 70%.

The reviewer raises an important point regarding the concern of false positives when conducting analyses within smaller samples. In the current study, we assessed our subjects across multiple distinct, yet related domains (i.e., heartbeat tapping, insula activation during cardiac interoceptive attention, breath holding, cold pressor performance, and self-report indices of interoception). While we did not produce statistically significant results for every analysis conducted (nonsignificant results are reported in the main text of the manuscript and the supplement), we observed a significant difference between groups on cold pressor and breath hold task performance as well as behavioral and neuroimaging assessments of cardiac interoception. We argue that erroneously receiving false positives across multiple measures of interoception is improbable, particularly given that 1) differences between groups were consistent across tasks and in the same direction (i.e., suicide attempters with blunted interoception relative to non-attempters), 2) we observed similar effect sizes across tasks that were in the moderate range (i.e., reducing suspicion for inflated effect sizes associated with small samples), and 3) our findings are supported by pre-existing theoretical work.

It should be noted that our sample size (N=102) is larger than what has been typically used in neuroimaging studies. The median sample size in a published neuroimaging study has been reported as 28 (Poldrack et al., 2017) and 33 subjects (Yeung, 2018), with nearly 95% of studies reporting a sample size of <100 subjects (Yeung, 2018). Additionally, with our data coming from a larger longitudinal study, we will have the opportunity to replicate our findings as more data are collected.

Design.

The potential role of suicide capacity highlighted in the manuscript is to facilitate “transitioning from suicidal ideation to action”. Thus, the group with attempts should have been matched to a group with ideation but no attempts. In contrast, matching on psychopathology is an inappropriate control for this research question, and at best is a rough and unsatisfactory proxy for ideation. Table 1 does report differences between the two groups on a single self-report item assessing suicidal ideation showing a moderate elevation in ideation among the attempter group (d is approximately.3). But the manuscript indicates the Columbia Suicide Severity Rating Scale was administered, and this provides an assessment of suicidal ideation that could be the basis for matching – why would this suicide ideation assessment be ignored when the difference between ideation and attempts is the focus of the manuscript? Matching the groups on ideation is critically important because all attempters have ideation; thus, in a design comparing attempters to non-attempters, a variable that correlates with ideation can masquerade as a correlate of attempts. We only know if a variable correlates with attempts above and beyond its relationship to ideation if ideation is explicitly and carefully controlled for. This design feature is necessary to address the manuscript’s focus on suicide capacity, since the whole point of capacity is that it may contribute to the difference between ideation alone and ideation that progresses to attempts.

We agree that matching on psychopathology alone would be an inappropriate and unsatisfactory proxy for ideation. However, we did not intend to use psychiatric symptom severity as a proxy for ideation. Rather, our goal was to match for illness markers that could independently impact our interoception variables. Anxiety, depression, eating disorders, and substance use disorders have all been previously associated with differences in interoception [e.g., response to cardiac and respiratory perturbation in anxiety disorders (Pohl et al., 1988; Van den Hout et al., 1987); differences in the insula BOLD signal during interoceptive attention in depression (Avery et al., 2014) and eating disorders (Kerr et al., 2016); cold pressor performance differences in individuals with depression (Schwier, Kliem, Boettger, and Bär, 2010) and substance use disorders (Pud, Cohen, Lawental, and Eisenberg, 2006); aberrant insula activation during an inspiratory breathing load task in individuals with a substance use disorder (Stewart et al., 2014); heightened sensitivity to heartbeat sensations (Khalsa et al., 2015) and aberrant insula response to respiratory perturbation in anorexia nervosa (Berner et al., 2018)]. By matching on psychopathology, we increased the likelihood that any differences observed on our measures of interoception were related to suicide attempt history rather than differences in psychopathology between groups. To clarify this in the manuscript, we have added text to the Discussion section (“We demonstrated these differences in a well-characterized sample of participants with similar levels of psychiatric symptoms, increasing the likelihood that the participants’ history of suicidal behavior was the driving force behind the differences observed in interoception, rather than varying features of psychopathology between groups”).

To address concerns about distinguishing ideators and attempters, we report on additional analyses in the Supplement showing that the relationship between interoception and suicide attempts is maintained even after covarying for suicidal ideation. We have also expounded on the limitations that we face by broadly comparing suicide attempters and non- attempters in the Discussion section of our manuscript, and call for additional research that will better enable us to examine the role of interoception in attempters, ideators, and non-ideators. We do believe, however, that the present examination of the role of interoception in suicide represents the strongest starting point for this emerging body of research to date.

I think there’s a mistake in Table 1.% Female is listed as 70% but the n is listed as just 4, which is well under 10%

We thank the reviewer for pointing out this error. The number of females in this cell should have been 47, not 4. Table 1 has been revised accordingly.

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Avery, J. A., Drevets, W. C., Moseman, S. E., Bodurka, J., Barcalow, J. C., and Simmons, W. K. (2014). Major depressive disorder is associated with abnormal interoceptive activity and functional connectivity in the insula. Biol Psychiatry, 76(3), 258-266. doi:10.1016/j.biopsych.2013.11.027

Berner, L. A., Simmons, A. N., Wierenga, C. E., Bischoff-Grethe, A., Paulus, M. P., Bailer, U.,. Kaye, W. H. (2018). Altered interoceptive activation before, during, and after aversive breathing load in women remitted from anorexia nervosa. Psychological medicine, 48(1), 142-154.

Dodd, D. R., Smith, A. R., Forrest, L. N., Witte, T. K., Bodell, L., Bartlett, M.,... Goodwin, N. (2018). Interoceptive deficits, nonsuicidal self-injury, and suicide attempts among women with eating disorders. Suicide Life Threat Behav, 48(4), 438-444.

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Harris, G., and Rollman, G. B. (1983). The validity of experimental pain measures. Pain, 17(4), 369-376.

Kerr, K. L., Moseman, S. E., Avery, J. A., Bodurka, J., Zucker, N. L., and Simmons, W. K. (2016). Altered Insula Activity during Visceral Interoception in Weight-Restored Patients with Anorexia Nervosa. Neuropsychopharmacology, 41(2), 521-528. doi:10.1038/npp.2015.174

Khalsa, S. S., Craske, M. G., Li, W., Vangala, S., Strober, M., and Feusner, J. D. (2015). Altered interoceptive awareness in anorexia nervosa: effects of meal anticipation, consumption and bodily arousal. International Journal of Eating Disorders, 48(7), 889-897.

Klonsky, E. D., and May, A. M. (2015). The three-step theory (3ST): A new theory of suicide rooted in the “ideation-to-action” framework. International Journal of Cognitive Therapy, 8, 114-129. doi:https://doi.org/10.1521/ijct.2015.8.2.114

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https://doi.org/10.7554/eLife.51593.sa2

Article and author information

Author details

  1. Danielle C DeVille

    1. Laureate Institute for Brain Research, Tulsa, United States
    2. Department of Psychology, The University of Tulsa, Tulsa, United States
    Contribution
    Conceptualization, Formal analysis, Investigation, Methodology
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8208-2705
  2. Rayus Kuplicki

    Laureate Institute for Brain Research, Tulsa, United States
    Contribution
    Formal analysis, Methodology
    Competing interests
    No competing interests declared
  3. Jennifer L Stewart

    1. Laureate Institute for Brain Research, Tulsa, United States
    2. Oxley College of Health Sciences, The University of Tulsa, Tulsa, United States
    Contribution
    Writing - review and editing, Conceptualization, Supervision, Funding acquisition, Methodology
    Competing interests
    No competing interests declared
  4. Tulsa 1000 Investigators

    Laureate Institute for Brain Research, Tulsa, United States
    Contribution
    Writing - review and editing, Conceptualization, Supervision, Funding acquisition, Methodology
    1. Robin L Aupperle, Laureate Institute for Brain Research, Tulsa, United States
    2. Jerzy Bodurka, Laureate Institute for Brain Research, Tulsa, United States
    3. Yoon-Hee Cha, Laureate Institute for Brain Research, Tulsa, United States
    4. Justin Feinstein, Laureate Institute for Brain Research, Tulsa, United States
    5. Jonathan B Savitz, Laureate Institute for Brain Research, Tulsa, United States
    6. Teresa A Victor, Laureate Institute for Brain Research, Tulsa, United States
  5. Martin P Paulus

    1. Laureate Institute for Brain Research, Tulsa, United States
    2. Oxley College of Health Sciences, The University of Tulsa, Tulsa, United States
    Contribution
    Conceptualization, Supervision, Funding acquisition, Methodology
    Competing interests
    No competing interests declared
  6. Sahib S Khalsa

    1. Laureate Institute for Brain Research, Tulsa, United States
    2. Oxley College of Health Sciences, The University of Tulsa, Tulsa, United States
    Contribution
    Conceptualization, Supervision, Funding acquisition, Methodology
    For correspondence
    skhalsa@laureateinstitute.org
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2124-8585

Funding

William K. Warren Foundation

  • Martin P Paulus

National Institute of Mental Health (K23MH112949)

  • Sahib S Khalsa

National Institute of General Medical Sciences (P20GM121312)

  • Jennifer L Stewart
  • Martin P Paulus
  • Sahib S Khalsa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Acknowledgements

The authors thank W Kyle Simmons, PhD, for helpful discussions that motivated the initial work on this project, Rachel Lapidus, MA, for helpful comments offered on the manuscript, Maria Puhl, PhD, and Wesley Thompson, PhD, for providing statistical consultation, the Tulsa-1000 clinical assessment team for participant recruitment and data collection, and the MRI technologists at the Laureate Institute for Brain Research for MRI data acquisition. The authors acknowledge Austin Lignieres, BS, James Hale, and Max Paulus for assisting with physiological data inspection and correction. This work has been supported in part by The William K Warren Foundation, by NIH/National Institute of Mental Health grant K23MH112949 (to SSK), and the National Institute of General Medical Sciences Center Grant Award Number 1P20GM121312 (JLS, MPP, SSK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Results presented in part at the Anxiety and Depression Association of America 39th Annual Scientific Meeting, March 2019, and at the Society of Biological Psychiatry 74th Annual Meeting, May 2019, in Chicago, IL.

The ClinicalTrials.gov identifier for the clinical protocol associated with data published in the current paper is NCT02450240, ‘Latent Structure of Multi-level Assessments and Predictors of Outcomes in Psychiatric Disorders’.

The Tulsa 1000 Investigators include the following contributors: Robin L Aupperle, Ph.D., Jerzy Bodurka, Ph.D., Justin S Feinstein, Ph.D., Sahib S Khalsa, M.D., Ph.D., Rayus Kuplicki, Ph.D., Martin P Paulus, M.D., Jonathan Savitz, Ph.D., Jennifer L Stewart, Ph.D., and Teresa A Victor, Ph.D.

Ethics

Human subjects: All study procedures were approved by the Western Institutional Review Board (WIRB protocol #20142082) and all research participants provided written informed consent prior to participation in the research.

Senior Editor

  1. Christian Büchel, University Medical Center Hamburg-Eppendorf, Germany

Reviewing Editor

  1. Alexander Shackman, University of Maryland, United States

Publication history

  1. Received: September 4, 2019
  2. Accepted: March 2, 2020
  3. Version of Record published: April 7, 2020 (version 1)
  4. Version of Record updated: April 8, 2020 (version 2)

Copyright

© 2020, DeVille et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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