Reduced corticolimbic habituation to negative stimuli characterizes bipolar depressed suicide attempters

Every 40 seconds one person dies from suicide worldwide, resulting in ∼800,000 deaths per year (WHO, 2019). More than half of these deaths are related to depression (Bachmann, 2018; Cavanagh et al., 2003), and despite the increase of antidepressant treatment options, the incidence rates of suicide is still rising (Turecki and Brent, 2016). Different sociodemographic and clinical factors have been associated to suicidal risk, but the identification of patients in acute phase is still based on the clinical interview and on the patients’ self-reported likelihood of future engagement in suicidal behaviors (Glenn and Nock, 2014). Consequently, a tremendous need exists to provide objective markers for suicide behavior, identifying novel predictive factors and therapeutic targets.

The most elevated rate of completed suicide is associated to Bipolar Disorder (BD) [see Miller and Black (2020) for a review]. Suicidality in BD is characterized by high levels of impulsivity (Baldessarini et al., 2019), that predispose bipolar patients to fatal reactions to stress and anger (Oquendo et al., 2000), and lethality, indicating that BD patients also attempt suicide using more violent methods and with greater intent to die (Tondo et al., 2021)

Amygdala is one of the core brain regions implicated in self-injurious behaviors across psychiatric disorders, due to its crucial role in defining emotional states, especially the negative ones, as well as in contributing to aggressive and impulsive behaviors (Haller, 2018; LeDoux, 2003; Siever, 2008). An erratic amygdala activity, paralleled by a reduced control of prefrontal cortex, has been extensively shown in BD, underlying emotional and mood dysregulation (Chen et al., 2011; Delvecchio et al., 2013; Vai et al., 2019), and it has also been related to suicidal behaviors among BD patients. For instance, abnormal amygdala connectivity was associated with suicide history and ideation severity and lethality in mood disorders (Alarcón et al., 2019; Ambrosi et al., 2019; Johnston et al., 2017; Kang et al., 2017; Wang et al., 2019). In terms of volumetric findings, results for both a reduced and increased amygdala volume were related to suicidality (Monkul et al., 2007; Wang et al., 2019).

In recent years, new insights are prompting amygdala habituation as robust phenotype reliably investigable during an fMRI experimental setting (Plichta et al., 2014). Habituation can be defined as a response decrement due to stimulus repetition, indicating a potential adaptive mechanism that limits the attentional resources to familiar and inconsequential stimuli, in favor to more salient ones (Ramaswami, 2014; Rankin et al., 2009). In healthy individuals, habituation to repeated emotional stimuli was observed in the amygdala, as well as in several cortico-limbic regions, such as the hippocampus and the medial/inferior temporal cortex (Feinstein et al., 2002; Fischer et al., 2000; Fischer et al., 2003; Plichta et al., 2014; Wright et al., 2001). Reduced amygdala habituation to emotional stimuli was found in several psychopathological conditions, known to be associated to an increased risk of suicide, such as borderline personality disorder (Bilek et al., 2019), internalizing problems in adolescents (van den Bulk et al., 2016), and depressive episodes in major depressive disorder (MDD) (Paris, 2019; Piqueras et al., 2019; Siegle et al., 2002; Zahid and Upthegrove, 2017). Furthermore, abnormal temporal dynamics of intrinsic brain activity was found to predict severity of suicidality in unmedicated bipolar patients (Gong et al., 2020a).

Therefore, we hypothesized that a reduced amygdala and cortico-limbic habituation rate during the implicit processing of negative emotions may define a possible biological marker of suicide attempting in BD, representing core biological underpinnings of impulsiveness and reactivity to stress and to anger. We also evaluated possible associations with current severity of depressive and suicidal symptoms.

Habituation was modelled with two complementary methodological approaches: 1) the absolute habituation, based on a regression approach (REG), that defines a rate of habituation independently from initial neural reactivity, and 2) the First minus Last block (FmL) method, that, despite less sensitive, allows to capture non-linear habituation rate (Plichta et al., 2014). Additionally, aiming at providing new candidate markers for suicidality in BD, we applied supervised machine learning (ML) pipelines on habituation rates to assess their ability in predicting bipolar SA at the individual level.

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