Internalizing psychopathologies (IPs), which include anxiety and depressive disorders, are prevalent illnesses characterized by abnormalities in emotional processing and emotion regulation (First et al., 2015, Kotov et al., 2017). This includes a negative information processing bias whereby affected individuals, relative to unaffected controls, tend to pay more attention to and have greater memory for negative stimuli relative to positive stimuli (Gollan et al., 2016, Everaert et al., 2012). Known as the negativity bias (Roiser et al., 2012), this abnormal processing of emotional information is a risk factor for development of internalizing psychopathology (Shook et al., 2007) and a target of psychosocial interventions for IPs (i.e., cognitive-behavioral therapy (Barlow et al., 2004)). In addition to driving increased reactivity to negative information, research suggests that the negativity bias also contributes to abnormal processing of neutral stimuli. For example, individuals with IPs tend to interpret neutral facial expressions as sad (Gollan et al., 2008) and demonstrate abnormal pattens of brain activation when viewing neutral stimuli (Oliveira et al., 2013). Other evidence further suggests that brain reactivity to neutral stimuli may not be significantly different than reactivity to negative stimuli in IPs (Brunetti et al., 2010). Of note, negativity bias for neutral stimuli may be an underlying risk factor for development of emotional disorders (Marusak et al., 2017).

Individuals with IPs also show additional evidence of negativity bias via abnormalities in the processing of self-referential information. Broadly, self-referential processing describes reactivity to stimuli that one experiences as strongly related to their own person (Northoff et al., 2006) at the phenomenal level of experience (i.e., not requiring reflection or objective reasoning (Legrand, 2007)) that is thus presumed to represent a foundational, automatic function (Lin et al., 2018). Individuals with IPs demonstrate a bias toward negative self-referential processing (Northoff, 2007) characterized by excessive self-focused attention that is persistent and self-critical (Nejad et al., 2013, Yoon et al., 2019), particularly in the context of greater emotional intensity (Mennin and Fresco, 2013). Critically, higher levels of negative self-referential processing is associated with higher generalized anxiety symptoms and stress-reactivity (Tracy et al., 2021) and is predictive of both current and future recurrence of major depressive episodes (LeMoult et al., 2017, Phillips et al., 2010).

A substantial number of studies have investigated the neural correlates and mechanisms of negativity bias in emotion and self-referential processing in IPs using targeted functional magnetic resonance imaging (fMRI) tasks. Collectively, research suggests that the observed biases toward negative stimuli and aberrant emotion processing in IPs are driven by a frontolimbic neural circuit. (Hamilton et al., 2012) The amygdala and the insula, which are involved in subjective emotional experience (Caria et al., 2010, Phan et al., 2004) and threat-related processing (Shankman et al., 2014), are key nodes of this circuit that show greater reactivity to negatively valenced stimuli (Groenewold et al., 2013, Buhle et al., 2014, Etkin and Wager, 2007) and are strongly implicated in the pathophysiology of IPs (Etkin and Wager, 2007). Notably, existing data suggest that activation in these regions while viewing aversive stimuli is associated with increased symptoms of anxiety in individuals with IPs (MacNamara et al., 2017). Further, a large body of literature has demonstrated that the default mode network (DMN), which is comprised of distributed network of brain regions (e.g., medial prefrontal cortex, posterior cingulate cortex/precuneus, and bilateral inferior parietal lobules) (Whitfield-Gabrieli and Ford, 2012) that are more active during rest (Raichle, 2015), has a central role in self-referential processing (Whitfield-Gabrieli and Ford, 2012). Activation of the DMN is thought to indicate self-reflective and stimulus-independent thought that occurs spontaneously when the brain is not engaged in a specific or attention-demanding task (Buckner et al., 2008). DMN activity is altered in IPs (Gentili et al., 2009, Zhao et al., 2007) – including during the viewing of neutral stimuli (Petrowski et al., 2014) – and activity in DMN brain regions contributes to disordered self-referential thinking (Sheline et al., 2009) and higher levels of negative self-attribution (Grimm et al., 2009, Kross et al., 2009) in IPs. Collectively, existing studies suggest that a negativity bias for both emotion and self-related information in IPs has identifiable neural underpinnings.

Despite known biases in the processing of neutral information in IPs, the vast majority of neuroimaging studies of emotion processing do not examine reactivity to neutral stimuli as a unique condition. Instead, neutral stimuli are typically used as a baseline condition that is subsequently contrasted with another experimental condition (i.e., valenced emotional stimuli to create an index of positive or negative emotional brain reactivity) (Infantolino et al., 2018). Thus, little is known about the neural processes underlying emotional experience for neutral stimuli and how these processes may differ between clinical and non-clinical groups or during neutral versus negative stimuli. As existing research suggests that individuals with IPs are prone to have negative reactions and negative interpretations of neutral information and that these individuals further tend to preferentially engage in self-referential processing for information to which they react negatively, examination of reactivity to neutral stimuli as a unique condition is crucial in clarifying potential group differences in neural reactivity.

Thus, our primary objective in the present study was to examine whether patterns of neural reactivity to neutral and negative stimuli differ between IP and control groups in brain areas relevant to emotional and self-referential processing. We hypothesized that brain activation in these areas would be significantly different between healthy controls and individuals with IPs for both neutral and negative stimuli (i.e., a significant interaction between group and condition). Given strong evidence of a negativity bias in the processing of emotional and neutral information in IPs, we hypothesized that, relative to controls, 1) individuals with IPs would show greater frontolimbic reactivity (i.e., insula and amygdala activation) for both neutral and negative stimuli, and 2) individuals with IPs would show greater DMN activation for negative stimuli. Further, as it remains unclear whether neural reactivity to neutral stimuli is related to anxious and/or affective symptoms among individuals with IPs, we examined correlations between brain activation and clinically-validated symptom measures to address this gap.