Fronto-limbic and autonomic disjunctions to negative emotion distinguish schizophrenia subtypes

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Abstract

Schizophrenia patients show a disconnection in amygdala-medial prefrontal cortex and autonomic arousal systems for processing fear. Concurrent functional magnetic resonance imaging [fMRI] and skin conductance recording were used to determine whether these disturbances are specific to fear, or present in response to other signals of danger. We also examined whether these disturbances distinguish a specific symptom profile. During scanning, 27 schizophrenia (13 paranoid, 14 nonparanoid) and 22 matched healthy control subjects viewed standardized facial expressions of fear, anger and disgust (versus neutral). Skin conductance responses [SCRs]were acquired simultaneously to assess phasic increases in arousal. ‘With-arousal’ versus ‘without-arousal’ responses were analysed using non-parametric methods. For controls, ‘with-arousal’ responses were associated with emotion-specific activity for fear (amygdala), disgust (insula) and anger (anterior cingulate), together with common medial prefrontal cortex [MPFC] engagement, as predicted. Schizophrenia patients displayed abnormally increased phasic arousal, with concomitant reductions in emotion-specific regions and MPFC. These findings may reflect a general disconnection between central and autonomic systems for processing signals of danger. This disjunction was most apparent in patients with a profile of paranoia, coupled with poor social function and insight. Heightened autonomic sensitivity to signals of fear, threat or contamination, without effective neural mechanisms for appraisal, may underlie paranoid delusions which concern threat and contamination, and associated social and interpersonal difficulties.

Introduction

Individuals with schizophrenia show impairments in processing facial expressions of emotion in both behavioral and neurocognitive tasks, which are particularly marked for threat-related expressions such as fear (Streit et al., 1997, Mandal et al., 1998, Edwards et al., 2002, Loughland et al., 2002). The amygdala and medial prefrontal cortex [MPFC] networks have a central role in processing fear (Williams et al., 2001, Williams et al., 2004a), and functional neuroimaging studies have also revealed pronounced disturbances in these networks in schizophrenia (Phillips et al., 1999, Gur et al., 2002, Williams et al., 2004b, Das et al., in press).

Perception of fearful face stimuli, presented as briefly as 500 ms, can produce a subjective experience of fear (Wild et al., 2001), consistent with the notion that these evolutionary-determined expressions signal biological responses to potential threat. It has been proposed that amygdala-MPFC networks are modulated by reciprocal connections to autonomic arousal systems, creating a feedback loop between the internal representation of emotionally salient stimuli and somatic emotional states (Damasio, 1996). In support of this mechanism, we have observed increases in skin conductance arousal with activation of amygdala-MPFC activation in healthy subjects (Williams et al., 2001, Williams et al., 2004a, Williams et al., 2005a).

In schizophrenia, by contrast, reductions in amygdala-MPFC responses to fear have been associated with excessive arousal, particularly in patients with paranoid symptomatology, suggesting a disconnection in the central-autonomic systems for processing signals of potential threat (Williams et al., 2004b). Here, we tested the prediction that this disjunction is associated with poor functional outcome, in terms of social functioning and insight, given evidence for a link between poor outcome and heightened arousal. We also investigated whether the arousal/amygdala-MPFC disjunction is present in response to other signals of negative emotion which relate to the content of paranoid delusions.

An extensive body of electrodermal research has identified two types of abnormality in schizophrenia: hyper- and hypo-responsivity (Bernstein et al., 1982, Gruzelier and Venables, 1972). Hyper-responsive schizophrenia patients show heightened skin conductance orienting to innocuous stimuli, along with an elevated skin conductance level and frequent non-specific skin conductance responses [SCRs] (Dawson and Schell, 2002). Notably, patients who show heightened orienting to innocuous stimuli have also been found to show heightened skin conductance responses to emotional film clip stimuli (Kring and Neale, 1996, Kring et al., 1999). Electrodermal hyper-responsivity is most often associated with poor symptomatic, social and functional outcome (Dawson and Schell, 2002). Hyper-responsivity is also an episode indicator, particularly in recent-onset schizophrenia (Dawson et al., 1994), and predicts schizophrenia-like features in longitudinal studies (e.g., Raine et al., 2002), suggesting its potential value as a marker of prognosis. On the other hand, electrodermal non-responding has been associated with better outcome in schizophrenia (Schell et al., 2002), although contrary reports exist (Öhman et al., 1989). It is also present in both first-degree relatives and remitted schizophrenia, pointing to its potential as a vulnerability marker (Schell et al., 2002).

Evidence that heightened skin conductance reactivity to emotional stimuli may be confined to a particular subgroup of schizophrenia patients (Kring and Neale, 1996, Kring et al., 1999) accords with the heterogenous presentation of this condition. In the previous study of functional magnetic resonance imaging [fMRI] with concurrent skin conductance recording, the disjunction of arousal and amygdala-MPFC activity distinguished schizophrenia patients with paranoid symptomatology (Williams et al., 2004b). The separation into paranoid versus nonparanoid subtypes has revealed comparatively consistent differences in neurocognitive profile (Zalewski et al., 1998, Zureick and Meltzer, 1988), relative to other clinical groupings. Consistent with the association of electrodermal hyper-responsivity with poor outcome in schizophrenia, paranoid schizophrenia has been associated specifically with poor adulthood adjustment (Karakula and Grzywa, 1999). Since emotional expressions are so central to social interaction and forming and maintaining social relationships (Keltner and Kring, 1998), we might expect these patients to be defined by poor social functioning in particular. Paranoid delusions have also been highly related to poor insight, an important factor in functional outcome (McEvoy et al., 1989).

The presence of fear-related deficits accords with the paranoid symptomatology of this subtype. However, paranoid delusions encompass fears of other sources of potential danger, including poisons and contaminants and aggression from others (Kim et al., 1993). Facial signals of disgust and anger are universally recognized social signals which communicate the potential presence of these dangers (Ekman et al., 1972). Fear, anger and disgust have been found to elicit common activity in the MPFC, consistent with a general role in the cognitive aspects of emotion processing, including attention to internal emotional state and emotion regulation (Phan et al., 2002, Williams et al., 2005a). While anger and disgust have been associated with amygdala activity, fear elicits the most robust amygdala response. Anger has most consistently been associated with activity in the anterior cingulate and orbitofrontal cortex, and disgust with the anterior insula and basal ganglia (Blair et al., 1999, Phan et al., 2002, Phillips et al., 1997, Phillips et al., 1998). We have shown that the MPFC and these emotion-specific regions are engaged with increased skin conductance arousal in healthy subjects: amygdala for fear, anterior cingulate for anger and insula and basal ganglia for disgust (Williams et al., 2005a).

In this study, we compared paranoid to nonparanoid schizophrenia and healthy controls on responses to fear, anger and disgust using fMRI and skin conductance recording. We sought to confirm the arousal and amygdala-MPFC disturbance to fear in paranoid patients, and to determine whether these patients show corresponding disjunctions between arousal and anterior cingulate-MPFC for anger and insula/basal ganglia-MPFC for disgust.

Section snippets

Participants

Subgroups of 13 paranoid (mean age = 26.8 years, S.D. = 9) and 14 nonparanoid (mean age = 27.8 years, S.D. = 10.3) schizophrenia patients were matched on age and sex distribution with 13 healthy control subjects (mean age = 25.1 years, S.D. = 8.1) (Table 1). Diagnoses of schizophrenia were based on the Composite International Diagnostic Interview (CIDI; Robins et al., 1998), and consensus by three psychiatrists (two independent from the study), according to DSM-IV criteria. Exclusion criteria for both

Results

As a new study of the patients from Williams et al. (2004b), the behavioral, SCR and fMRI results for fear may be considered a verification of the findings from this previous study.

Discussion

In this study, we investigated whether symptoms of fear and social dysfunction in schizophrenia are underpinned by a breakdown in the neural systems for processing signals of danger, and their interaction with autonomic arousal. We explored the generality of this breakdown in terms of signals of fear, anger and disgust, given that paranoid delusions may encompass fear of events in the environment, persecutory beliefs and poisons or contaminants (Kim et al., 1993). Schizophrenia patients with

Acknowledgements

This study was supported by funding from the Australian Research Council (ARC) and Rebecca Cooper Medical Research Foundation, with infrastructure support from NISAD. LW is a Pfizer Senior Research Fellow, and PD is supported by NISAD.

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