Subjective Emotional Over-arousal to Neutral Social Scenes in Paranoid Schizophrenia Psychosis Is Significantly Reduced by Effective Antipsychotic Pharmacotherapy

Svetlozar Haralanov^{1, 2, 3}, Evelina Haralanova^{1, 2, 3, 4, 5},  Petya Terziivanova^{2, 3, *}, Hans-Juergen Moeller⁴, Kristina Hennig-Fast^{4, 5, 6}

¹E-Motion Center, Institute for Cognitive-Affective Neuroscience, Sofia, Bulgaria

²Department of Psychiatry, Medical University, Sofia, Bulgaria

³University Hospital of Neurology and Psychiatry "St. Naum", Luben Russev Sofia, Bulgaria

⁴Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Nussbaumstraße Munich, Germany

⁵Neuro-Cognitive Psychology, Department of Psychology, Ludwig-Maximilians-University, Leopoldstr, Munich, Germany

⁶Clinical Psychology and Health Psychology, Faculty of Psychology, University of Vienna, Liebiggasse, Vienna, Austria

Abstract

We have recently found that patients with paranoid schizophrenia experience abnormally elevated subjective emotional arousal (SEA) in response to low-arousing/neutral but not to high-arousing/aversive social scenes. The aim of the present study was to test an explanation of this finding by exploring the relative contributions of psychosis and antipsychotic pharmacotherapy. We compared the SEA to the same two types of stimuli in 15 actively psychotic and 15 therapeutically improved post-psychotic inpatients with paranoid schizophrenia contrasted to 30 healthy controls. The results revealed that the SEA to the neutral stimuli was significantly higher in the psychotic than in the post-psychotic subgroup, being abnormally high in both of them relative to controls. Conversely, their SEA to the aversive stimuli was as high as that of the controls. Additionally, we demonstrated that during psychosis the patients experience low-arousing/neutral scenes as if they are high-arousing, thus misattributing emotional salience to them. During the post-psychotic phase this deficient differentiation between salient and nonsalient stimuli is partially restored. We discussed how these findings and their explanations could bridge the gap between objective neurobiological and subjective psychological mechanisms of psychotic-symptom formation and antipsychotic-treatment response, respectively. We argued that an elevated endogenous SEA underlies subjective symptoms of psychosis and accordingly is a key target for antipsychotic pharmacotherapy. We further proposed a practical application of our simple SEA-rating-task as a promising neurobehavioral probe for fMRI studies of these mechanisms as well as a potential surrogate endpoint measure of antipsychotic-treatment response, including in clinical trials of novel antipsychotic drugs.

Keywords

Antipsychotic Pharmacotherapy, Paranoid Schizophrenia Psychosis, Emotional Arousal, Emotional Experience, Emotional Salience Misattribution, Social Cognition

Received: March 31, 2015
Accepted: April 20, 2015
Published online: May 27, 2015

@ 2015 The Authors. Published by American Institute of Science. This Open Access article is under the CC BY-NC license. http://creativecommons.org/licenses/by-nc/4.0/

1. Introduction

According to the influential circumplex model of emotions [1-5], which has been validated for schizophrenic patients as well [6], the affective states can be characterized by two relatively independent dimensions: valence and arousal. Emotional valence refers to the hedonic tone of an experience ranging from negative/unpleasant to positive/pleasant; while emotional arousal refers to a sense of mobilization ranging from low/inactivated to high/activated. Therefore, all emotions can be understood as combinations of these two basic dimensions [7,8]. Anxiety and fear, for instance, might be viewed as high-arousal/negative-valence affective states that produce aversive (including paranoid) behaviors [9]. Notably, being an independent dimension, emotional arousal should be discriminated from the intensity of a given (negative or positive) emotional valence [5,8,10,12].

Beyond valence and arousal, another important dimension of emotions is their social relevance [13-15]. For example, paranoid anxiety and fear are social emotions that concern non-existing threats from other people and misinterpretation of neutral social environments as hostile, threatening, frightening, and dangerous [16-19]. So, they could be seen as defensive social emotions [16,18,20,26]. Accordingly, paranoid delusions [16-18,27] and hallucinations [28-31] have a distrustful interpersonal orientation [27] or interpersonal sensitivity [19,23]: the patients are focused on receiving (actually interpreting) messages from outside people (persecutors and/or voices) that provoke avoidant social behaviors [27,32,36]. Furthermore, abnormalities in affective processing and social cognition are considered to be central features of schizophrenia and psychotic symptoms to represent distortions or errors in comprehending the social world [15,37]. The fundamental role of defensive social emotions in paranoid schizophrenia has been emphasized by the classical phenomenology, which described the first symptom of incipient psychosis as delusional mood [38] or trema (stage fright) [39], subjectively experienced as anxiety and/or fear associated with (most frequently unconscious) anticipation of some social threats. Delusional mood is typically followed or accompanied by delusional perception, clinically manifested as misattribution of threatening significance to insignificant and innocuous social situations [40-45]. Both delusional mood and delusional perception have been conceptualized to reinforce each other by creating a vicious circle, thus paving the way for delusion formation and hallucinogenesis in paranoid schizophrenia [21]. In the same vein, over-attribution of relevance to otherwise irrelevant social cues has been found to play a prominent role in early stages of schizophrenic psychoses, when patients feel that the world is full of signs that point to a yet unrevealed secret [46]. Likewise, within the framework of the basic-symptom concept of schizophrenia, it has been shown that one of the earliest manifestations of paranoid psychosis is an internally generated hyperalert state of consciousness that mimics the response to external dangers [47]. Anxiety, worry and misattribution of threat to neutral social stimuli have been hypothesized to elicit and further maintain delusion formation and/or hallucinogenesis in paranoid schizophrenia psychoses [16,21,48,52]. Consistent with clinical observations and theoretical hypotheses, a meta-analysis of laboratory studies has found that schizophrenic patients experience relatively stronger aversion to neutral stimuli [53]. Moreover, within the categorical model of emotions, which implies a differentiation between a limited number of basic emotions [54,55], analyses of error patterns have discovered that neutral emotional expressions are misperceived (misinterpreted) as fearful by stable remitted [56] or as angry by acutely paranoid [57] schizophrenic patients. Similar assignment of emotional valence to neutral words was reported in patients with persecutory delusions [58]. Such findings give evidence that patients with paranoid schizophrenia tend to misattribute negative emotional valence to social stimuli that are normally classified as neutral. Analogous threat assignment to neutral social situations has been reproduced using virtual reality experiments in patients with persecutory delusions [59,60], patients with paranoia [61], individuals at high risk for psychosis [62], individuals who rated higher on trait paranoia [17,19], and even in some clinically healthy individuals from the general population [50]. The misattribution of threat to neutral avatar behaviors in these experiments was strongly predicted by higher levels of anxiety and worry, thus confirming the important role of defensive emotions for the emergence of paranoid beliefs. Accordingly, the persecutory delusions were conceptualized as affect-laden beliefs regarding other people, which are formed to make sense of and explain increased emotional arousal [63-65].

Our group has previously found that the subjective emotional arousal (SEA) to neutral but not to aversive social scenes was significantly higher in schizophrenic inpatients hospitalized for acute paranoid psychosis than in healthy controls [65]. Recently this finding was essentially supported and somewhat extended by a meta-analysis of 26 studies (including our own) that have investigated the self-reported arousal to a range of affective and neutral stimuli in patients with schizophrenia [12]. The authors concluded that patients and controls report similar arousal in response to affective (pleasant and unpleasant) stimuli, but patients report higher arousal in response to neutral stimuli. Such a conclusion in fact confirms our results [65]. Furthermore, our neurobiological explanatory hypothesis was supported (though indirectly) by the latest findings that schizophrenic patients not only misattribute emotional importance/salience to neutral stimuli but also activate amygdala and other mesolimbic structures in response to these stimuli to a greater extent than healthy controls [66-68].

The aim of the present study was to better explain the previous empirical findings by dissecting the role of psychosis from that of the antipsychotic treatment. Here we provide a new analysis of our data in order to test the hypothesis that during active psychosis an abnormally elevated baseline level of SEA is misattributed to emotionally ambiguous neutral stimuli but it is subsequently attenuated by effective antipsychotic treatment [65]. We subdivided the schizophrenic group into actively psychotic and therapeutically improved post-psychotic subgroups and compared their SEA in response to the same neutral and aversive social scenes to that of the healthy controls. Based on our theoretical predictions, we anticipated that the SEA to the neutral social scenes would be highest in the psychotic subgroup, relatively lower in the post-psychotic one, and lowest in the control group. In opposition, we expected that the SEA to the aversive social scenes in both schizophrenic subgroups would be as high as that in the control group.

2. Materials and Methods

2.1. Subjects

This article is based on the previously published study from 30 male schizophrenic inpatients hospitalized for acute paranoid psychosis and 30 matched healthy controls [65]. For our current purposes we subdivided the patients into two subgroups of psychotic (n=15) and post-psychotic (n=15) patients and analyzed their data separately. All three groups – healthy subjects, psychotic and post-psychotic patients – were well matched (see Table 1). There were no significant differences between them on demographic characteristics as age, education and parental education. There was also a good match between the two patient subgroups in terms of their clinical profile. They did not differ in duration of illness, medication and PANSS score for negative symptoms. The differences between the two patient subgroups were based on the study design and were only in terms of PANSS score for positive symptoms and episode duration.

Table 1. Demographic and clinical characteristics of participants.

Note: SD = standard deviation; N/A = Not applicable; PANSS = Positive and Negative Syndrome Scale; PANSS: Negative = subscale for negative symptoms; PANSS: Positive = subscale for positive symptoms, *** = statistical significance at level p=.001.

Inclusion and exclusion criteria for patients and controls were the same as in the previous study. All patients were hospitalized for an acute psychotic state with well-expressed positive symptoms and all they were on Aripiprazole as monotherapy. The 15 patients included in the psychotic subgroup were investigated as soon as possible after their hospitalization (before being improved by the antipsychotic treatment). On the subscale for positive symptoms of the Positive and Negative Syndrome Scale (PANSS) they scored 17 or more with at least one item rated 4 or more. The 15 patients from the post-psychotic subgroup were hospitalized for an acute psychosis as well, but were followed-up until a certain degree of therapeutic remission was achieved before taking part in the study. They were with decreased severity of residual positive symptoms being not yet remitted. On the positive subscale of PANSS the post-psychotic patients scored below 17 with no items rated 4 or more.

Informed consent was obtained from all individual participants included in the study. All procedures performed in the study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

2.2. Apparatus, Stimuli and Design Procedure

The task (including the apparatus, stimuli and design procedure) is described in detail in the previous article [65]. Here we provide a brief summary.

2.2.1. Apparatus

The experiment was carried out in a quiet laboratory examination room on a laptop with a 14’’ diameter screen. The task was administered on a Presentation Software (www.neurobs.com). Stimuli and a rating scale were alternatively projected onto the display.

2.2.2. Stimuli

Stimuli were color photographs depicting social scenes - with at least one person presented. They were selected from the International Affective Picture System - IAPS [69] and the Munich Affective Picture System - MAPS [70], so that we can have photos, depicting complex scenes with social content for various dimensions of valence and arousal. For our study we have chosen 10 stimuli with low-arousing/emotionally neutral and 10 with high-arousing/affect-laden aversive content. The neutral scenes presented persons attending public events or engaged in work, hobbies or everyday tasks. The aversive scenes presented people in situations of abuse, poverty, physical threat, loss, grief, injuries and disaster. Stimuli were selected based on their ratings in the normative MAPS study [70]. The ratings have been based on the Self-Assessment Manikin - SAM [71] on 9-point rating scales for valence and arousal. The neutral and the aversive scenes were matched on size, color brightness, picture complexity, number of depicted persons and format. In addition to the 20 social complex scenes, there were 20 non-social and non-arousing baseline pictures, introduced to neutralize the impression of the scenes by masking their psychological effects.

2.2.3. Design and Procedure

Each subject was tested individually. Written and oral instructions were provided together with practice trials prior the actual experiment with individual feedback to assure comprehension both in controls and in patients. Before the experimental task there was a preliminary task to practice rating on the rating scale, which was a moving bar, appropriate and easily applicable in fMRI studies. In the experimental task participants were asked to rate their own subjective emotional arousal (SEA) after seeing a social scene presented on the screen. While a scene was shown subjects had to view it passively and be prepared to rate the evoked level of SEA. The task consisted of 20 trials, randomized across two conditions - aversive and neutral. For further details see [65].

2.3. Data Analysis

The study was cross-sectional and we did both within- and between-subjects comparisons. To examine whether the SEA differed across affective categories, depending on group, a 2 x 2 repeated measures ANOVA was used with affective category (low-arousing/neutral vs. high-arousing/aversive) as a within-subjects factor and group (psychotic vs. post-psychotic schizophrenia patients vs. healthy controls) as a between-subjects factor. Planned independent samples t-tests were also performed. All analyses were done with the SPSS software (version 14.0, SPSS Inc., 2000).

3. Results

One-way ANOVA revealed a significant group difference in the subjective emotional arousal (SEA) for the neutral social scenes F(2, 57)=32.48, p=.001, but a lack of group difference for the aversive social scenes F(2, 57)=1.48, p=.24. To understand between which groups exactly there was a difference in the SEA for the neutral stimuli, independent samples t-tests were made. All three groups differed significantly from one another. Psychotic patients (5.52±1.41) had significantly higher SEA than both the post-psychotic patients (4.02±1.48): t(28)=-2.85, p=.01 and the healthy controls (2.53±0.88): t(19.60)=-7.54, p=.001. Post-psychotic patients also had higher SEA than the controls: t(19.02)=-3.57, p=.001. When we examined the role of the affective category, the paired samples t-tests revealed that in the control group, the SEA for the neutral and for the aversive stimuli was significantly different: t(29)=-11.75, p=.001. For the post-psychotic patients the difference was only marginally significant: t(14)=-2.03, p=.06. For the psychotic patients there was a lack of significant difference: t(14)=-.22, p=.83. (Figure 1)

Figure 1. Comparison among the subjective emotional arousal (SEA) levels evoked by the 2 affective categories of social scenes in the 3 investigated groups.

** = statistical significance at level p=.01; *** = statistical significance at level p=.001

4. Discussion

The present study is the first to explore the role of psychosis and antipsychotic treatment, respectively, for the previously discovered [65] abnormally high level of SEA in response to low-arousing/neutral but not to high-arousing/aversive social scenes in patients with paranoid schizophrenia. The empirical fact itself has been subsequently confirmed [12]. There have been data about its supposed neurobiological mechanisms [46,72,76] that were additionally supported in the last years [66-68]. Now we reveal that the SEA to the neutral scenes is significantly higher in the actively psychotic than in the therapeutically improved post-psychotic inpatients, being significantly higher in both schizophrenic subgroups relative to healthy controls. This new finding gives evidence that the abnormally elevated level of SEA to the neutral social scenes [65] is highest during the active phase of psychosis but afterwards (during the early post-psychotic phase) it is significantly reduced presumably by the effective antipsychotic pharmacotherapy. On the other hand, the present study reveals that the level of SEA to the aversive social scenes in the two schizophrenic subgroups was not different from that of the controls, so it neither depends on the psychotic state nor on the antipsychotic-treatment response. Taken together, these findings attest that the abnormal elevation of SEA during the psychotic phase and its reduction during the post-psychotic phase of paranoid schizophrenia concern only the low-arousing/neutral but not the high-arousing/aversive social scenes. Hence, the previously revealed abnormal reactivity (oversensitivity) to neutral stimuli in schizophrenic patients [12,65] was validated once again but with the specification that it is associated mainly with the psychotic state, whereas the effective antipsychotic pharmacotherapy acts in the opposite direction and significantly reduces it.

The findings are consistent with our preliminary hypothesis that the neurobiological mechanisms underpinning the subjective symptoms of psychosis directly produce an elevated level of baseline SEA (anxious over-arousal or delusional mood), thereby inducing intolerance of ambiguity, which results in oversensitivity to neutral (non-salient) social scenes and aberrant assignment of emotional salience to them [65]. In the context of emotional tasks, the neutral social stimuli are indeed ambiguous, since they do not possess their own unambiguous emotional valence (positive or negative) nor they evoke considerable SEA in healthy controls. Psychotic patients might be particularly sensitive to such stimuli as they are intolerant of ambiguity and inclined to make hasty decisions (e.g. jumping to conclusions or threat assignment) in ambiguous social situations [48,52,63,77,82]. Intolerance of ambiguity has been usually associated with anxiety and worry [83-86] and previous studies have found that anxious patients tend to appraise ambiguous social stimuli as more dangerous and to classify them as threatening [87], i.e. as high-arousing/aversive. It was documented that anxious patients and healthy controls similarly appraise unambiguous threats, but the anxious patients appraise ambiguous threats as more dangerous than do healthy controls, thus demonstrating a compromised capacity to separate safety from threat and a failure to inhibit fear responses in safe contexts [87]. A recent cognitive model of delusion formation in paranoid schizophrenia (paranoia) has assumed psychotic social anxiety to be a key emotion that leads to a search for meaning and explanation, thus contributing to creation of threat beliefs [17,52,59,63,88]. Accordingly, persecutory delusions have been viewed as compensatory attempts to explain the unjustified social anxiety and increased anxious arousal [63,64,89,90]. Such concepts are based on the idea that similar mechanisms might elicit paranoid and anxiety states [51,52,63,82,88,91,94]. At the same time, both these states could be seen as resulting from abnormal regression (though to a different degree) toward earlier immature phases of emotional development [21,22]. Although neutral social stimuli normally indicate safety, their social significance might be distorted in immature children, who exhibit greater amygdala activation in response to neutral than to fearful faces, indicating that, until discrimination and appraisal processes mature, neutral social stimuli are deemed more ambiguous [87,95,96]. Notably, similar data for overactivation of the amygdala [66-68,72] and other limbic structures [46,73,75,76] in response to neutral faces have been reported in psychotic schizophrenic patients and subjects at high risk for psychosis.

Our present study demonstrates the fact that during active psychosis the level of SEA to neutral social scenes is comparable to that of the aversive ones. This fact suggests that psychotic patients perceive ambiguous (low-arousing/neutral) social stimuli as if they were high-arousing/aversive and thus unconsciously misattribute emotional salience to them. As psychotic patients are basically over-aroused [97-99], it is conceivable that they fail to inhibit their abnormally elevated baseline SEA in safe (neutral) contexts, while keeping their normally high SEA in aversive contexts. Other studies have also demonstrated abnormalities in the ability of psychotic patients to discriminate between motivationally salient and neutral stimuli [66,68,73,100,103]. Theoretically, such findings are explainable by a malfunction of the fundamental human capacity to differentiate safe from dangerous social stimuli, which is learned throughout early development [87,95,96]. Analogous failure to distinguish between threat and safety might explain why schizophrenic patients experience stronger aversion to neutral stimuli [53] and tend to misattribute negative emotional valence to them [56-58].

At a more neurobiological level, this inability of schizophrenic patients to discriminate between neutral and aversive social stimuli could be explained by the influential "aberrant salience hypothesis" [104-108], which postulates that during psychosis an exaggerated release of dopamine in the mesolimbic system occurs out of context and independent of the situation. Thus dopamine, which under normal conditions is a mediator of contextually relevant salience, in psychotic states becomes a creator of aberrant salience to otherwise irrelevant neutral stimuli. The process is often associated clinically with a sense of anxiety [107], i.e. a high-arousal/aversive emotional state. The aberrant salience hypothesis has been admitted and/or validated by many researchers in the field [46,58,81,109,120]. A related hypothesis has also postulated that during psychosis an imbalance in dopamine systems underlies increased anxiety (over-arousal) and the assignment of emotional salience to insignificant emotionally neutral stimuli [72]. Notably, the causal role of dopamine increase for the misattribution of aberrant salience to task-irrelevant neutral stimuli has been recently revealed in previously never-medicated patients with Parkinson’s disease after starting their treatment with dopamine agonists [121] and analogous misattribution of relevance to task-irrelevant neutral stimuli has been demonstrated experimentally after administration of amphetamine in healthy volunteers [122]. Hence, we might assume that the elevated level of endogenous SEA in psychotic patients, which leads to misattribution of salience (relevance, importance) to otherwise nonsalient neutral stimuli, might be explained by the same exaggerated and chaotic firing of mesolimbic dopaminergic neurons, out of context and independent of the situation, which has been conceptualized by the aberrant salience hypothesis [104]. Such an explanation is in line with our finding that the antipsychotic pharmacotherapy significantly reduces the abnormally elevated SEA to neutral social scenes.

Moreover, our hypothesis for a neurobiologically generated (endogenous) subjective emotional over-arousal (aberrantly assigned to neutral social scenes) could be supported by the recent functional-neuroimaging data for overactivation of limbic structures, like the amygdala [46,66,68,72,76,103], the hippocampus [75,105], and the parahippocampal gyrus [73] to neutral social stimuli in prodromal and/or psychotic schizophrenic patients. Other studies have provided direct evidence that inappropriate activation of the amygdala, the midbrain, and the ventral striatum in response to neutral stimuli is associated with the severity of delusional symptoms in patients with schizophrenia [76]. Additional neuroimaging evidence has been accumulated about overactivation of cortical midbrain network during emotional and/or social appraisals in schizophrenia [11,34,37,66,101,123], especially during psychosis [33]. Previous research suggests that psychotic-symptom formation (reality distortion dimension) of paranoid schizophrenia is linked with an endogenous overactivation of limbic structures that are part of the "fear systems" [74] within the emotional brain [124], which are normally activated in case of external danger [124-127] and some of them (e.g. the amygdala) are involved in the detection and attribution of salience [128]. A number of studies on emotional processing in schizophrenia have found evidence for a behavioral bias or an elevated neural response to affectively neutral, nonsalient stimuli during emotional processing [56,58,73,74,100,101,103,113,129], which in some studies has been linked to psychotic symptoms [73,130,131] or specifically to paranoid delusions [58, 113, 129,  132]. This abnormal brain response to neutral stimuli has been proposed to reflect a tendency to attend preferentially, or misattribute motivational salience, to nonsalient information during psychotic states [104,105]and has been linked to abnormalities in emotional appraisal [37,103,131,133]. Based on our present data, we may theorize that during active psychosis an overactivation of the limbic system elicits a state of abnormally elevated baseline SEA, which is "projected" to ambiguous, nonsalient (emotionally neutral) social stimuli, thus leading to aberrant assignment of emotional salience to them. By unifying the different levels of explanation, we might generalize that psychotic patients are emotionally over-aroused and thus oversensitive to emotionally neutral (ambiguous) social stimuli due to underlying mesolimbic hyperdopaminergia [46,104,120] and/or overactivation of the "fear systems" within the limbic brain [74,130].

Just in the opposite direction is the explanation of our finding that during the post-psychotic phase of paranoid schizophrenia, the level of SEA to neutral but not to aversive social scenes is significantly lower than during active psychosis. This finding might shed new light on the mechanisms of the antipsychotic-treatment response and could be explained by the propensity of the antipsychotic pharmacotherapy to restore the deficient selective inhibition of the context-inappropriate high SEA to neutral stimuli, while preserving the context-appropriate high SEA to aversive stimuli. It is logical to assume that the post-psychotic patients partially succeed to differentiate safety from threat and to inhibit their abnormally elevated SEA to neutral social scenes, thus approximating the healthy controls. Our explanation of this tendency toward normalization is that (by dampening the abnormally high level of baseline SEA) the antipsychotic pharmacotherapy reduces the oversensitivity to ambiguous (emotionally neutral) social stimuli and thus dampens the misattribution of emotional salience to them. In fact, both psychotic and post-psychotic patients experience significantly higher SEA to neutral but not to aversive social scenes relative to healthy controls. So, both schizophrenic subgroups fail to selectively inhibit their inappropriately elevated endogenous SEA in neutral social contexts, but this deficient selective inhibition is partly restored (though not normalized) in the post-psychotic subgroup. We may admit that the antipsychotic treatment selectively dampens only the inappropriately high SEA to neutral social stimuli, while leaving almost unaffected the appropriately high SEA to aversive stimuli. It appears that the antipsychotic pharmacotherapy selectively inhibits the abnormally high level of endogenous SEA and thus prevents its external projection to emotionally ambiguous neutral social scenes, but keeps relatively intact the normally high level of exogenous SEA evoked by unambiguously high-arousing aversive scenes. Therefore, according to our interpretation, the antipsychotic mechanisms are selectively focused on the internally but not on the externally generated high level of SEA. To the best of our knowledge, such a mechanism of the antipsychotic treatment has not been discussed until now. In principle, it could be incorporated in the mechanism postulated by the above mentioned aberrant salience hypothesis [104-108], which admits that antipsychotic drugs are efficacious because (by suppressing the underlying mesolimbic hyperdopaminergia) they dampen the aberrant salience misattributed to otherwise neutral stimuli [104-108,115,117,119]. Our present data might explain how the reduction of mesolimbic hyperdopaminergia dampens the aberrant assignment of emotional salience to neutral (nonsalient) social stimuli. According to our interpretation, the effective antipsychotic pharmacotherapy not only suppresses the mesolimbic hyperdopaminergia but also dampens the overactivation of the fear (defense) systems in neutral (safe) contexts, thereby selectively attenuating the elevated endogenous SEA and its misattribution ("projection") to low-arousing/neutral social stimuli. A direct confirmation of such a hypothesis would be achieved relatively easy by analogous comparisons between the SEA ratings of psychotic and post-psychotic patients with paranoid schizophrenia during functional-neuroimaging (fMRI) recordings, since our task was explicitly designed just for this type of research [134]. We expect a significant overactivation of limbic structures (particularly the amygdala) in response to neutral but not to aversive social scenes during active psychosis and its relative reduction during the post-psychotic phase of the illness. It is worthy to note that ratings of SEA have already been successfully used to discriminate between fMRI-data of different subgroups of patients and healthy controls [135,136].

From a more practical point of view, we could argue that the level of SEA to neutral social scenes might serve as a proxy measure of the neurobiological mechanisms of both psychotic-symptom formation and antipsychotic-treatment response in patients with paranoid schizophrenia. So, its abnormal elevation during active psychosis might be used as a subclinical state-marker for psychosis as well as a surrogate measure of the level of yet inaccessible mesolimbic hyperdopaminergia supposedly underlying the psychotic state [110,115,117,119]. Correspondingly, we could predict that its degree of relative attenuation during the post-psychotic phase might be used as a surrogate endpoint measure of the antipsychotic-treatment response. Importantly, if our assumptions prove to be true, then our simple, not expensive and easy-to-perform task with SEA ratings could be applied as a promising neurobehavioral probe for fMRI-studies of the pro-psychotic and anti-psychotic brain mechanisms, respectively [134]. It could be successfully applied in the everyday practice for subclinical treatment monitoring, including in clinical trials of novel antipsychotic drugs [137]. Future research with a follow-up (prospective) design would be necessary to verify the feasibility of these perspectives.

The present study is only an initial step to a more profound explanation of the mechanisms that underlie psychotic-symptom formation in paranoid schizophrenia and their suppression by effective antipsychotic treatment, particularly within the framework of the new field of SEA. Together with the above discussed advantages, the present study has some limitations. One of them is the fact that we have investigated only males, aiming to select more homogenous groups and to prevent the confounding role of gender. Therefore, future studies that comprise females would be necessary to enhance the generalization of our results. Concerning the generalization of the theoretical interpretations, we should admit that they are not yet conclusive due to the relatively small size of the investigated groups. However, we claim that the conceptual basis of our explanations is solid enough to allow plausible assumptions that would serve at least for further hypothesis-testing efforts. Another issue that should be considered is that we have measured only the level of SEA, because we have been particularly concerned with the subjective experience of patients with paranoid schizophrenia. Having in mind that tonic electrodermal hyper-arousal is part of a transient intermediate state that may lead to a psychotic episode in vulnerable individuals [97], in future studies it would be interesting to include some objective measures of autonomic arousal [97-99,138,140], such as skin conductance response, heart rate, pupilometry, and electroencephalography, in order to compare them with the level of SEA. As a next step, a direct functional neuroimaging recording during the execution of the task would help to reveal the brain mechanisms that underlie the SEA to affective and non-affective stimuli in patients and controls. Furthermore, it would be important to replicate the findings with a longitudinal study.

There are many directions for more research on the topic [141]. Further analyses could take into account the reaction-time measures and the content of the different neutral social scenes. It would be also recommendable to compare the SEA to the same stimuli in different psychotic syndromes, such as hallucinatory vs. delusional, as well as acute vs. chronic psychoses. It would be interesting to use analogous neutral social stimuli from other modalities, e.g. by using audio stimuli with social significance from the International Affective Digitized Sound System [142]. An acoustic task may be even more sensitive in patients with paranoid schizophrenia, particularly during the phase of florid psychosis, because the difficulty to detect and recognize ambiguous sounds would stimulate the patients to project their dominant emotional experiences, especially paranoid fears, since the acoustic modality is specifically associated with unseen or hidden threats and dangers [48,79]. Another direction is to study non-psychotic schizophrenic patients, e.g. during stable therapeutic remission or long-term deficit states. Longitudinal follow-up studies of the level of SEA to low-arousing/neutral and high-arousing/affective social scenes in never medicated psychotic patients (before and after treatment) could also provide valuable results. Last but not least is the option to include high-arousing/positive, low-arousing/positive and low-arousing/negative social scenes in future research of the level of SEA in other fields of psychiatry and clinical neuroscience.

5. Conclusion

The present study is the first to provide evidence that the previously revealed abnormally high level of SEA to low-arousing/neutral social scenes in patients with paranoid schizophrenia is psychotic-state related and accordingly it is significantly reduced by effective antipsychotic treatment. At the same time, the SEA evoked by high-arousing/aversive social scenes is neither depending on the psychotic state nor on the antipsychotic pharmacotherapy. To explain these crucial findings we propose a hypothesis that subcortical (limbic) mechanisms of psychotic-symptom formation directly produce an abnormally elevated baseline SEA, which then is unconsciously projected (misattributed) to low-arousing/neutral social stimuli, due to their emotional ambiguity. Afterward, the effective antipsychotic pharmacotherapy acts in the opposite direction. By suppressing the neurobiological mechanisms of psychosis it tends to restore the selective inhibition of the inappropriately high SEA in safe contexts, while preserving the normally high SEA in aversive contexts. So, the effective antipsychotic pharmacotherapy selectively dampens the internally generated SEA, thus reducing its misattribution to low-arousing/neutral stimuli, while keeping the externally generated SEA, evoked by high-arousing/aversive stimuli. The revealed mechanisms of SEA would represent the missing link between the objective (brain) and subjective (mind) mechanisms of both psychotic-symptom formation and subsequent antipsychotic-treatment response. From a theoretical point of view, this would contribute to bridge the explanatory gap between the basic objective disease process in the brain and the resulting subjective experiences not only during the transition from acute psychosis to post-psychotic remission but also during the mirror transition from pre-psychotic high-risk and prodromal states to full-blown psychosis [143-147]. So, our findings could have important theoretical and practical implications in the very promising field of early detection and preventive treatment of such states.

Acknowledgements

We gratefully acknowledge the financial support from the Bavarian Research Foundation (Bayerische Forschungsstiftung) within the Neuro-Cognitive Psychology (NCP) Program and DAAD. The German Research Foundation (DFG, IRTG 1328) and Medical University, Sofia also provided partial funding for the project. We appreciate the contribution of Anna Beraldi for the preliminary selection and evaluation of the stimuli. We also wish to thank Diana Shkodrova, MD, PhD for the helpful discussions and for her valuable inputs and useful comments on the study and the manuscript.

References

1. Russell JA (1980) A circumplex model of affect. J Pers Soc Psychol 39:1161-1178.
2. Feldman LA (1995) Valence focus and arousal focus: Individual differences in the structure of affective experience. J Pers Soc Psychol 69:153-166.
3. Barrett LF, Russell JA (1999) The structure of current affect: controversies and emerging consensus. Curr Dir Psychol Sci 8:10-14.
4. Gerber AJ, Posner J, Gorman D, Colibazzi T, Yu S, Wang Z, Kangarlu A, Zhu H, Russell J, Peterson BS (2008) An affective circumplex model of neural systems subserving valence, arousal, and cognitive overplay during the appraisal of emotional faces. Neuropsychologia 46:2129-2139.
5. Gerdes AB, Wieser MJ, Mulbereger A, Weyers P, Alpers GW, Plichta MM, Breuer F, Pauli P (2010) Brain activations to emotional pictures are differentially associated with valence and arousal ratings. Front Hum Neurosci 4:175.
6. Kring AM, Barrett LF, Gard DE (2003) On the broad applicability of the affective circumplex: Representations of affective knowledge among schizophrenic patients. Psychol Sci 14:2007-2014.
7. Russell JA (2003) Core affect and psychological construction of emotion. Psychol Rev 110:145-172.
8. Feng C, Wang L, Liu C, Zhu X, Dai R, Mai X, Luo Y-J (2012) The time course of the influence of valence and arousal on the implicit processing of affective pictures. PLoS ONE 7(1):e29668.
9. Posner J, Russell JA, Peterson BS (2005) The circumplex model of affect: An integrative approach to affective neuroscience, cognitive development, and psychopathology. Dev Psychopathol 17(3):715-734.
10. Jones BE (2003) Arousal systems. Front Biosci 8:438-451.
11. Lakis N, Jimenez JA, Mancini-Marie A, Stip E, Lavoie ME, Mendrek A (2011) Neural correlates of emotional recognition memory in schizophrenia: effects of valence and arousal. Psychiatry Res 194:245–256.
12. Llerena K, Strauss GP, Cohen AS (2012) Looking at the other side of the coin: A meta-analysis of self-reported emotional arousal in people with schizophrenia. Schizophr Res 142:65-70.
13. Britton JC, Phan KL, Taylor SF, Welsh RC, Berridge KC, Liberzon I (2006) Neural correlates of social and nonsocial emotions: An fMRI Study. Neuroimage 31:397-409.
14. Sakaki M, Niki K, Mather M (2012) Beyond arousal and valence: the importance of the biological versus social relevance of emotional stimuli. Cogn Affect Behav Neurosci 12:115-139.
15. Bjorkquist OA, Herbener ES (2013) Social perception in schizophrenia: Evidence of temporo-occipital and prefrontal dysfunction. Psychiatry Res: Neuroimaging 212(3):175-182.
16. Green MJ, Phillips ML (2004) Social threat perception and the evolution of paranoia. Neurosci Biobehav Rev 28:233-242.
17. Freeman D (2007) Suspicious minds: the psychology of persecutory delusions. Clin Psychol Rev 27(4):425-457.
18. Freeman D, Freeman J (2008) Paranoia: The 21st Century Fear. Oxford, UK: Oxford University Press.
19. Freeman D, Pugh K, Vorontsova N, Antley A, Slater M (2010) Testing the continuum of delusional beliefs: an experimental study using virtual reality. J Abnorm Psychol 119(1):83-92.
20. McNaughton N, Corr PJ (2004) A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neurosci Biobehav Rev 28:285-305.
21. Haralanova E, Haralanov S, Shkodrova D (2007) Emotional dysregulation and psychotic symptom formation in paranoid schizophrenia. Bulg Neurol Psychiatr Practice 1:13-16.
22. Haralanova E, Haralanov S, Shkodrova D (2008) Emotional production in "non-affective" psychoses: clinical and theoretical implications. Neurol Psychiatry 1:24-27.
23. Lincoln TM, Mehl S, Ziegler M, Kesting ML, Exner C, Rief W (2010) Is fear of others linked to an uncertain sense of self? The relevance of self-worth, interpersonal self-concepts, and dysfunctional beliefs to paranoia. Behav Ther 41:187-197.
24. Haralanov S, Haralanova E, Docheva Y, Shkodrova D (2013) Hyperaffectivity and psychotic-symptom formation in paranoid schizophrenia: a novel approach toward endogenous psychoses. Neurol Psychiatry 3:75-87.
25. Kesting M-L, Bredenpohl M, Klenke J, Westermann S, Lincoln TM (2013) The impact of social stress on self-esteem and paranoid ideation. J Behav Ther Exp Psychiatry,44:122-128.
26. Hartmann MM, Sundag J, Lincoln TM (2014) Are self-other discrepancies a unique risk factor for paranoid symptoms? Cogn Ther Res 38:62-70.
27. Beck AT, Rector NA, Stolar N, Grant P (2009) Schizophrenia: cognitive theory, research, and therapy. The Gulford Press,New York/London.
28. Hayward M, Berry K, Ashton A (2011) Applying interpersonal theories to the understanding of and therapy for auditory hallucinations: a review of the literature and directions for further research. Clin Psychol Rev 31:1313-1323.
29. Paulik G (2012) The role of social schema in the experience of auditory hallucinations: a systematic review and a proposal for the inclusion of social schema in a cognitive behavioral model of voice hearing. Clin Psychol Psychother 19:459-472.
30. Bell V (2013) A community of one: social cognition and auditory verbal hallucinations. PLOS Biol 11(12): e1001723.
31. Horga G, Fernandez-Egea E, Mane A, Font M, Schatz KC, Falcon C, Lomena F, Bernardo M, Parellada E (2014) Brain metabolism during hallucination-like auditory stimulation in schizophrenia. PLoS One 9(1):e84987.
32. Wible CG, Preus AP, Hashimoto R (2009) A cognitive neuroscience view of schizophrenic symptoms: abnormal activation of a system for social perception and communication. Brain Imaging Behav 3:85-110.
33. Wible CG (2012) Schizophrenia as a disorder of social communication. Schizophr Res Treatment ID920485.
34. Taylor SF, Chen AC, Tso IF, Liberzon I, Welsh RC (2011) Social appraisal in chronic psychosis: role of medial frontal and occipital networks. J Psychiatr Res 45(4):526-538.
35. Ilankovic LM, Allen PP, Engel R, Kambeitz J, Riedel M, Mueller N, Hennig-Fast K (2011) Attentional modulation of external speech attribution in patients with hallucinations and delusions. Neuropsychologia 49(5): 805-812.
36. Kambeitz-Ilankovic L, Hennig-Fast K, Benetti S, Kambeitz J, Pettersson-Yeo W, O´Daly O, McGuire P, Allen P (2013) Attentional modulation of source attribution in first-episode psychosis: A functional magnetic resonance imaging study. Schizophr Bull 39(5):1027-1036.
37. Holt DJ, Lakshmanan B, Freudenreich O, Goff DC, Rauch SL, Kuperberg GR (2011) Dysfunction of a cortical midline network during emotional appraisals in schizophrenia. Schizophr Bull 37:164-176.
38. Jaspers K (1913) Allgemeine Psychopathologie. Springer, Berlin.
39. Conrad K (1958) Die beginnende Schizophrenie. Thieme Verlag, Stuttgart.
40. Ciompi L.(1994) Affect logic: An integrative model of the psyche and its relation to schizophrenia. Br J Psychiatry 164 (Suppl. 23):51-55.
41. Fuchs T (2005) Delusional mood and delusional perception - a phenomenological analysis. Psychopathology 38(3):133-139.
42. Chadwick PK (2007) Peer-professional first-person account: schizophrenia from the inside – phenomenology and the integration of causes and meanings. Schizophr Bull 33(1):166-173.
43. Mishara AL (2010) Klaus Conrad (1905-1961): delusional mood, psychosis, and beginning schizophrenia. Schizophr Bull 36(1):9-13.
44. Mishara AL, Fusar-Poli P (2013) The phenomenology and neurobiology of delusion formation during psychosis onset: Jaspers, Truman symptoms, and aberrant salience. Schizophr Bull, 39:278-286.
45. Maj M (2013) Karl Jaspers and the genesis of delusions in schizophrenia. Schizophr Bull 39:242-243.
46. Heinz A, Schlagenhauf F (2010) Dopaminergic dysfunction in schizophrenia: salience attribution revisited. Schizophr Bull 36:472-485.
47. Klosterkoetter J (1992) The meaning of basic symptoms for the genesis of the schizophrenic nuclear syndrome. Jpn J Psychiatry Neurol 46(3):609-630.
48. Shkodrova D (1991) On the auditory information processing in schizophrenia: experimental studies on the verbal encoding of rhythmical click-stimulations. PhD dissertation, Sofia: Medical University.
49. Freeman D, Garety PA (1999) Worry, worry processes and dimensions of delusions: An exploratory investigation of a role for anxiety processes in the maintenance of delusional distress. Behav Cogn Psychother 27:47-62.
50. Freeman D, Pugh K, Antley A, Slater M, Bebbington P, Gittins M, Dunn G, Kuipers E, Fowler D, Garety P. (2008) A virtual reality study of paranoid thinking in the general population. Br J Psychiatry 192:258-263.
51. Freeman D, Fowler D (2009) Routes to psychotic symptoms: trauma, anxiety and psychosis-like experiences. Psychiatry Res 169:107-112.
52. Freeman D, Startup H, Dunn G, Cernis E, Wingham G, Pugh K, Cordwell J, Kingdon D (2013) The interaction of affective and psychotic processes: A test of the effects of worrying on working memory, jumping to conclusions, and anomalies of experience in patients with persecutory delusions. J Psychiatr Res 47(12):1837-1842.
53. Cohen AS, Minor KS (2010) Emotional experience in patients with schizophrenia revisited: Meta-analysis of laboratory studies. Schizophr Bull 36:143-150.
54. Ekman P (1992) An argument for basic emotions. Cogn Emot 6:169-200.
55. Panksepp J (2005) Affective consciousness: core emotional feelings in animal and humans. Conscious Cogn 14:19-69.
56. Kohler CG, Turner TH, Bilker WB, Brensinger CM, Siegel SJ, Kanes SJ, Gur RE, Gur RC (2003). Facial emotion recognition in schizophrenia: intensity effects and error pattern. Am J Psychiatry 160:1768-1774.
57. Pinkham AE, Brensinger C, Kohler C, Gur RE, Gur RC (2011) Actively paranoid patients with schizophrenia over attribute anger to neutral faces. Schizophr Res 125(2-3):174-178.
58. Holt DJ, Titone D, Long LS, Goff DC, Cather C, Rausch SL, Judge A, Kuperberg GR (2006) The misattribution of salience in delusional patients with schizophrenia. Schizophr Res 83:247-256.
59. Freeman D (2008) Studying and treating schizophrenia using virtual reality: a new paradigm. Schizophr Bull 34(4):605-610.
60. Ellett L, Freeman D, Garety PA (2008) The psychological effect of an urban environment on individuals with persecutory delusions: the Camberwell walk study. Schizophr Res 99(1-3):77-84.
61. Broome MR, Zanyi E, Hamborg T, Selmanovic E, Czanner S, Birchwood M, Chalmers A, Singh SP (2013) A high-fidelity virtual environment for the study of paranoia. Schizophr Res Treatment 2013:538185.
62. Valmaggia L, Freeman D, Green C, Garety P, Swapp D, Antley A, Prescott C, Fowler D, Kuipers E, Bebbington P, Slater M, Broome M, McGuire PK (2007) Virtual reality and paranoid ideation in people with an ‘at risk mental state’ for psychosis. Br J Psychiatry 191:s63-s68.
63. Freeman D, Garety PA (2004) The psychology of persecutory delusions. Psychology Press, Howe.
64. Boden MT, Berenbaum H (2012) Facets of emotional clarity and suspiciousness. Pers Indiv Dif 53:426-430.
65. Haralanova E, Haralanov S, Beraldi A, Moeller HJ, Hennig-Fast K (2012) Subjective emotional over-arousal to neutral social scenes in paranoid schizophrenia. Eur Arch Psychiatry Clin Neurosci 262:59-68.
66. Anticevic A, Van Snellenberg JX, Cohen RE, Repovs G, Dowd EC, Barch DM (2012) Amygdala recruitment in schizophrenia in response to aversive emotional material: a meta-analysis of neuroimaging studies. Schizophr Bull 38:608–621.
67. Lakis N, Mendrek A (2013) Individuals diagnosed with schizophrenia assign emotional importance to neutral stimuli: an fMRI study. ISRN Psychiatry 2013:965428.
68. Mier D, Lis S, Zygrodnik K, Sauer C, Ulferts J, Gallhofer B, Kirsch P (2014) Evidence for altered amygdala activation in schizophrenia in an adaptive emotion recognition task. Psychiatry Res: Neuroimaging 221(3):195-203.
69. Lang PJ, Bardley MM, Cuthbert BN (2005) International affective picture system (IAPS): Affective ratings of pictures and instruction manual. Technical Report A-6. University of Florida, Gainesville, FL
70. Beraldi A, Haralanova E, Engel RR, Fast K (2006) Eine neue affektive Bildersammlung: die Muenchner affektive Bildersammlung (MABS), Presentation at DGPs, Nuernberg, September 17– 21.
71. Bradley MM, Lang PJ (1994) Measuring emotion: the Self-Assessment Manikin and the Semantic Differential. J Behav Ther Exp Psychiatry 25(1):49-59.
72. Aleman A, Kahn RS (2005) Strange feelings: Do amygdala abnormalities dysregulate the emotional brain in schizophrenia? Prog Neurobiology 77:283-298.
73. Surguladze S, Russell T, Kucharska-Pietura K, Travis MJ, Giampietro V, David AS, Phillips ML (2006) A reversal of the normal pattern of parahippocampal response to neutral and fearful faces is associated with reality distortion in schizophrenia. Biol Psychiatry 60:423-431.
74. Hall J, Whalley HC, McKirdy JW, Romaniuk L, McGonigle D, McIntosh AM, Baig BJ, Gountouna VE, Job DE, Donaldson DI, Sprengelmeyer R, Young AW, Johnstone EC, Lawrie SM (2008) Overactivation of fear systems to neutral faces in schizophrenia. Biol Psychiatry 64:70-73.
75. Seiferth NY, Pauli K, Habel U, Kellermann T, Shah NJ, Ruhrmann S, Klosterkoetter J, Schneider F, Kircher T (2008) Increased neural response related to neutral faces in individuals at risk for psychosis. Neuroimage 40:289-297.
76. Romaniuk L, Honey GD, King JRL, Whalley HC, McIntosh AM, Levita L, Hughes M, Johnstone EC, Day M, Lawrie SM, Hall J (2010) Midbrain activation during Pavlovian conditioning and delusional symptoms in schizophrenia. Arch Gen Psychiatry 67:1246-1254.
77. Corcoran R, Cummins S, Rowse G, Moore R, Blackwood N, Howard R, Kinderman P, Bentall RP (2006) Reasoning under uncertainty: heuristic judgments in patients with persecutory delusions or depression. Psychol Med 31:1-10.
78. Phillips ML, David AS (2002) Cognitive impairments as causes of positive symptoms in schizophrenia. In: Sharma T & Harvey P (Eds.). Cognition in Schizophrenia: Impairments, Importance and Treatment Strategies. Oxford University Press, New York: pp. 210-228.
79. Shkodrova D, Haralanova E, Haralanov S (2007) Cognitive mechanisms of delusion formation in paranoid psychosis. Bulg Neurol Psychiatr Practice 4(1):17-20.
80. McKay R, Langdon R, Coltheart M (2007) Jumping to delusions? Paranoia, probabilistic reasoning, and need for closure. Cognit Neuropsychiatry 12:362-376.
81. Speechley WJ, Whitman JC, Woodward TS (2010) The contribution of hyperslaience to the jumping to conclusions bias associated with delusions in schizophrenia. J Psychiatry Neurosci 35:7-17.
82. Lincoln TM, Lange J, Burau J, Exner C, Moritz S (2010) The effect of state anxiety on paranoid ideation and jumping to conclusions: An experimental investigation. Schizophr Bull 36:1140-1148.
83. Dugas MJ, Ladouceur R (2000) Targeting intolerance to uncertainty in two types of worry. Bahav Modif 24:635-657.
84. Buhr K, Dugas MJ (2006) Investigating the construct validity of intolerance of uncertainty and its unique relationship with worry. J Anxiety Disord 20:222-236.
85. Moser JS, Hajcak G, Huppert JD, Foa EB, Simons RF (2008) Interpretation bias in social anxiety as detected by event-related brain potentials. Emotion 8:693-700.
86. White LK, Suway JG, Pine DS, Bar-Haim Y, Fox NA (2011) Cascading effects: The influence of attention bias to threat on the interpretation of ambiguous information. Behav Res Ther 49:244-251.
87. Britton JC, Lissek S, Grillon C, Norcross MA, Pine DS (2011) Development of anxiety: the role of threat appraisal and fear learning. Depress Anxiety 28(1):5-17.
88. Freeman D, Garety PA (2003) Connecting neurosis and psychosis: the direct influence of emotion on delusions and hallucinations. Behav Res Ther 41:923–947.
89. Boden MT, Berenbaum H (2010) The bidirectional relations between affect and belief. Rev Gen Psychol 14:227-239.
90. Boden MT, Berenbaum H, Topper M (2012) Intuition, affect, and peculier beliefs. Pers Individ Dif 52:845-848.
91. Startup H, Freeman D, Garety PA (2007) Persecutory delusions and catastrophic worry in psychosis: developing the understanding of delusion distress and persistence. Behav Res Ther 45(3):523-537.
92. Freeman D, Gittins M, Pugh K, Antley A, Slater M, Dunn G (2008) What makes one person paranoid and another person anxious? The differential prediction of social anxiety and persecutory ideation in an experimental situation. Psychol Med 38(8):1121-32.
93. Lincoln TM, Hohenhaus F, Hartmann M (2013) Can paranoid thoughts be reduced by targeting negative emotions and self-esteem? An experimental investigation of a brief compassion-focused intervention. Cogn Ther Res 37:390-402.
94. Fusar-Poli P, Nelson B, Valmaggia L, Yung AR, McGuire PK (2014) Comorbid depressive and anxiety disorders in 509 individuals with an at-risk mental state: impact on psychopathology and transition to psychosis. Schizophr Bull 40:120-131.
95. Thomas KM, Drevets WC, Whalen PJ, Eccard CH, Dahl RE, Ryan ND, Casey BJ (2001) Amygdala response to facial expressions in children and adults. Biol Psychiatry 49(4):309-316.
96. Tottenham N, Phuong J, Flannery J, Gabard-Durnam L, Goff B (2013) A negativity bias for ambiguous facial-expression valence during childhood: converging evidence from behavior and facial corrugator muscle responses. Emotion 13:92-103.
97. Dawson ME, Nuechterlein KH, Schell AM (1992) Electrodermal anomalies in recent-onset schizophrenia: relationships to symptoms and prognosis. Schizophr Bull 18(2):295-311.
98. Kring AM, Neale JM (1996) Do schizophrenic patients show a disjunctive relationship among expressive, experiential, and psychophysiological components of emotion? J Abnorm Psychol 102:249-257.
99. Williams LM, Das P, Harris AWF, Liddell BB, Brammer MJ, Olivieri G, Skerrett D, Phillips ML, David AS, Peduto A, Gordon E  (2004) Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia. Am J Psychiatry 161: 480-489.
100. Jensen J, Willeit M, Zipursky RB, Savina I, Smith AJ, Menon M, Crawley AP, Kapur S (2008) The formation of abnormal associations in schizophrenia: neural and behavioral evidence. Neuropsychopharmacology 33:473-479.
101. Murray GK, Corlett PR, Clark L, Pessiglione M, Blackwell AD, Honey G, Jones PB, Bullmore ET, Robbins TW, Fletcher PC (2008) Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol Psychiatry 13:239. 267-276.
102. Holt DJ, Coombs G, Zeidan MA, Goff DC, Milad MR (2012) Failure of neural responses to safety cues in schizophrenia. Arch Gen Psychiatry 69:893-903.
103. Holt DJ, Kunkel L, Weiss AP, Goff DC, Wright CI, Shin LM, Rauch SL, Hootnick J, Heckers S (2006) Increased medial temporal lobe activation during the passive viewing of emotional and neutral facial expressions in schizophrenia. Schizophr Res 82:153-162.
104. Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160:13-23.
105. Kapur S (2003) Motivational salience - The variable linking dopamine, psychosis, antipsychotics. Schizophr Res 60(Suppl 1):100
106. Kapur S (2004) How antipsychotics become anti-'psychotic' - from dopamine to salience to psychosis. Trends Pharmacol Sci 25(8):402-406.
107. Kapur S, Mamo DC (2004). Why antipsychotics are anti-"psychotic". In: McDonald C, Schulze K, Murray RM, Wright P (Eds.). Schizophrenia: Challenging the Orthodox. Taylor & Francis, London: pp. 113-125.
108. Kapur S, Mizrahi R, Li M (2005). From dopamine to salience to psychosis – linking biology, pharmacology and phenomenology of psychosis. Schizophr Res 79:59-68.
109. Cicero DC, Becker TM, Martin EA, Docherty AR, Kerns JG (2013) The role of aberrant salience and self-concept clarity in psychotic-like experiences. Personal Disord 4(1):33-42.
110. Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr Bull 35:549-562.
111. Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Grasby PM (2009) Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry 66(1):13-20.
112. Morrison PD, Murray RM (2009) From real-word events to psychosis: the emerging neuropharmacology of delusions. Schizophr Bull 35:668-674.
113. Roiser JP, Stephan KE, den Ouden HE, Barnes TR, Friston KJ, Joice EM (2009) Do patients with schizophrenia exhibit aberrant salience? Psychol Med 39:199-209.
114. Galdos M, Simons C, Fernandez-Rivas A, Wichers M, Peralta C, Lataster T, Amer G, Myin-Germeys I, Allardyce J, Gonzalez-Torres, van Os J (2011) Affectively salient meaning in random noise: a task sensitive to psychosis liability. Schizophr Bull 37:1179-1186.
115. Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69:776-786.
116. Roiser JP, Howes OD, Chaddock CA, Joyce EM, McGuire P (2013) Neural and behavioral correlates of aberrant salience in individuals at risk for psychosis. Schizophr Bull 39:1328-1336.
117. Lahera G, Freund N, Saiz-Rutz J (2013) Salience and dysregulation of the dopaminergic system. Rev Psiquiatr Salud Ment 6:45-51
118. Balog Z, Somlai Z, Keri S (2013) Aversive conditioning, schizotypy, and affective temperament in the framework of the salience hypothesis. Pers Indiv Diff 54:109-112.
119. Winton-Brown TT, Fusar-Poli P, Ungless MA, Howes OD (2014) Dopaminergic basis of salience dysregulation in psychosis. Trends Neurosci 37:85-89.
120. Lee SK, Chun JW, Lee JS, Park HJ, Jung YC, Seok JH, Kim JJ (2014) Abnormal neural processing during emotional salience attribution of affective asymmetry in patients with schizophrenia. PLoS One 9(3):e90792.
121. Nagy H, Levy-Gigi E, Somlai Z, Takats A, Bereczki D, Keri S (2012) The effect of dopamine agonists on adaptive and aberrant salience in Parkinson’s disease. Neuropsychopharmacol 37:950-958.
122. Knutson B, Bjork JM, Fong GW, Hommer D, Mattay VS, Weinberger DR (2004) Amphetamine modulates human incentive processing. Neuron 43:261-269.
123. Taylor SF, Welsh RC,Chen AC, Velander AJ, Liberzon I (2007) Medial frontal hyperactivity in reality distortion. Biol Psychiatry 61:1171-1178.
124. LeDoux, J. (1996). The Emotional Brain: The Mysterious Underpinnings of Emotional Life. Simon & Schuster, New York.
125. Adolphs R, Tranel D, Damasio H, Damasio A (1995) Fear and human amygdala. J Neurosci 15:5879-5891.
126. Davis M, Whalen PJ (2001) The amygdala: vigilance and emotion. Mol Psychiatry14:13–34.
127. Amaral DG (2003) The amygdala, social behavior, and danger detection. Ann N Y Acad Sci 1000:337-347.
128. Liberzon I, Phan KL, Decker LR, Taylor SF (2003) Extended amygdala and emotional salience: a PET activation study of positive and negative affect. Neuropsychopharmacol 28:726-733.
129. Phillips ML, Senior C, David AS (2000) Perception of threat in schizophrenics with persecutory delusions: an investigation using visual scan paths. Psychol Med 30(1):157-167.
130. Taylor SF, Liberzon I, Decker LR, Koeppe RA (2002). A functional anatomic study of emotional experience in schizophrenia. Schizophr Res 58:159-172.
131. Esslinger C, Englisch S, Inta D, Rausch F, Schirmbeck F, Mier D, Kirsch P, Meyer-Lindenberg A, Zink M (2012) Ventral striatal activation during attribution of stimulus saliency and reward anticipation is correlated in unmedicated first episode schizophrenia patients. Schizophr Res 140:114-120.
132. Corlett PR, Murray GK, Honey GD, Aitken MR, Shanks DR, Robbins TW, Bullmore ET, Dickinson A ,Fletcher PC (2007) Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions. Brain 130(pt 9):2387-2400.
133. Whitfield-Gabrieli S, Thermenos HW, Milanovic S, Tsuang MT, Faraone SV, McCarley RW, Shenton ME, Green AI, Nieto-Castanon A, LaViolette P, Wojcik J, Gabrieli JD, Seidman LJ (2009) Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci U S A 106:1279-1284.
134. Haralanova E, Beraldi A, Haralanov S, Fast K (2006) Neuropsychological measures for cognitive-affective dysregulation in paranoid schizophrenia: Implications for functional neuroimaging research. Eur Neuropsychopharmacol (Suppl 4):S388.
135. Phan KL, Taylor SF, Welsh RC, Decker LR, Noll DC, Nichols TE, Britton JC, Liberzon I (2003) Activation of the medial prefrontal cortex and extended amygdala by individual ratings of emotional arousal: a fMRI study. Biol Psychiatry 53:211-215.
136. Phan KL,Taylor SF, Welsh RC, Ho SH, Britton JC, Liberzon I (2004) Neural correlates of individual ratings of emotional salience: a trial-related fMRI study. Neuroimage 21:768-780.
137. Haralanova E, Haralanov S, Shkodrova D, Svinarov D (2011) Pharmacodynamic biomarkers for optimizing the antipsychotic pharmacotherapy in schizophrenia. Neurol Psychiatry 1:28-32.
138. Das P, Harris AWF, Liddell B, Brown KJ, Brammer MJ, Olivieri G, Peduto A, Williams LM (2003) A disjunction in central and autonomic responses to emotion stimuli in schizophrenia: Evidence from concurrent fMRI and skin conductance arousal recording. Neuroimage, 19:37-45.
139. Zahn TP, Pickar D (2005) Autonomic activity in relation to symptom ratings and reaction time in unmedicated patients with schizophrenia. Schizophr Res 79(2-3):257-270.
140. Bradley MM, Miccoli L, Escrig MA, Lang PJ (2008) The pupil as a measure of emotional arousal and autonomic activation. Psychophysiology 45(4):602–607.
141. Falkai P, Moeller H-J (2012) Emotional status: diagnosis and treatment for severe psychiatric disorders. Eur Arch Psychiatry Clin Neurosci 262:1-2.
142. Bradley MM, Lang PJ (2007) The International Affective Digitized Sounds (2nd Edition; IADS-2): Affective ratings of sounds and instruction manual. Technical report B-3. University of Florida, Gainesville, Fl.
143. Haralanov S, Haralanova E, Dzhupanov G, Shkodrova D (2015) Latent readiness for psychotic-symptom formation in individuals at high risk for schizophrenia: theoretical and practical issues. In: Stoyanov D (Ed.) Towards New Philosophy of Mental Health: Perspectives from Neuroscience and Humanities. Cambridge Scholars Publishing, Newcastle: pp. 89-105.
144. Fusar-Poli P, Borgwardt S, Bechdolf A, Addington J, Riecher-Roessler A, Schultze-Lutter F,Keshavan M,Wood S,Ruhrmann S,Seidman LJ,Valmaggia L,Cannon T,Velthorst E,De Haan L,Cornblatt B,Bonoldi I,Birchwood M,McGlashan T,Carpenter W,McGorry P,Klosterkoetter J,McGuire P, Yung A (2013) The psychosis high-risk state: a comprehensive state-of-the-art review. JAMA Psychiatry 70(1):107-120.
145. Fusar-Poli P, Borgwardt SJ, McGuire P (2012) Vulnerability to psychosis: from neurosciences to psychopathology. Psychology Press, New York, USA.
146. Stoyanov D, Machamer P, Schaffner KF (2013). In quest for scientific psychiatry: Toward bridging the explanatory gap. Philosophy Psychiatry Psychology 20(3):261-273.
147. Stoyanov DS, Borgwardt S, Varga S (2015) Translational validity accross neuroscience and psychiatry. In: Zachar P, Stoyanov D, Aragona M, Jablensky A (Eds.) Alternative Perspectives on Psychiatric Validation. Oxford University Press, Oxford, UK: pp.128-146.