Imagery, emotion, and bioinformational theory: From body to brain.

The bioinformational theory of emotional imagery is a model of the hypothetical mental representations activated when people imagine emotionally engaging events, and was initially proposed to guide research and practice in the use of imaginal exposure as a treatment for fear and anxiety (Lang, 1979). In this 50 year overview, we discuss the development of bioinformational theory and its impact on the study of psychophysiology and psychopathology, most importantly assessing its viability and predictions in light of more recent brain-based studies of neural functional activation. Bioinformational theory proposes that narrative imagery, typically cued by language scripts, activates an associative memory network in the brain that includes stimulus (e.g., agents, contexts), semantic (e.g., facts and beliefs) and, most critically for emotion, response information (e.g., autonomic and somatic) that represents relevant real-world coping actions and reactions. Psychophysiological studies in healthy and clinical samples reliably find measurable response output during aversive and appetitive narrative imagery. Neuroimaging studies confirm that emotional imagery is associated with significant activation in motor regions of the brain, as well as in regions implicated in episodic and semantic memory retrieval, supporting the bioinformational view that narrative imagery prompts mental simulation of events that critically includes the actions and reactions engaged in emotional contexts.

Neural correlates of repeated retrieval of emotional autobiographical events.

Understanding the neural correlates of repetitive retrieval of emotional events is critical in addressing pathological emotional processing, as repeated processing is central for a number of different therapeutic interventions. In the current study, single-trial functional brain activity was assessed in key regions implicated in episodic retrieval, including the medial prefrontal cortex (mPFC), anterior hippocampus, posterior hippocampus, and the posteromedial parietal cortex (i.e., posterior cingulate cortex and the precuneus) following repeated retrieval of pleasant and unpleasant autobiographical events. Replicating previous studies, repetition prompted reduced blood-oxygen-level-dependent (BOLD) amplitude in the anterior hippocampus and the mPFC, but not in the posterior hippocampus, due to no functional activity during mental imagery, or in the posteromedial parietal cortex, due to enhanced activation that was sustained across repetitions. Neural activation during pleasant and unpleasant autobiographical retrieval did not differ as a function of repetition, indicating similar processing effects regardless of motivational relevance. Taken together, the hedonic valence of retrieved memories does not affect functional activity associated with repeated retrieval of episodic events, in which the pattern of BOLD amplitude change suggests a dissociation between the hippocampal-prefrontal circuit, which shows repetition suppression, and the posteromedial parietal cortex, which shows sustained activation.

The Startle-Evoked Potential: Negative Affect and Severity of Pathology in Anxiety/Mood Disorders.

BACKGROUND: The National Institute of Mental Health Research Domain Criteria initiative encourages a search for dimensional biological measures of psychopathology unconstrained by current diagnostic categories. Consistent with this aim, the presented research studies a large sample of anxiety and mood disorder patients, assessing differences in principal diagnoses and comorbidity patterns, clinicians' ratings, and questionnaire measures of negative affect and life dysfunction as they relate to a potential brain marker of pathology: the amplitude of the event-related potential (ERP) elicited by a startle-evoking stimulus. METHODS: Patients seeking evaluation or treatment for anxiety and mood disorders (N = 208) participated in two tasks at the University of Florida (Gainesville, FL): 1) imagining emotional and neutral events and 2) viewing emotional and neutral pictures while acoustic startle probes were presented and the ERP was recorded. For a comparison patient group (N = 120), startle probes were administered and ERPs recorded at the University of Greifswald (Greifswald, Germany) while performing the same imagery task. RESULTS: Reduced positive amplitude of a centroparietal startle-evoked ERP (156-352 ms after onset) significantly predicted higher questionnaire scores of anxiety/depression, reports of increased life dysfunction, greater comorbidity, and clinician ratings of heightened severity and poorer prognosis. The effect was general across principal diagnoses, found for both the Florida and German samples, and consistent in pattern despite differences in the tasks administered. CONCLUSIONS: The startle-evoked ERP reliably predicts severity and breadth of psychopathology, independent of task context. It is a potential significant contributor to a needed array of biological measures that might improve classification of anxiety and mood disorders.

Phase II Study of First-Line Trebananib Plus Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: Trebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2. BACKGROUND: Ang-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC). METHODS: Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2. RESULTS: Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts. CONCLUSION: There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

RDoC, DSM, and the reflex physiology of fear: A biodimensional analysis of the anxiety disorders spectrum.

Evidence is presented supporting a dimension of defensive reactivity that varies across the anxiety disorder spectrum and is defined by physiological responses during threat-imagery challenges that covary with objective measures of psychopathology. Previous imagery studies of anxiety disorders are reviewed, highlighting that, regardless of contemporary diagnostic convention, reliable psychophysiological patterns emerge for patients diagnosed with circumscribed fear compared to those diagnosed with pervasive anxious-misery disorders. Based on the heuristic outlined by the Research Domain Criteria (RDoC) initiative, an exploratory transdiagnostic analysis is presented, based on a sample of 425 treatment-seeking patients from across the spectrum of DSM-IV anxiety diagnoses. Using a composite index of startle reflex and heart rate reactivity during idiographic fear imagery for each patient, a defensive dimension was defined by ranking patients from most defensively reactive to least reactive and then creating five groups of equivalent size (quintile; N = 85). Subsequent analyses showed significant parallel trends of diminishing reactivity in both electrodermal and facial electromyographic reactions across this defensive dimension. Negative affectivity, defined by questionnaire and extent of functional interference, however, showed consistent, inverse trends with defensive reactivity-as reports of distress increased, defensive reactivity was increasingly attenuated. Notably, representatives of each principal diagnosis appeared in each quintile, underscoring the reality of pronounced within-diagnosis heterogeneity in defensive reactivity. In concluding, we describe our new RDoC research project, focusing on the assessment of brain circuit function as it determines hypo/hyperreactivity to challenge-somatic and autonomic-and may relate to patients' stress history and genetic inheritance.

Pathological anxiety and function/dysfunction in the brain's fear/defense circuitry.

Research from the University of Florida Center for the Study of Emotion and Attention aims to develop neurobiological measures that objectively discriminate among symptom patterns in patients with anxiety disorders. From this perspective, anxiety and mood pathologies are considered to be brain disorders, resulting from dysfunction and maladaptive plasticity in the neural circuits that determine fearful/defensive and appetitive/reward behavior (Insel et al., 2010). We review recent studies indicating that an enhanced probe startle reflex during the processing of fear memory cues (mediated by cortico-limbic circuitry and thus indicative of plastic brain changes), varies systematically in strength over a spectrum-wide dimension of anxiety pathology-across and within diagnoses-extending from strong focal fear reactions to a consistently blunted reaction in patients with more generalized anxiety and comorbid mood disorders. Preliminary studies with functional magnetic resonance imaging (fMRI) encourage the hypothesis that fear/defense circuit dysfunction covaries with this same dimension of psychopathology. Plans are described for an extended study of the brain's motivation circuitry in anxiety spectrum patients, with the aim of defining the specifics of circuit dysfunction in severe disorders. A sub-project explores the use of real-time fMRI feedback in circuit analysis and as a modality to up-regulate circuit function in the context of blunted affect.

Defensive mobilization in specific phobia: fear specificity, negative affectivity, and diagnostic prominence.

BACKGROUND: Understanding of exaggerated responsivity in specific phobia-its physiology and neural mediators-has advanced considerably. However, despite strong phenotypic evidence that prominence of specific phobia relative to co-occurring conditions (i.e., principal versus nonprincipal disorder) is associated with dramatic differences in subjective distress, there is yet no consideration of such comorbidity issues on objective defensive reactivity. METHODS: A community sample of specific phobia (n = 74 principal; n = 86 nonprincipal) and control (n = 76) participants imagined threatening and neutral events while acoustic startle probes were presented and eyeblinks (orbicularis occuli) recorded. Changes in heart rate, skin conductance level, and facial expressivity were also measured. RESULTS: Principal specific phobia patients far exceeded control participants in startle reflex and autonomic reactivity during idiographic fear imagery. Distinguishing between single and multiple phobias within principal phobia and comparing these with nonprincipal phobia revealed a continuum of decreasing defensive mobilization: single patients were strongly reactive, multiple patients were intermediate, and nonprincipal patients were attenuated-the inverse of measures of pervasive anxiety and dysphoria (i.e., negative affectivity). Further, as more disorders supplanted specific phobia from principal disorder, overall defensive mobilization was systematically more impaired. CONCLUSIONS: The exaggerated responsivity characteristic of specific phobia is limited to those patients for whom circumscribed fear is the most impairing condition and coincident with little additional affective psychopathology. As specific phobia is superseded in severity by broad and chronic negative affectivity, defensive reactivity progressively diminishes. Focal fears may still be clinically significant but not reflected in objective defensive mobilization.

Aversive imagery in panic disorder: agoraphobia severity, comorbidity, and defensive physiology.

BACKGROUND: Panic is characterized as a disorder of interoceptive physiologic hyperarousal, secondary to persistent anticipation of panic attacks. The novel aim of this research was to investigate whether severity of agoraphobia within panic disorder covaries with the intensity of physiological reactions to imagery of panic attacks and other aversive scenarios. METHODS: A community sample of principal panic disorder (n = 112; 41 without agoraphobia, 71 with agoraphobia) and control (n = 76) participants imagined threatening and neutral events while acoustic startle probes were presented and the eye-blink response (orbicularis oculi) recorded. Changes in heart rate, skin conductance level, and facial expressivity were also measured. RESULTS: Overall, panic disorder patients exceeded control participants in startle reflex and heart rate during imagery of standard panic attack scenarios, concordant with more extreme ratings of aversion and emotional arousal. Accounting for the presence of agoraphobia revealed that both panic disorder with and without situational apprehension showed the pronounced heart rate increases during standard panic attack imagery observed for the sample as a whole. In contrast, startle potentiation to aversive imagery was more robust in those without versus with agoraphobia. Reflex diminution was most dramatic in those with the most pervasive agoraphobia, coincident with the most extreme levels of comorbid broad negative affectivity, disorder chronicity, and functional impairment. CONCLUSIONS: Principal panic disorder may represent initial, heightened interoceptive fearfulness and concomitant defensive hyperactivity, which through progressive generalization of anticipatory anxiety ultimately transitions to a disorder of pervasive agoraphobic apprehension and avoidance, broad dysphoria, and compromised mobilization for defensive action.

Repetitive exposure: brain and reflex measures of emotion and attention.

Effects of massed repetition on the modulation of the late positive potential elicited during affective picture viewing were investigated in two experiments. Despite a difference in the number of repetitions across studies (from 5 to 30), results were quite similar: The late positive potential continued to be enhanced when participants viewed emotional, compared to neutral, pictures. On the other hand, massed repetition did prompt a reduction in the late positive potential that was most pronounced for emotional pictures. Startle probe P3 amplitude generally increased with repetition, suggesting diminished attention allocation to repeated pictures. The blink reflex, however, continued to be modulated by hedonic valence, despite massive massed repetition. Taken together, the data suggest that the amplitude of the late positive potential during picture viewing reflects both motivational significance and attention allocation.

Threat of suffocation and defensive reflex activation.

The current study examined emotional reflex reactions of participants threatened with respiratory distress caused by imposing a resistive load at inspiration. Cues signaling threat (breathing MAY be difficult) and safe periods were intermixed while startle reflexes, heart rate, skin conductance, and facial EMG activity were measured. Compared to safe cues, threat cues elicited significant startle potentiation, enhanced skin conductance, heightened corrugator EMG changes, and pronounced "fear bradycardia" consistent with defensive activation in the context of threatened respiratory dysfunction. These data indicate that anticipating respiratory resistance activates defensive responding, which may mediate symptomatology in patients with panic and other anxiety disorders.

Aversive imagery in posttraumatic stress disorder: trauma recurrence, comorbidity, and physiological reactivity.

BACKGROUND: Posttraumatic stress disorder (PTSD) is characterized as a disorder of exaggerated defensive physiological arousal. The novel aim of the present research was to investigate within PTSD a potential dose-response relationship between past trauma recurrence and current comorbidity and intensity of physiological reactions to imagery of trauma and other aversive scenarios. METHODS: A community sample of principal PTSD (n = 49; 22 single-trauma exposed, 27 multiple-trauma exposed) and control (n = 76; 46 never-trauma exposed, 30 trauma exposed) participants imagined threatening and neutral events while acoustic startle probes were presented and the eye-blink response (orbicularis occuli) was recorded. Changes in heart rate, skin conductance level, and facial expressivity were also indexed. RESULTS: Overall, PTSD patients exceeded control participants in startle reflex, autonomic responding, and facial expressivity during idiographic trauma imagery and, though less pronounced, showed heightened reactivity to standard anger, panic, and physical danger imagery. Concerning subgroups, control participants with and without trauma exposure showed isomorphic patterns. Within PTSD, only the single-trauma patients evinced robust startle and autonomic responses, exceeding both control participants and multiple-trauma PTSD. Despite greater reported arousal, the multiple-trauma relative to single-trauma PTSD group showed blunted defensive reactivity associated with more chronic and severe PTSD, greater mood and anxiety disorder comorbidity, and more pervasive dimensional dysphoria (e.g., depression, trait anxiety). CONCLUSIONS: Whereas PTSD patients generally show marked physiological arousal during aversive imagery, concordant with self-reported distress, the most symptomatic patients with histories of severe, cumulative traumatization show discordant physiological hyporeactivity, perhaps attributable to sustained high stress and an egregious, persistent negative affectivity that ultimately compromises defensive responding.

Emotion and the motivational brain.

Psychophysiological and neuroscience studies of emotional processing undertaken by investigators at the University of Florida Laboratory of the Center for the Study of Emotion and Attention (CSEA) are reviewed, with a focus on reflex reactions, neural structures and functional circuits that mediate emotional expression. The theoretical view shared among the investigators is that expressed emotions are founded on motivational circuits in the brain that developed early in evolutionary history to ensure the survival of individuals and their progeny. These circuits react to appetitive and aversive environmental and memorial cues, mediating appetitive and defensive reflexes that tune sensory systems and mobilize the organism for action and underly negative and positive affects. The research reviewed here assesses the reflex physiology of emotion, both autonomic and somatic, studying affects evoked in picture perception, memory imagery, and in the context of tangible reward and punishment, and using the electroencephalograph (EEG) and functional magnetic resonance imaging (fMRI), explores the brain's motivational circuits that determine human emotion.

Fearful imagery in social phobia: generalization, comorbidity, and physiological reactivity.

BACKGROUND: Social phobia has been characterized as a disorder of exaggerated fear of social threat and heightened sensitivity to imagery of social failure. METHODS: To assess the physiological basis of this description, social phobia patients (n=75) and demographically matched control participants (n=75) imagined neutral and fearful events while acoustic startle probes were occasionally presented and eye-blink responses (orbicularis occuli) recorded. Changes in heart rate, skin conductance level, and facial expressivity were also indexed. In addition to comparing control participants and social phobia patients, the influences of diagnostic subtype (circumscribed, generalized), comorbid depression, and chronicity were assessed. RESULTS: Patients exceeded control participants in startle reflex and autonomic responding during imagery of social threat, whereas the groups evinced commensurate reactivity to contents depicting commonly shared fears (survival threat). Individuals with circumscribed performance phobia were similar to control participants, with the exception of more robust reactions to idiographic, performance fear imagery. In contrast, generalized phobic patients were characterized by longer disorder chronicity and demonstrated heightened sensitivity to a broader range of fear contents. Those with generalized phobia plus comorbid depression showed attenuation of fear-potentiated startle and reported the most protracted social anxiety. CONCLUSIONS: Subtypes of social phobia can be objectively distinguished in patterns of physiological reactivity. Furthermore, subtypes vary systematically in chronicity and defensive engagement with the shortest disorder duration (circumscribed phobia) associated with the most robust and focal physiological reactivity, followed by broader defensive sensitivity in more chronic generalized phobia, and finally attenuation of the formerly exaggerated fear potentiation in the comorbidly depressed, the most chronic form.

Fear of pain and defensive activation.

Fear of pain and its relationship to dental fear was investigated by measuring autonomic reactions (skin conductance and heart rate) in individuals reporting high and low dental fear when in the presence of a cue that threatened the presentation of electric shock ("threat") or not ("safe"). Acoustic startle probes were also presented during both threat and safe periods, and the reflexive eye blink, the skin conductance response, and cardiac changes to the startle probe measured. All participants reacted with greater defensive reactivity, including potentiated startle blinks, heightened skin conductance, and cardiac deceleration in the context of threat, compared to safe, cues. Individuals reporting high dental fear were significantly more reactive during threat periods, compared to low fear individuals, showing larger blink reflexes and heightened electrodermal activity, as well as heightened autonomic responses to the startle probe itself. Individual differences in defensive reactivity persisted even after participants received a single mild shock halfway through the experiment. The data indicate that threat of shock elicits heightened defensive reactivity in those reporting high dental fear, consistent with the hypothesis that fear of potentially painful events may be a potent mediator of the anxiety involved in anticipated medical and dental treatment.

Cross-modal attention capture by affective stimuli: evidence from event-related potentials.

The P3 component of the event-related potential (ERP) to an acoustic startle probe is modulated during picture viewing, with reduced P3 amplitude when participants view either pleasant or unpleasant, as opposed to neutral, pictures. We have interpreted this as reflecting capture of attentional resources by affective pictures, with fewer resources available for processing the secondary startle probe. In the present study, we tested this resource allocation hypothesis by presenting either pictures or sounds as foreground stimuli, with the prediction that P3 amplitude in response to secondary startle probes would be reduced for affectively engaging foregrounds regardless of modality. Using dense-array electroencephalography and a source estimation procedure, we observed that P3 amplitude was indeed smaller when startle probes were presented during emotional, as opposed to neutral, stimuli for both sound and picture foregrounds. Source modeling indicated a common frontocentral maximum of P3 modulation by affect. The data support the notion that emotionally arousing stimuli transmodally attract resources, leading to optimized processing of the affective stimuli at the cost of the processing of concurrent stimuli.

The neural basis of narrative imagery: emotion and action.

It has been proposed that narrative emotional imagery activates an associative network of stimulus, semantic, and response (procedural) information. In previous research, predicted response components have been demonstrated through psychophysiological methods in peripheral nervous system. Here we investigate central nervous system concomitants of pleasant, neutral, and unpleasant narrative imagery with functional magnetic resonance imaging. Subjects were presented with brief narrative scripts over headphones, and then imagined themselves engaged in the described events. During script perception, auditory association cortex showed enhanced activation during affectively arousing (pleasant and unpleasant), relative to neutral imagery. Structures involved in language processing (left middle frontal gyrus) and spatial navigation (retrosplenium) were also active during script presentation. At the onset of narrative imagery, supplementary motor area, lateral cerebellum, and left inferior frontal gyrus were initiated, showing enhanced signal change during affectively arousing (pleasant and unpleasant), relative to neutral scripts. These data are consistent with a bioinformational model of emotion that considers response mobilization as the measurable output of narrative imagery.

Psychopathy and physiological response to emotionally evocative sounds.

Despite considerable evidence that psychopathic criminals are deviant in their emotional reactions, few studies have examined responses to both pleasurable and aversive stimuli or assessed the role of different facets of psychopathy in affective deviations. This study investigated physiological reactions to emotional sounds in prisoners selected according to scores on the 2 factors of Hare's Psychopathy Checklist--Revised (PCL-R; R. D. Hare, 1991). Offenders high on the PCL-R emotional-interpersonal factor, regardless of scores on the social deviance factor, showed diminished skin conductance responses to both pleasant and unpleasant sounds, suggesting a deficit in the action mobilization component of emotional response. Offenders who scored high only on the social deviance factor showed a delay in heart rate differentiation between affective and neutral sounds. These findings indicate abnormal reactivity to both positive and negative emotional stimuli in psychopathic individuals, and suggest differing roles for the 2 facets of psychopathy in affective processing deviations.

The psychophysiology of anxiety disorder: fear memory imagery.

Psychophysiological response to fear memory imagery was assessed in specific phobia, social anxiety disorder, panic disorder with agoraphobia, post-traumatic stress disorder (PTSD), and healthy controls. Heart rate, skin conductance, and corrugator muscle were recorded as participants responded to tone cues signaling previously memorized descriptor sentences. Image contents included personal fears, social fears, fears of physical danger, and neutral (low arousal) scenes. Reactions to acoustic startle probes (eyeblink) were assessed during recall imagery and nonsignal periods. Participants were significantly more reactive (in physiology and report of affect) to fear than neutral cues. Panic and PTSD patients were, however, less physiologically responsive than specific phobics and the socially anxious. Panic and PTSD patients also reported the most anxiety and mood symptoms, and were most frequently comorbidly depressed. Overall, physiological reactivity to sentence memory cues was greatest in patients with focal fear of specific objects or events, and reduced in patients characterized by generalized, high negative affect.