Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3.

BACKGROUND: GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. METHODS: The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. RESULTS: We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. CONCLUSION: Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.

Application of the National Comprehensive Cancer Network-distress thermometer in pediatric patients during autologous and allogeneic hematopoietic stem cell transplantation and relationship to blood parameters of the stress axis.

PURPOSE: Hematopoietic stem cell transplantations (HSCT) are extremely stressful procedures for pediatric patients. The activation of the hypothalamic pituitary adrenocortical axis (HPA) can influence the immune system negatively and therefore the overall outcome. The distress thermometer (DT) is an easy to use tool for the self-assessment of perceived distress. METHODS: In this prospective study, a DT with an attached problem list was used in 40 pediatric patients undergoing HSCT and in one parent of each patient. The patients were aged 10-18 years. The patients' cortisol, thyroid stimulating hormone, free triiodothyronine and thyroxine levels were measured regularly during the in-patient stay. RESULTS: After admission to the hospital, the stress levels of the pediatric patients and their parents increased and reached their maximum on the day of HSCT. The overall stress values of the parents were higher than those of their children. There was a significant difference in the parents' stress levels on the day of HSCT, as compared to their stress levels on other days. The mean cortisol values of the pediatric patients also increased after admission, reaching significant elevated levels above the upper normal limit 1 week after HSCT and on discharge day. Although the pediatric patients experienced mainly exhaustion, especially on the day of transplantation, their parents mainly felt worry and anxiety. Interestingly, the rate of worry among children increased in the post-transplant period and reached its maximum on the day of discharge. CONCLUSIONS: In summary, a significantly increased stress level is shown for both the patients and their parents. This is reflected for the patients both in the DT scores and in the increased cortisol values. For the parents, the focus is primarily on worry and anxiety, for the patients primarily on exhaustion and worry.

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.

Matched versus Haploidentical Hematopoietic Stem Cell Transplantation as Treatment Options for Primary Immunodeficiencies in Children.

Primary immunodeficiencies (PIDs) are inherited disorders of the immune system with allogeneic hematopoietic stem cell transplantation (HSCT) as the only curative treatment in some of them. In case an HLA-matched donor is not available, HSCT from a haploidentical family donor may be considered. We compared the outcomes of HSCT from HLA-matched unrelated or related donors (MUDs or MRDs) and mismatched related haploidentical donors (MMRDs) in patients with a variety of PIDs in 2 centers. A total of 44 pediatric patients were evaluated. We reviewed the outcomes of 25 children who underwent transplantation with HLA-matched grafts (MRD, n = 13; MUD, n = 12) and 19 patients receiving haploidentical stem cells. Bone marrow (BM) was transplanted in 85% (MRD) and 75% (MUD) of the matched cohort and peripheral blood stem cells (PBSCs) in 15% (MRD), 25% (MUD), and 100% (MMRD). All but 9 patients (MRD, n = 6; MMRD, n = 3) with severe combined immunodeficiency (SCID) received a chemotherapy-based conditioning regimen. Immune reconstitution of T, B, and natural killer cells was comparable for all groups with an advantage of recipients of MRD grafts in early CD4 reconstitution. However, deaths due to viral infections occurred more often in the haploidentical cohort. The disease-free survival was 91.7% (MRD), 66.7% (MUD), and 62.7% (MMRD), respectively. Grade II to IV acute graft-versus-host disease (GVHD) occurred in 15% (MRD), 8% (MUD), and 21% (MMRD) of the patients. Only 1 patient had severe grade IV GVHD in the MRD group, whereas no grade >II GVHD was observed in the MUD or MMRD cohort. These data indicate that in the absence of a suitable HLA-identical family donor, haploidentical HSCT may be a viable option for patients with life-threatening disease and urgent need of HSCT.

Systemic antitumor effect by regional hyperthermia combined with low-dose chemotherapy and immunologic correlates in an adolescent patient with rhabdomyosarcoma - a case report.

Introduction: An abscopal effect is a clinical observation whereby a local treatment is associated with regression of metastatic cancer at a site distant from the primary location of treatment. Here, we describe the clinical systemic effect induced by regional hyperthermia combined with low-dose chemotherapy and provide immunologic correlates.Case presentation: A 15-year-old patient had been diagnosed with alveolar rhabdomyosarcoma (ARMS). All previous treatment options failed in the patient including haploidentical stem cell transplantation and donor lymphocyte infusion. The patient presented with local and metastatic disease, and upon admission, underwent regional hyperthermia combined with low-dose chemotherapy. Immediately following therapy severe skin reactions were observed. Skin biopsies revealed an intraepithelial lymphocytic infiltration dominated by CD3+/CD8+ T cells with a regular network of dendritic cells. Clinical images compared before and during sequential treatment cycles showed complete metabolic response of the local tumor for more than 10 months of therapy. In addition, metastases completely regressed although they were not direct targets of regional hyperthermia. The systemic effect was associated with enhanced frequency of NK cells and T cells expressing the lectin-like natural-killer group 2 D activating receptor (NKG2D), an increase of the CD56bright subset of NK cells, as well as an increase of effector/memory and effector CD8+ and CD4+ T cells in the blood while the percentage of CD25+FOXP3+ regulatory T cells declined.Conclusions: Regional hyperthermia combined with low-dose chemotherapy had the potential to create a systemic effect which was associated with activation of NK cells and T cells.

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.

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.

Oscillatory brain activity in the alpha range is modulated by the content of word-prompted mental imagery.

Mental imagery is a fundamental cognitive process of interest to basic scientists and clinical researchers. This study examined large-scale oscillatory brain activity in the alpha band (8-12 Hz) during language-driven mental imagery using dense-array EEG. Three experiments demonstrated relative increases in alpha amplitude: (1) during imagery prompted by words compared to fixation without imagery instruction, (2) during imagery of word content compared to imagery of geometric shapes, and (3) during imagery of emotionally evocative words compared to imagery of less emotionally arousing content. Alpha increases for semantically loaded imagery were observed in parieto-occipital regions, sustained throughout the imagery period. Findings imply that alpha oscillations index active memory and internal cognitive processing, reflecting neural communication in cortical networks representing motor, semantic, and perceptual aspects of the imagined scene.

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.

Phlebotonics for haemorrhoids.

BACKGROUND: Haemorrhoids are variceal dilatations of the anal and perianal venous plexus and often develop secondary to the persistently elevated venous pressure within the haemorrhoidal plexus (Kumar 2005). Phlebotonics are a heterogenous class of drugs consisting of plant extracts (i.e. flavonoids) and synthetic compounds (i.e. calcium dobesilate). Although their precise mechanism of action has not been fully established, they are known to improve venous tone, stabilize capillary permeability and increase lymphatic drainage. They have been used to treat a variety of conditions including chronic venous insufficiency, lymphoedema and haemorrhoids.Numerous trials assessing the effect of phlebotonics in treating the symptoms and signs of haemorrhoidal disease suggest that there is a potential benefit. OBJECTIVES: The aim of this review was to investigate the efficacy of phlebotonics in alleviating the signs, symptoms and severity of haemorrhoidal disease and verify their effect post-haemorrhoidectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2011 issue 9 , MEDLINE (1950 to September 2011) and EMBASE (1974 to September 2011). SELECTION CRITERIA: Only randomised controlled trials evaluating the use of phlebotonics in treating haemorrhoidal disease were used. No cross-over or cluster-randomized trials were included for analysis and any trial which had a quasi-random method of allocation was excluded. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and analysed the eligibility of the data for inclusion. Disagreements were resolved by meaningful discussion. MAIN RESULTS: We considered twenty-four studies for inclusion in the final analysis. Twenty of these studies (enrolling a total of 2344 participants) evaluated the use of phlebotonics versus a control intervention. One of these twenty studies evaluated the use of phlebotonics with a medical intervention and another study with rubber band ligation.The remaining four studies included two which compared different forms of phlebotonics with each other, one study which evaluated phlebotonics with a medical intervention and one study which compared the use of phlebotonics with infrared photocoagulation. Eight studies were excluded for various reasons including poor methodological quality.Phlebotonics demonstrated a statistically significant beneficial effect for the outcomes of  pruritus (OR 0.23; 95% CI 0.07 to 0.79) (P=0.02), bleeding (OR 0.12; 95% CI 0.04 to 0.37) (P=0.0002), bleeding post-haemorrhoidectomy (OR 0.18; 95% 0.06 to 0.58)(P=0.004), discharge and leakage (OR 0.12; 95% CI 0.04 to 0.42) (P=0.0008) and overall symptom improvement (OR 15.99 95% CI 5.97 to 42.84) (P< 0.00001), in comparison with a control intervention. Although beneficial they did not show a statistically significant effect compared with a control intervention for pain (OR 0.11; 95% CI 0.01 to 1.11) (P=0.06), pain scores post-haemorrhoidectomy (SMD -1.04; 95% CI -3.21 to 1.12 ) (P= 0.35) or post-operative analgesic consumption (OR 0.54; 95% CI 0.30 to 0.99)(P=0.05). AUTHORS' CONCLUSIONS: The evidence suggests that there is a potential benefit in using phlebotonics in treating haemorrhoidal disease as well as a benefit in alleviating post-haemorrhoidectomy symptoms. Outcomes such as bleeding and overall symptom improvement show a statistically significant beneficial effect and there were few concerns regarding their overall safety from the evidence presented in the clinical trials.However methodological limitations were encountered. In order to enhance our conclusion further, more robust clinical trials which take into account these limitations will need to be performed in the future.

Caspofungin as antifungal prophylaxis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis.

BACKGROUND: Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) often receive intravenous liposomal amphotericin B (L-AmB) as antifungal prophylaxis. There are no guidelines for antifungal prophylaxis in children in this situation. Caspofungin (CAS), a broad-spectrum echinocandin, could be an effective alternative with lower nephrotoxicity than L-AmB. METHODS: We retrospectively analyzed the safety, feasibility, and efficacy of CAS in our center, and compared the results with L-AmB as antifungal monoprophylaxis in pediatric patients undergoing HSCT. 60 pediatric patients received L-AmB (1 or 3 mg/kg bw/day) and another 60 patients received CAS (50 mg/m2/day) as antifungal monoprophylaxis starting on day one after HSCT. The median ages of patients receiving L-AmB and CAS were 7.5 years and 9.5 years, respectively. RESULTS: No proven breakthrough fungal infection occurred in either group during the median treatment period of 23 days in the L-AmB group and 24 days in the CAS group. One patient receiving CAS developed probable invasive aspergillosis. During L-AmB treatment, potassium levels significantly decreased below normal values. Patients treated with L-AmB had more drug-related side effects and an increased need for oral supplementation with potassium, sodium bicarbonate and calcium upon discharge as compared with the CAS group. CAS was well-tolerated and safe in this cohort of immunocompromised pediatric patients, who underwent high-dose chemotherapy and HSCT. CONCLUSION: Prophylactic CAS and L-AmB showed similar efficacy in this biggest cohort of pediatric patients after allogeneic HSCT reported, so far. A prospective randomized trial in children is warranted to allow for standardized guidelines.

The anxiety spectrum and the reflex physiology of defense: from circumscribed fear to broad distress.

Guided by the diagnostic nosology, anxiety patients are expected to show defensive hyperarousal during affective challenge, irrespective of the principal phenotype. In the current study, patients representing the whole spectrum of anxiety disorders (i.e., specific phobia, social phobia, panic disorder with or without agoraphobia, obsessive-compulsive disorder, generalized anxiety disorder (GAD), posttraumatic stress disorder(PTSD)), and healthy community control participants, completed an imagery-based fear elicitation paradigm paralleling conventional intervention techniques. Participants imagined threatening and neutral narratives as physiological responses were recorded. Clear evidence emerged for exaggerated reactivity to clinically relevant imagery--most pronounced in startle reflex responding. However, defensive propensity varied across principal anxiety disorders. Disorders characterized by focal fear and impairment (e.g., specific phobia) showed robust fear potentiation. Conversely, for disorders of long-enduring, pervasive apprehension and avoidance with broad anxiety and depression comorbidity (e.g., PTSD secondary to cumulative trauma, GAD), startle responses were paradoxically diminished to all aversive contents. Patients whose expressed symptom profiles were intermediate between focal fearfulness and broad anxious-misery in both severity and chronicity exhibited a still heightened but more generalized physiological propensity to respond defensively. Importantly, this defensive physiological gradient--the inverse of self-reported distress--was evident not only between but also within disorders. These results highlight that fear circuitry could be dysregulated in chronic, pervasive anxiety, and preliminary functional neuroimaging findings suggest that deficient amygdala recruitment could underlie attenuated reflex responding. In summary, adaptive defensive engagement during imagery may be compromised by long-term dysphoria and stress-a phenomenon with implications for prognosis and treatment planning.

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.

Long-term IL-2 therapy after transplantation of T cell depleted stem cells from alternative donors in children.

The aim of this pilot study was to evaluate the feasibility of long-term subcutaneous application of low-dose IL-2 in children with malignancies at very high risk of relapse who underwent highly T cell and B cell depleted HLA-identical (MUD) or full haplotype mismatched related hematopoetic stem cell transplantation. We studied 11 patients with acute leukemias / myelodysplastic syndrome and juvenile myelomonocytic leukemia (active disease and/or second stem cell transplantation, n = 8; ≥CR 2, n = 2) and relapsed or progressive Ewing's sarcoma (n = 2) who received prophylactic IL-2 treatment for a high probability of disease recurrence after allo-HSCT. Toxicities from IL-2 were transient fever, fatigue and local inflammation. In one patient GvHD grade III with no clear association to IL-2 administration occurred. IL-2 administration was started at median day 57 (range 13-154) post-transplant for a mean duration of 28 days (range 15-250). IL-2 administration clearly increased NK cell activity. 3 of 11 patients (ALL, AML, multifocal Ewings sarcoma) survived with a follow-up of ten years. In conclusion, long-term low-dose IL-2 subcutaneous application is feasible in children due to a low side effect profile even after HLA mismatched transplantation and may be a strategy to prevent relapse in pediatric malignancies with extremely high risk of relapse.

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.

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.