The mechanisms underlying the genesis of migraine pain remain enigmatic largely because of the absence of any identifiable cephalic pathology. Based on numerous indirect lines of evidence, 2 nonmutually exclusive hypotheses have been put forward. The first theorizes that migraine pain originates in the periphery and requires the activation of primary afferent nociceptive neurons that innervate cephalic tissues, primarily the cranial meninges and their related blood vessels. The second maintains that nociceptor activation may not be required and that the headache is promoted primarily as a result of abnormal processing of sensory signals in the central nervous system. This paper reviews the evidence leading to these disparate theories while siding with the primacy of nociceptor activation in the genesis migraine headache. The paper further examines the potential future use of established human models of migraine for addressing the origin of migraine headache.

Environmental exposure to high-frequency voltage transients (HFVT), also termed dirty electricity, has been advocated among electro(hyper)sensitive interest groups as an important biological active component of standard electromagnetic pollution. A literature search was conducted in PubMed, in which only seven articles were identified. Exposure to HFVT was associated with increased cancer risks, while preferential removal of 4-100 kHz HFVT from 50-60 Hz ELF circuits was linked to a variety of improvements in health (plasma glucose levels in diabetic patients, symptoms of multiple sclerosis, asthma and other respiratory illnesses, and insomnia), well-being (tiredness, frustration, general health, irritation, sense of satisfaction, mood), and student behavior. However, all these published studies were subject to significant methodological flaws in the design of the studies, the assessment of exposure, and the statistical analysis, which prevented valid assessment of a causal link between this exposure metric and adverse effects. Environmental exposure to HFVT is an interesting EMF exposure metric, which might explain the spurious results from epidemiological studies using 'standard' ELF and RF exposure metrics. However, at present, methodological problems in published studies prohibit the valid assessment of its biological activity.Journal of Exposure Science and Environmental Epidemiology advance online publication, 24 March 2010; doi:10.1038/jes.2010.8.

ABSTRACT Introduction. Women's sexual pain disorders include dyspareunia and vaginismus and there is need for state-of-the-art information in this area. Aim. To update the scientific evidence published in 2004, from the 2nd International Consultation on Sexual Medicine pertaining to the diagnosis and treatment of women's sexual pain disorders. Methods. An expert committee, invited from six countries by the 3rd International Consultation, was comprised of eight researchers and clinicians from biological and social science disciplines, for the purpose of reviewing and grading the scientific evidence on nosology, etiology, diagnosis, and treatment of women's sexual pain disorders. Main Outcome Measure. Expert opinion was based on grading of evidence-based medical literature, extensive internal committee discussion, public presentation, and debate. Results. A comprehensive assessment of medical, sexual, and psychosocial history is recommended for diagnosis and management. Indications for general and focused pelvic genital examination are identified. Evidence-based recommendations for assessment of women's sexual pain disorders are reviewed. An evidence-based approach to management of these disorders is provided. Conclusions. Continued efforts are warranted to conduct research and scientific reporting on the optimal assessment and management of women's sexual pain disorders, including multidisciplinary approaches. van Lankveld JJDM, Granot M, Weijmar Schultz WCM, Binik YM, Wesselmann U, Pukall CF, Bohm-Starke N, and Achtrari C. Women's sexual pain disorders. J Sex Med 2010;7:615-631.

Abstract Background In diseases defined primarily by the subjective nature of patient self-report, placebo effects can overwhelm the capacity of randomized controlled trials to detect medication-placebo differences. Moreover, it is unclear whether such placebo effects represent genuine psychobiological phenomena or just shifts in selective attention. Knowledge of predictors of the placebo response could improve the design of clinical trials and the delivery of personalized medical care. Methods In patients with irritable bowel syndrome (IBS), a subset of our previous study that were randomized to placebo treatment (sham acupuncture) or no-treatment group (waitlist), we tested an enriched panel of 10 serum biomarkers at the enrolment and the 3rd week of intervention, using a multiplex electrochemiluminescent immunoassay. Key Results More pronounced changes overtime in serum levels of osteoprotegerin (OPG) have been found in patients who received placebo treatment compared with the waitlist group (P = 0.039). Moreover, serum levels of OPG at baseline were found to be higher (P = 0.0167) in patients who subsequently achieved adequate relief (AR) of their IBS symptoms, independently of their treatment group. Besides, serum levels of TNF-related weak inducer of apoptosis (TWEAK) at baseline were also higher (P = 0.0144) in patients who reported AR and in particular in those who received the placebo treatment. Conclusions & Inferences These two measurable biological parameters associated with placebo, namely serum OPG and TWEAK, provide a proof of principle for discovering putative molecular signatures of placebo response in IBS and perhaps in other illnesses with patient self-reported outcomes.

BACKGROUND: The role of placebos is often misunderstood, leading both to overvaluation and to inappropriate disdain. The effect of a placebo that contains no pharmacologically active substance is often confused with the effect of administration by a physician. The aim of this article is to review the current data on placebos, evaluate these data critically, and provide a well-founded and understandable explanation of the effects that placebos do and do not possess. METHODS: Selective literature review. RESULTS: Recent studies employing modern imaging techniques have provided objective correlates of the effect of placebo administration for certain indications. A recent paper even suggested a genetic basis for it. Two main mechanisms underlie the effect of placebo administration: conditioned reflexes, which are subconscious, and the patient's expectations, which are conscious. Further factors include the physician's personality and the setting in which the treatment takes place. CONCLUSIONS: The mechanisms of action of placebo administration, with which positive therapeutic effects can be achieved with little effort, should be consciously exploited by physicians when giving their patients pharmacologically active medications as well.

OBJECTIVE: The objective of our study was to evaluate the effects of paroxetine on emotional functioning in three arms: double-blind paroxetine (DBPX), single-blind paroxetine (SBPX), and double-blind placebo (DBPO). Healthy psychologists and psychiatrists were elected for their ability to analyze with correct sensibility changes in their emotions. METHOD: Thirty nonanxious, nondepressed participants working as psychiatrists (N = 18) or psychologists (N = 12) were randomly assigned to receive an ambulatory treatment with paroxetine (DBPX N = 10, SBPX N = 10) or placebo (DBPO N = 10). Paroxetine was administered for 4 weeks at 20 mg/day. Emotional functioning was evaluated with the Emotional State Questionnaire (ESQ), a self-questionnaire designed to assess four emotional dimensions:"recognition,""expression,""internal emotional experience," and "social context." Changes in emotional measures from baseline to D0, D7, D14, D28, and D42 were compared between treatment groups. RESULTS: Analyses of ESQ showed in DBPX a significant decrease from baseline to D28 in internal emotional experience as compared to SBPX and DBPO groups. A different influence of gender between treatment groups on emotional recognition was observed. CONCLUSIONS: This is the first study assessing the impact of a 4-week paroxetine treatment on emotional functioning in healthy psychiatrists and psychologists. The DBPX group was distinguishable from both SBPX and DBPO groups by a decrease in internal emotional experience, suggesting that two factors could be involved in the clinical response to paroxetine: a decrease in emotional feeling and treatment awareness.

BACKGROUND: Attitudes and expectations about treatment have been associated with symptomatic outcomes, adherence and utilization in patients with psychiatric disorders. No measure of patients' anticipated benefits of treatment on domains of everyday functioning has previously been available.MethodThe Anticipated Benefits of Care (ABC) is a new, 10-item questionnaire used to measure patient expectations about the impact of treatment on domains of everyday functioning. The ABC was collected at baseline in adult out-patients with major depressive disorder (MDD)(n=528), bipolar disorder (n=395) and schizophrenia (n=447) in the Texas Medication Algorithm Project (TMAP). Psychometric properties of the ABC were assessed, and the association of ABC scores with treatment response at 3 months was evaluated. RESULTS: Evaluation of the ABC's internal consistency yielded Cronbach's alpha of 0.90-0.92 for patients across disorders. Factor analysis showed that the ABC was unidimensional for all patients and for patients with each disorder. For patients with MDD, lower anticipated benefits of treatment was associated with less symptom improvement and lower odds of treatment response [odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57-0.87, p=0.0011]. There was no association between ABC and symptom improvement or treatment response for patients with bipolar disorder or schizophrenia, possibly because these patients had modest benefits with treatment. CONCLUSIONS: The ABC is the first self-report that measures patient expectations about the benefits of treatment on everyday functioning, filling an important gap in available assessments of attitudes and expectations about treatment. The ABC is simple, easy to use, and has acceptable psychometric properties for use in research or clinical settings.

Background: Understanding patients' ambivalence about treatment persistence may be useful in tailoring retention interventions for individual patients with major depressive disorder. Methods: Participants (n = 265) with major depressive disorder were enrolled into an 8-week trial with a selective serotonin reuptake inhibitor. At baseline and week 2, the participants were asked about their intent to return for the next visit, complete the study and continue in the study should they experience side effects or no improvement. Dropouts were defined as participants who discontinued attending clinic visits before completing the trial. Results: Participants who at baseline reported an uncertain/negative intent to continue if they experienced side effects or no improvement dropped out at a significantly higher rate by weeks 6 and 8. Uncertain/negative intent at week 2 predicted attrition at all following visits. Dropouts without side effects were more likely to have reported an uncertain/negative intent to attend at both baseline and week 2, while dropouts who experienced side effects were more likely to have reported an uncertain/negative intent to attend only at baseline. Positive intent to continue was associated with greater symptom improvement in both dropouts and completers despite the possibility of lack of efficacy. Conclusions: Participants' pretreatment concerns about continuing antidepressant treatment in the presence of side effects signals challenges to the completion of a full 8-week acute phase treatment, even if the participant does not develop side effects. Individualized review of concerns and tailoring appropriate interventions may be necessary to reduce attrition.

Summary We tested the hypothesis that pre-operative forced-air warming is as effective for anxiolysis as intravenous midazolam, using a blinded, placebo controlled factorial design. One hundred and twenty patients were randomly assigned to cotton blanket and saline injection (n = 30), forced-air warmer and saline injection (n = 30), midazolam 30 mug.kg(-1) and cotton blanket (n = 30), and forced-air warmer and midazolam 30 mug.kg(-1)(n = 30). Patients completed visual analogue scales for anxiety and thermal comfort, and the State-Trait Anxiety Inventory, at baseline and after 20 min. The estimated effect of midazolam on visual analogue scores for anxiety was -10 (95% CI -3 to -18; p = 0.007) and on state anxiety was -5 (95% CI -7 to -4; p = 0.03). Warming had no influence on visual analogue scores for anxiety (p = 0.50) or state anxiety (p = 0.33), but its estimated effect on thermal comfort was +23 (95% CI 19-27; p < 0.0001). There was no interaction between midazolam and warming. Pre-operative warming was not equivalent to midazolam for anxiolysis and cannot be recommended solely for this purpose.

Placebo analgesia involves the endogenous opioid system, as administration of the opioid antagonist naloxone decreases placebo analgesia. To investigate the opioidergic mechanisms that underlie placebo analgesia, we combined naloxone administration with functional magnetic resonance imaging. Naloxone reduced both behavioral and neural placebo effects as well as placebo-induced responses in pain-modulatory cortical structures, such as the rostral anterior cingulate cortex (rACC). In a brainstem-specific analysis, we observed a similar naloxone modulation of placebo-induced responses in key structures of the descending pain control system, including the hypothalamus, the periaqueductal gray (PAG), and the rostral ventromedial medulla (RVM). Most importantly, naloxone abolished placebo-induced coupling between rACC and PAG, which predicted both neural and behavioral placebo effects as well as activation of the RVM. These findings show that opioidergic signaling in pain-modulating areas and the projections to downstream effectors of the descending pain control system are crucially important for placebo analgesia.

OBJECTIVE: To address the role of anxiety and depression symptoms in altered pain processing in irritable bowel syndrome (IBS). DESIGN: In this functional magnetic resonance imaging (fMRI) study, the blood oxygen level-dependent (BOLD) response to rectal distensions delivered at previously determined individual discomfort thresholds were assessed. PATIENTS: N=15 female irritable bowel syndrome (IBS) patients with normal rectal pain thresholds and N=12 healthy women. Measures: The correlation of anxiety and depression symptoms, measured with the Hospital Anxiety and Depression Scale (HADS), with subjective pain ratings and the BOLD response during distension-induced brain activation were analyzed within IBS. Group differences in pain-induced brain activation with and without controlling for HADS scores were evaluated. RESULTS: IBS patients experienced significantly more pain and discomfort upon rectal distensions in the scanner, despite unaltered rectal sensory thresholds. Anxiety and depression scores were associated with these subjective stimulus ratings, but not with rectal sensory thresholds. Anxiety symptoms in IBS were significantly associated with pain-induced activation of the anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC). Depression scores correlated with activation of the prefrontal cortex (PFC) and cerebellar areas within IBS. Group comparisons with 2-sample t-test revealed significant activation in the IBS versus controls contrast in the anterior insular cortex (IC) and PFC. Inclusion of anxiety and depression scores, respectively, as confounding variables led to a loss of significant group differences. CONCLUSIONS: Altered central processing of visceral stimuli in IBS is at least in part mediated by symptoms of anxiety and depression, which may modulate the affective-motivational aspects of the pain response.

The sympathetic nervous system (SNS) is able to modulate immune functions via adrenoceptor-dependent mechanisms. Activation of beta(2)-adrenergic receptors (AR) on CD4(+) T lymphocytes has been shown to inhibit Th1-cytokine production and cell proliferation. Here we investigated the role of the calcium/calmodulin-dependent protein phosphatase calcineurin (CaN), a key element of the Tcell receptor (TCR)-signaling pathway, in beta(2)-AR-mediated suppression of T cell function. Purified rat splenic CD4(+) T cells were stimulated with anti-CD3/anti-CD28 in presence or absence of the beta(2)-AR agonist terbutaline (TERB). Treatment with TERB induced a dose-dependent inhibition of cellular CaN activity, along with a reduction in IL-2 and IFN-gamma production, and T cell proliferation. Co-administration of the beta-AR antagonist nadolol abolished these effects. Blockade of the cAMP-dependent protein kinase A (PKA) with the inhibitor H-89 completely prevented TERB-induced CaN inhibition. However, a receptor-independent rise in the second messenger cAMP was not sufficient to suppress CaN activity. Disruption of the interaction between PKA and A-kinase anchoring protein (AKAP) by the inhibitor peptide St-Ht31 fully blocked TERB-induced CaN inhibition, demonstrating that PKA-AKAP interaction is essential for the beta(2)-AR-mediated CaN inhibition. Taken together, this study provides evidence for a link between the beta(2)-AR and TCR signaling pathways since expression of IL-2 and IFN-gamma in activated T cells largely depends on dephosphorylation of the transcription factor NFAT by CaN, and identifies a novel intracellular mechanism that can lead to downregulation of T cell function after SNS activation.

BACKGROUND & AIMS:: In patients with irritable bowel syndrome (IBS), pain amplification and hypervigilance might result from altered affective-motivational modulation of the pain response. We investigated the effects of emotional context on the behavioral and neural response to visceral stimuli in IBS patients. METHODS:: We used functional magnetic resonance imaging (fMRI) to assess the blood oxygen level-dependent response to non-painful and painful rectal distensions 15 female IBS patients and 12 healthy women. Distensions were delivered during psychological stress or relaxation; data were compared with those in a neutral condition (control). Group and context-dependent differences in the processing of visceral stimulation were assessed at behavioral and the neuronal levels. Secondary analyses of group differences were performed using anxiety scores as a covariate because of higher anxiety symptoms among patients with IBS. RESULTS:: During rectal stimulation, IBS patients demonstrated more pronounced stress-induced modulation of neural activation in multiple brain regions, including the insula, mid-cingulate cortex, and ventrolateral prefrontal cortex. In response to relaxation, IBS patients demonstrated reduced modulation of distension-induced activation in the insula. During relaxation, the difference observed between groups could be accounted for by higher anxiety symptoms in patients with IBS; differential effects of stress in the insula and prefrontal regions were not attributable to anxiety. CONCLUSIONS:: IBS patients appear to have disrupted emotional modulation of neural responses to visceral stimuli, possibly reflecting the neural basis for altered visceral interoception by stress and negative emotions.

Although placebos have long been considered a nuisance in clinical research, today they represent an active and productive field of research and, because of the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. Indeed, there exists not a single but many placebo effects, with different mechanisms and in different systems, medical conditions, and therapeutic interventions. For example, brain mechanisms of expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena, such as Pavlovian conditioning, cognitive, and social learning. There is also some experimental evidence of different genetic variants in placebo responsiveness. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, the neural networks that are involved have been identified: that is, the opioidergic-cholecystokinergic-dopaminergic modulatory network in pain and part of the basal ganglia circuitry in Parkinson's disease. Important clinical implications emerge from these recent advances in placebo research. First, as the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and rituals of the therapeutic act, may change the chemistry and circuitry of the patient's brain. Second, the mechanisms that are activated by placebos are the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Third, if prefrontal functioning is impaired, placebo responses are reduced or totally lacking, as occurs in dementia of the Alzheimer's type.Neuropsychopharmacology advance online publication, 30 June 2010; doi:10.1038/npp.2010.81.

BACKGROUND: The motivation of patients with functional gastrointestinal disorders to accept psychotherapy (PT) as a treatment option is not known. OBJECTIVE: The authors investigated motivation for patients' refusal to participate and dropout from PT/medical management programs. METHOD: Consecutive patients with symptoms suggestive of functional bowel disorders, seen at the outpatient clinic of a tertiary gastrointestinal (GI) center were evaluated for their motivation to undergo PT. Data from 85 patients were evaluated in two phases: In Phase 1, patients were asked about willingness to participate in PT if it were offered; in Phase 2, patients were offered PT. In both samples, PT motivation was also measured by standardized psychometric scales. RESULTS: Age, gender, social status, and clinical symptom severity did not predict willingness to participate in or accept PT. Motivation was higher when patients were directly recruited in a GI setting than a psychosomatic outpatient unit. Quantitative assessment of PT motivation also did not correlate with declared PT motivation or participation. Assessment of interpersonal problems were among the few variables that were related to participation in PT. CONCLUSION: Motivation for PT in patients with functional gastrointestinal disorders is low and is not determined by clinical, but, rather, by interpersonal problems that may exist beyond and independent of GI symptoms.

OBJECTIVE: To investigate associations between active and passive coping, psychiatric symptoms of depression and anxiety, and quality of life in women with polycystic ovary syndrome (PCOS). To assess the relative contribution of these coping strategies to reduced quality of life in an attempt to clarify the possible relevance of coping for impaired psychosocial well-being in PCOS. DESIGN: Internet-based survey. PARTICIPANTS: 448 German women with PCOS. METHODS: Coping (Freiburg Questionnaire of Coping-with-Illness), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), and quality of life (Short Form 12 Health Survey [SF-12]) were assessed in an Internet-based survey. Correlation and regression analyses were conducted. RESULTS: In women with PCOS, passive coping was significantly associated with greater anxiety (r=.65; p <.001), depression (r=.61; p <.001), and reduced psychological quality of life (r=-.64, p <.001). In stepwise multiple regression analyses, passive coping, together with depression, anxiety and body mass index (BMI), explained 50.1% of the SF-12 psychological sum score, while active coping did not enter any regression model. CONCLUSION: Data suggested that faced with the diagnosis of PCOS, passive coping may constitute a maladaptive strategy associated with anxiety and depression symptoms and compromised quality of life. Hence, efforts to incorporate psychosocial aspects into counselling and care for women with PCOS should take coping strategies into consideration. Nurses and other health care providers may help to improve coping strategies through education and psychosocial support in women with PCOS.

With growing use of acupuncture treatment in various clinical conditions, the question has been posed whether the reported effects reflect specific mechanisms of acupuncture or whether they represent placebo responses, as they often are similar in effect size and resemble similarities to placebo analgesia and its mechanisms. We reviewed the available literature for different placebos (sham procedures) used to control the acupuncture effects, for moderators and potential biases in respective clinical trials, and for central and peripheral mechanisms involved that would allow differentiation of placebo effects from acupuncture and sham acupuncture effects. While the evidence is still limited, it seems that biological differences exist between a placebo response, e.g. in placebo analgesia, and analgesic response during acupunture that does not occur with sham acupuncture. It seems advisable that clinical trials should include potential biomarkers of acupuncture, e.g. measures of the autonomic nervous system function to verify that acupuncture and sham acupuncture are different despite similar clinical effects.

For many years, placebos have been defined by their inert content and their use as controls in clinical trials and treatments in clinical practice. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. There is also evidence that placebo effects can exist in clinical practice, even if no placebo is given. Further promotion and integration of laboratory and clinical research will allow advances in the ethical use of placebo mechanisms that are inherent in routine clinical care, and encourage the use of treatments that stimulate placebo effects.

Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. There is a growing interest in probiotics within the scientific community, with consumers, and in the food industry. The interactions between the gut and intestinal microbiota and between resident and transient microbiota define a new arena in physiology, an understanding of which would shed light on the "cross-talk" between humans and microbes. The different beneficial effects of specific probiotic strains may be translated into different health claims. However, there is a need for comprehensive and harmonized guidelines on the assessment of the characteristics and efficacy of probiotics and of foods containing them. An international expert group of ILSI has evaluated the published evidence of the functionality of different probiotics in 4 areas of (human) application: 1) metabolism, 2) chronic intestinal inflammatory and functional disorders, 3) infections, and 4) allergy. Based on the existing evidence, concrete examples of demonstration of benefits and gaps are listed, and guidelines and recommendations are defined that should help design the next generation of probiotic studies.

OBJECTIVE:: The processing of food cues in eating-disordered patients has recently been increasingly investigated. Outlined is current evidence from pictorial food stimuli studies. METHOD:: PubMed and PsychINFO were searched for quantitative pictorial food stimuli studies investigating healthy controls and expert-diagnosed eating-disordered patients. RESULTS:: Patients with eating disorders (ED) demonstrated cue reactivity to food stimuli. Results from functional imaging suggest sensory disengagement and higher emotional involvement while self-reported data and facial EMG revealed that food pictures were perceived as less pleasurable. Different experimental paradigms have demonstrated an attentional bias for food cues in ED. Currently, psychophysiological data is widely inconclusive. DISCUSSION:: Evidence suggests cue reactivity to food pictures in eating-disordered patients. However, the overall picture is inconclusive because methodological problems and the integration of findings from different experimental approaches pose a challenge to the research field.(c) 2010 by Wiley Periodicals, Inc. Int J Eat Disord 2010.

Placebo analgesia is the occurrence of an analgesic drug effect without drugs. The response is learned through conditioning and mediated by expectancy. It lies on the up-regulation of the pain-modulating areas and the down-regulation of the pain-encoding regions. A further mechanism is the retrieval of the brain circuit activity previously excited by drugs. We describe the case of an infant affected by a tracheal agenesis who underwent a series of operative and diagnostic bronchoscopies for which she received midazolam and fentanyl. After 61 procedures the infant showed a somatosensory response which in our interpretation reflected a placebo effect. Ontogenetic considerations and specific observations indicate that the infant had the appropriate competences in her learning and memory systems and nociceptive and antinociceptive circuits for the placebo effect to take place. Generalizing, the introduction of placebo manipulation in infant pain management may be taken into consideration; its approach through observational and experimental studies is the preliminary target.

Although placebos have long been considered a nuisance in clinical research, today they represent an active and productive field of research and, because of the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. Indeed, there exists not a single but many placebo effects, with different mechanisms and in different systems, medical conditions, and therapeutic interventions. For example, brain mechanisms of expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena, such as Pavlovian conditioning, cognitive, and social learning. There is also some experimental evidence of different genetic variants in placebo responsiveness. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, the neural networks that are involved have been identified: that is, the opioidergic-cholecystokinergic-dopaminergic modulatory network in pain and part of the basal ganglia circuitry in Parkinson's disease. Important clinical implications emerge from these recent advances in placebo research. First, as the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and rituals of the therapeutic act, may change the chemistry and circuitry of the patient's brain. Second, the mechanisms that are activated by placebos are the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Third, if prefrontal functioning is impaired, placebo responses are reduced or totally lacking, as occurs in dementia of the Alzheimer's type.Neuropsychopharmacology advance online publication, 30 June 2010; doi:10.1038/npp.2010.81.

Co-polymer poly(lactic-co-glycolic acid)(PLGA) nanotechnology has been developed for many years and has been approved by the US FDA for the use of drug delivery, diagnostics and other applications of clinical and basic science research, including cardiovascular disease, cancer, vaccine and tissue engineering. This article presents the more recent successes of applying PLGA-based nanotechnologies and tools in these medicine-related applications. It focuses on the possible mechanisms, diagnosis and treatment effects of PLGA preparations and devices. This updated information will benefit to both new and established research scientists and clinical physicians who are interested in the development and application of PLGA nanotechnology as new therapeutic and diagnostic strategies for many diseases.

Conditional responses in rodents such as locomotion have been reported for drugs of abuse and similar to the placebo response in humans, may be associated with the expectation of reward. We examined several conditional opioid-like responses and the influence of drug expectation on conditioned place preference and concomitant conditional locomotion. Male C57BL/6J mice were conditioned with the selective mu opioid receptor agonist fentanyl (0.2mg/kg, i.p.) in a novel context and subsequently given a vehicle injection. In separate experiments, locomotor activity, Straub tail, hot plate sensitivity, and conditioned place preference (CPP) were measured. Mice exhibited multiple conditional opioid-like responses including conditional hyperlocomotion, a conditional pattern of opioid-like locomotion, Straub tail, analgesia, and place preference. Modulating drug expectation via administration of fentanyl to "demonstrator" mice in the home cage did not affect the expression of conditioned place preference or the concomitant locomotor activity in "observer" mice. In summary, Pavlovian conditioning of an opioid in a novel context induced multiple conditional opioid-like behaviors and provides a model for studying the neurobiological mechanisms of the placebo response in mice.

Although it is well documented that fear responses develop following aversive Pavlovian conditioning, it is unclear whether fear learning also manifests in the form of attentional biases for fear-related stimuli. Boschen, Parker, and Neumann (Boschen, M. J., Parker, I.,& Neumann, D. L.(2007). Changes in implicit associations do not occur simultaneously to Pavlovian conditioning of physiological anxiety responses. Journal of Anxiety Disorders, 21, 788-803.) showed that despite the acquisition of differential skin conductance conditioned responses to angry faces paired (CS+) and unpaired (CS-) with an aversive shock, development of implicit associations was not subsequently observed on the Implicit Association Test. In the present study, participants (N=76) were assigned either to a Shock or NoShock group and completed a similar aversive Pavlovian conditioning procedure with angry face CS+ and CS- stimuli. Participants next completed a visual probe task in which the angry face CS+ and CS- stimuli were paired with angry face control stimuli and neutral faces. Results confirmed that differential fear conditioning was observed in the Shock group but not in the NoShock group, and that the Shock group subsequently showed a selective attentional bias for the angry face CS+ compared with the CS- and control stimuli during the visual probe task. The findings confirm the interplay between learning-based mechanisms and cognitive processes, such as attentional biases, in models of fear acquisition and have implications for treatment of the anxiety disorders.

Previous research shows that an 'angry face' conditioned stimulus will elicit conditioned skin conductance responses (SCR) after a small number of trials pairing it with a mild electric shock. Such conditioning occurs even with masked presentations of the facial stimulus. Furthermore, the Implicit Association Test (IAT) has been demonstrated to be sensitive to the presence of information processing biases seen in specific phobias. We examined the ability of the IAT to detect changes in implicit associations that arise from pairing one facial image (CS+) with a mild electro-tactile stimulation whereas a second facial image (CS-) was presented alone. Participants (N=117) were assigned to one of four groups: a group that received no shocks with unmasked presentation of the facial images; a group that received no shocks with masked presentation; a group with shocks delivered simultaneously to the masked presentation of the CS+; and a group that received shocks simultaneous to unmasked CS+ presentation. Learning was assessed through both SCR and the IAT. Results showed that while it was possible to condition a SCR to the CS+, this learning was not detectable using the IAT. Implications of the discrepancies in the outcome measures are discussed.

This article reviews evidence and theories concerning the nature of stimulus representations in Pavlovian conditioning. It focuses on the elemental approach developed in stimulus sampling theory (R. C. Atkinson & W. K. Estes, 1963; R. R. Bush & F. Mosteller, 1951b) and extended by I. P. L. McLaren and N. J. Mackintosh (2000, 2002) and contrasts this with models that invoke notions of configural representations that uniquely code for different patterns of stimulus inputs (e.g., J. M. Pearce, 1987, 1994; R. A. Rescorla & A. R. Wagner, 1972; A. R. Wagner & S. E. Brandon, 2001). The article then presents a new elemental model that emphasizes interactions between stimulus elements. This model is shown to explain a range of behavioral findings, including those (e.g., negative patterning and biconditional discriminations) traditionally thought to be beyond the explanatory capabilities of elemental models. Moreover, the model offers a ready explanation for recent findings reported by R. A. Rescorla (2000, 2001, 2002b) concerning the way that stimuli with different conditioning histories acquire associative strength when conditioned in compound.((c) 2006 APA, all rights reserved).

The nature and determinants of the placebo response are widely unknown and are discussed controversially. This review presents a unifying concept for the understanding of the placebo response in clinical trials and practice based on three components:"Regression to the mean","Pavlovian conditioning", and "Signal detection theory", and discusses the respective literature in light of experimental and clinical findings from psychology, psychiatry, neurology, and gastroenterology, with specific emphasis on "brain imaging" of the placebo response.

The nature and determinants of the placebo response are widely unknown, as are the underlying psychological and biological mechanisms. High placebo response rates in functional bowel disorders (functional dyspepsia, irritable bowel syndrome) are similar to those in non-intestinal diseases (depression, pain, Parkinson's disease) and not too dissimilar to other organic gastrointestinal diseases (duodenal ulcer, inflammatory bowel diseases). Methodological reasons (regression to the mean, shift in signal detection through manipulation of expectations) and psycho-biological mechanisms (Pavlovian conditioning of biological processes) are proposed to explain a large component of the response variance in clinical trials. Psychobiological mechanisms of the placebo response in functional and organic diseases can also be identified in brain function studies (such as imaging).

A new way of EEG analysis is developed, which makes it possible to reveal a reaction of the brain cortex to external stimulation at a low response level. The method is based on the creation of an image of the EEG curve in the discrete phase space and comparison of a current condition with the conditions from a certain basic set. The strength of reaction to external stimulation is defined by the incidence of conditions novel with respect to the basic ones.