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Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

Functional neurological disorder (FND) is a common and disabling disorder that is often considered difficult to treat, particularly in adults. Psychological therapies are often recommended for FND. Outcome research on psychological therapies for FND has grown in recent years but has not been systematically evaluated since 2005. This study aims to build on that by systematically reviewing the evidence-base for individual outpatient cognitive behavioural and psychodynamic psychotherapies for FND. Medical databases were systematically searched for prospective studies of individual outpatient psychotherapy for FND with at least five adult participants. Studies were assessed for methodological quality using a standardised assessment tool. Results were synthesised, and effect sizes calculated for illustrative purposes. The search strategy identified 131 relevant studies, of which 19 were eligible for inclusion: 12 examining cognitive behavioural therapy (CBT) and 7 investigating psychodynamic therapy (PDT). Eleven were pre–post studies and eight were randomised controlled trials. Most studies recruited a single symptom-based subtype rather than all presentations of FND. Effect sizes, where calculable, showed generally medium-sized benefits for physical symptoms, mental health, well-being, function and resource use for both CBT and PDT. Outcomes were broadly comparable across the two therapy types, although a lack of high-quality controlled trials of PDT is a significant limitation, as is the lack of long-term follow-up data in the majority of identified CBT trials. In conclusion, both CBT and PDT appear to potentially offer some benefit for FND, although better quality studies are needed.

Objectives: There has been extensive research in evaluating chronic pain in the context of litigation while considering the implications that it can have on healthcare outcomes and rehabilitation progress. The aim of this article is to present retrospective observational data about the levels of disability and distress reported by patients with ongoing litigation at the start and following a UK-based multi-disciplinary pain management programme (PMP) when compared with those without litigation. Method: Between June 2014 and September 2017, 859 patients attended and completed a 16-day PMP at a tertiary-level National Health Service (UK) pain clinic. Patients were split into two groups: (1) litigation (n = 110) and (2) non-litigation (n = 749). As a part of the assessment procedure, the patients were given a battery of psychological and physical measures to complete over two time points. Results: Patients with litigation are statistically significantly more distressed at assessment but make comparable clinically meaningful change in PMP intervention when compared with a non-litigation sample. A very small proportion of the variance in depression scores post-treatment is accounted for by the context of litigation (0.5%), which may be accounted for by employment status. There was no effect of litigation on physical outcome post-intervention. Discussion: This article concludes that it is not appropriate to merely assume that the context of litigation results in limited positive psychological and physical outcomes post-PMP. There are some limitations to the clinical sample presented in respect to the conclusions.

ObjectiveResponsiveness to direct verbal suggestions (suggestibility) has long been hypothesized to represent a predisposing factor for functional neurological disorder (FND) but previous research has yielded conflicting results. The aim of this study was to quantitatively evaluate whether FND patients display elevated suggestibility relative to controls via meta-analysis.MethodsFour electronic databases were searched in November 2019, with the search updated in April 2020, for original studies assessing suggestibility using standardized behavioural scales or suggestive symptom induction protocols in FND patients and controls. The meta-analysis followed Cochrane, PRISMA, and MOOSE guidelines. Data extraction and study quality coding were performed by two independent reviewers. Standardized suggestibility scores and responsiveness to symptom induction protocols were used to calculate standardized mean differences (SMDs) between groups.ResultsOf 26,643 search results, 19 articles presenting 11 standardized suggestibility datasets (FND: n = 316; control: n = 360) and 11 symptom suggestibility datasets (FND: n = 1285; control: n = 1409) were included in random-effects meta-analyses. Meta-analyses revealed that FND patients displayed greater suggestibility than controls on standardized behavioural scales (SMD, 0.48 [95% CI, 0.15, 0.81]) and greater responsiveness to suggestive symptom induction (SMD, 1.39 [95% CI, 0.92, 1.86]). Moderation analyses presented mixed evidence regarding the extent to which effect sizes covaried with methodological differences across studies. No evidence of publication bias was found.ConclusionsThese results corroborate the hypothesis that FND is characterized by heightened responsiveness to verbal suggestion. Atypical suggestibility may confer risk for FND and be a cognitive marker that can inform diagnosis and treatment of this condition.

A dualistic mind-body understanding of functional neurological disorders (FNDs), also known as conversion disorders, has led to the view that the cause of the symptom should be either psychological (psychogenic) or physical (neurogenic-"organic"). One of the most influential psychological approaches is the Freudian model of conversion, which suggests that FNDs arise from a defense process in which emotional stress is converted into physical symptoms. This conversion theory has been challenged in recent years, accompanied by a shift in emphasis toward neuropathophysiological models of FND and away from historical psychological concepts. In this review, the authors consider the contemporary relevance of the conversion model from the neuroscientific perspective to reconcile the role of both psychological and biological factors in FND. A narrative review of recent neuroscientific findings pertaining to the conversion model of FND, encompassing neuroimaging, cognitive psychology, biological markers, and epigenetic studies, was performed. Research on the role of psychological stressors is discussed. Neurobiological mechanisms of repression of traumatic memories and their translation into physical symptoms are then explored. Finally, the role of physical symptoms as a potential protective defense mechanism against social stressors is considered. The authors argue that the conversion concept is consistent with recent neuroscientific research findings, and the model allows psychological and neurobiological concepts to be reconciled within a single account of FND that begins to resolve the dualistic mind-body dichotomy.

Purpose Small-scale dosimetry studies generally consider an artificial environment where the tumors are spherical and the radionuclides are homogeneously biodistributed. However, tumor shapes are irregular and radiopharmaceutical biodistributions are heterogeneous, impacting the energy deposition in targeted radionuclide therapy. To bring realism, we developed a dosimetric methodology based on a three-dimensional in vitro model of follicular lymphoma incubated with rituximab, an anti-CD20 monoclonal antibody used in the treatment of non-Hodgkin lymphomas, which might be combined with a radionuclide. The effects of the realistic geometry and biodistribution on the absorbed dose were highlighted by comparison with literature data. Additionally, to illustrate the possibilities of this methodology, the effect of different radionuclides on the absorbed dose distribution delivered to the in vitro tumor were compared. Methods The starting point was a model named multicellular aggregates of lymphoma cells (MALC). Three MALCs of different dimensions and their rituximab biodistribution were considered. Geometry, antibody location and concentration were extracted from selective plane illumination microscopy. Assuming antibody radiolabeling with Auger electron (125 I and 111 In) and β- particle emitters (177 Lu, 131 I and 90 Y), we simulated energy deposition in MALCs using two Monte Carlo codes: Geant4-DNA with "CPA100" physics models for Auger electron emitters and Geant4 with "Livermore" physics models for β- particle emitters. Results MALCs had ellipsoid-like shapes with major radii, r, of ~0.25, ~0.5 and ~1.3 mm. Rituximab was concentrated in the periphery of the MALCs. The absorbed doses delivered by 177 Lu, 131 I and 90 Y in MALCs were compared with literature data for spheres with two types of homogeneous biodistributions (on the surface or throughout the volume). Compared to the MALCs, the mean absorbed doses delivered in spheres with surface biodistributions were between 18% and 38% lower, while with volume biodistribution they were between 15% and 29% higher. Regarding the radionuclides comparison, the relationship between MALC dimensions, rituximab biodistribution and energy released per decay impacted the absorbed doses. Despite releasing less energy, 125 I delivered a greater absorbed dose per decay than 111 In in the r ~ 0.25 mm MALC (6.78·10-2 vs 6.26·10-2 µGy·Bq-1 ·s-1 ). Similarly, the absorbed doses per decay in the r ~ 0.5 mm MALC for 177 Lu (2.41·10-2 µGy·Bq-1 ·s-1 ) and 131 I (2.46·10-2 µGy·Bq-1 ·s-1 ) are higher than for 90 Y (1.98·10-2 µGy·Bq-1 ·s-1 ). Furthermore, radionuclides releasing more energy per decay delivered absorbed dose more uniformly through the MALCs. Finally, when considering the radiopharmaceutical effective half-life, due to the biological half-life of rituximab being best matched by the physical half-life of 177 Lu and 131 I compared to 90 Y, the first two radionuclides delivered higher absorbed doses. Conclusion In the simulated configurations, β- emitters delivered higher and more uniform absorbed dose than Auger electron emitters. When considering radiopharmaceutical half-lives, 177 Lu and 131 I delivered absorbed doses higher than 90 Y. In view of real irradiation of MALCs, such a work may be useful to select suited radionuclides and to help explain the biological effects.

ObjectivesWe aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes.MethodsA systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group.ResultsFive FND-specific measures were identified—three clinician-rated and two patient-rated—but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost–utility (eg, healthcare resource use and quality-adjusted life years).ConclusionsThere are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population.

This paper describes a condensed version of psychodynamic interpersonal therapy (PIT), Psychodynamic Interpersonal-Empathy (PI-E), which consists of the first level of competencies of the PIT model. The intention is to use basic psychodynamic principles and skills to enhance delivery of manualised, cognitive therapy based treatments. The intervention is designed to improve two common factors of therapy: the bond between client and therapist, and the ability of the therapist to create positive expectations through an explanation and understanding of the person’s problems. Both of these so-called common factors are consistently associated with clinical outcomes. Training has been developed specifically for low-intensity therapists who are employed in the Improving Access to Psychological Treatment programme. Training focuses upon 5 basic components of PI: negotiation; picking up cues;using statements rather than questions; focusing on feelings and understanding hypotheses. When used skilfully together, these simple components, offer a powerful way of empathizing with and deepening the collaborative work with the client. They all help the therapist to focus upon how the client is feeling ‘here and now’ in the session. Training in the model has the potential to improve outcomes and reduce drop-out rates by enabling therapists to manage problem scenarios in an empathic way.

Idiopathic environmental intolerance refers to a group of poorly understood health conditions characterized by heterogeneous somatic symptoms that occur in response to environmental triggers, but for which no physiological causes can be found. We focus on three varieties, namely symptoms attributed to (a) chemical substances, (b) electromagnetic fields, and (c) infrasound and vibroacoustic sources. As no clear link with organ pathology or dysfunction has been established so far, we review critical evidence about alternative causal mechanisms as a platform for a novel unifying model of these conditions. There is consistent evidence that expectancy and nocebo mechanisms are critically involved. Using recent predictive coding models of brain functioning, we describe a comprehensive new model to explain how symptoms come about and become linked to specific environmental cues. This new model integrates phenomenally different pathologies, suggests testable new hypotheses, and specifies implications for treatment.

Using the Internet to obtain health information (“online health research”, OHR) is commonplace. This paper provides a systematic narrative review of evidence concerning the relationship between OHR and health anxiety. We conclude that health anxiety is associated with more frequent self-reported OHR, heightened distress after OHR, and increased doctor visits post-OHR. Evidence suggests that OHR often has a reassurance seeking function and can relieve anxiety, but that it can also cause alarm and become a distressing, compulsive behaviour. We present a novel model that integrates these perspectives and existing research within a single explanatory framework that distinguishes between problematic OHR and compulsive OHR and describes the role of positive and negative metacognitions in their respective development.

Delusional disorder (DD) is still considered a diagnosis of exclusion for a difficult-to-treat condition characterised by the presence of delusional beliefs in the absence of other psychiatric symptoms. Attempts to contextualise psychological processes recognised since the earliest observations of this disorder have had very limited impact on improving some fixed beliefs. In the Cambridge Early Intervention in Psychosis Service we have observed a particular phenomenon, often categorised as a delusional idea in the context of DD, which manifests through highly repetitive belief expression that fails to respond to pharmacological and psychological treatments. Key aspects of this phenomenon are similar to those observed in dissociative (functional neurological) presentations. Drawing on the Integrative Cognitive Model of functional neurological disorders, we developed a successful psychological intervention that places less emphasis on challenging delusional content and focuses more on dismantling dissociation and underlying affective factors associated with the activation of the fixed belief. Our initial findings reinforce the need to continue developing a multi-level phenomenological approach to define a variety of symptoms traditionally grouped under the concept of “delusion.”

Aims/Objectives Impulse control behaviors (ICBs) affect 15%–35% of Parkinson’s Disease patients. There is evidence of increased carer strain due to these behaviours; however, little is known about clinical variables mediating this effect. This study aims to investigate the factors predictive of carer burden within a cohort of Parkinson’s Disease patients with ICBs. Identification of such factors may allow for targeted therapeutic intervention. Method Data was collected from 45 patients with clinically significant ICBs and their carers including levodopa equivalent daily dosage, assessments of motor and neuropsychiatric symptoms, cognitive function and ICBs. Carer burden was assessed using the Zarit Burden Interview (ZBI). Univariate analyses were performed using Spearman’s Rank Correlation Coefficient. A backward model was used to remove variables to create a final multivariate model using ZBI score as the dependent variable. Results Univariate analysis identified significant correlations between ZBI and total NPI (rs=0.50, p Conclusions This is the largest study to date, looking at associations between carer burden and ICBs. Our findings indicate low mood, poor motivation, social disinhibition and neuropsychiatric symptom burden to be significant factors in carer burden. We also observe that carers reporting poorer health had increased carer strain. Further work should explore methods of physical and psychosocial support and coping strategies for carers.

The current study aimed to explore the phenomenon of disease-related ‘query escalation’ in high/low health anxious Internet users ( N = 40). During a 15-minute health-related Internet search, participants rated their anxiety and the perceived seriousness of information on each page. Post-search interviews determined the reasons for, and effects of, escalating queries to consider serious diseases. Both groups were found to be significantly more anxious after escalating queries. The high group was significantly more likely to escalate queries. Evaluating personal relevance of material was the main reason for escalations and moderated anxiety post-escalation. We conclude that searching for online disease information can increase anxiety, particularly for people worried about their health.

Psychogenic Nonepileptic Seizures (PNES) superficially resemble epileptic seizures but are thoughtto have a psychological rather than epileptic basis. Patients with PNES vary widely in terms ofbackground, personality profiles, comorbidities, response to treatment and outcomes. Previousaccounts interpreting these seizures as the activation of dissociated material, a physical manifestationof emotional distress, hard-wired reflex responses, or learned behaviours cannot explain key featuresof the phenomenon. Drawing on a brief review of the literature on etiology, correlates andphenomenology of PNES, this paper integrates existing approaches and data within a novelexplanatory framework that applies to all PNES patients with subjectively involuntary seizures.Following the Integrative Cognitive Model of medically unexplained symptoms, we suggest that thecentral feature of all PNES is the automatic activation of a mental representation of seizures (the“seizure scaffold”) in the context of a high level inhibitory processing dysfunction. This often arisesin response to elevated autonomic arousal, and may disrupt the individual‟s awareness of distressingmaterial, but can become divorced from abnormal autonomic and emotional activity. This modelaccounts both for existing findings and the heterogeneity of patients with PNES, whilst leading to anumber of novel hypotheses against which it can be evaluated.

Psychogenic non-epileptic seizures (PNES) are common in neurological settings and often associated with considerable distress and disability. The psychological mechanisms underlying PNES are poorly understood and there is a lack of well-established, evidence-based treatments. This paper advances our understanding of PNES by providing a comprehensive systematic review of the evidence pertaining to the main theoretical models of this phenomenon. Methodological quality appraisal and effect size calculation were conducted on one hundred forty empirical studies on the following aspects of PNES: life adversity, dissociation, anxiety, suggestibility, attentional dysfunction, family/relationship problems, insecure attachment, defence mechanisms, somatization/conversion, coping, emotion regulation, alexithymia, emotional processing, symptom modelling, learning and expectancy. Although most of the studies were only of low to moderate quality, some findings are sufficiently consistent to warrant tentative conclusions: (i) physical symptom reporting is elevated in patients with PNES; (ii) trait dissociation and exposure to traumatic events are common but not inevitable correlates of PNES; (iii) there is a mismatch between subjective reports of anxiety and physical arousal during PNES; and (iv) inconsistent findings in this area are likely to be attributable to the heterogeneity of patients with PNES. Empirical, theoretical and clinical implications are discussed.

This paper presents a simulation framework for dynamic PET-MR. The main focus of this framework is to provide motion-resolved MR and PET data and ground truth motion information. This can be used in the optimisation and quantitative evaluation of image registration and in assessing the error propagation due to inaccuracies in motion estimation in complex motion-compensated reconstruction algorithms. Contrast and tracer kinetics can also be simulated and are available as ground truth information. To closely emulate medical examination, input and output of the simulation are files in standardised open-source raw data formats. This enables the use of existing raw data as a template input and ensures seamless integration of the output into existing reconstruction pipelines. The proposed framework was validated in PET-MR and image registration applications. It was used to simulate a FDG-PET-MR scan with cardiac and respiratory motion. Ground truth motion information could be utilised to optimise parameters for PET and synergistic PET-MR image registration. In addition, a free-breathing dynamic contrast enhancement (DCE) abdominal scan of a patient with hepatic lesions was simulated. In order to correct for breathing motion, a motion-corrected image reconstruction scheme was used and a Toft's model was fit to the DCE data to obtain quantitative DCE-MRI parameters. Utilising the ground truth motion information, the dependency of quantitative DCE-MR images on the accuracy of the motion estimation was evaluated. We demonstrated that respiratory motion had to be available with an average accuracy of at least the spatial resolution of the DCE-MR images in order to ensure an improvement in lesions visualisation and quantification compared to no motion correction. The proposed framework provides a valuable tool with a wide range of scientific PET and MR applications and will be available as part of the open-source project Synergistic Image Reconstruction Framework (SIRF).

Objective High symptom reporting (HSR) and medically unexplained symptoms (MUS) are associated with considerable distress, disability, healthcare utilization and costs, but are poorly understood, and current treatments are of limited benefit. Most models of HSR and MUS implicate cognitive-perceptual factors, such as increased body-focused attention, reduced perceptual thresholds and a tendency to experience somatic misperception, but little is known about the causal role of these variables. We investigated this issue by studying whether there is a longitudinal relationship between perceptual-attentional variables and later clinical outcomes in primary care patients. Method Primary care patients (N = 102) completed clinical (physical symptom reporting, health anxiety and healthcare utilization) and perceptual-attentional (body-focused attention, perceptual threshold, somatic misperception) measures at baseline and then again six months later (N = 72). Hierarchical regression was used to examine cross-lagged relationships between baseline and follow-up scores. Results Contrary to expectation, attending away from the body at baseline predicted increased not decreased symptom reporting six months later. Neither perceptual threshold nor somatic misperception predicted clinical outcomes at six months. Conclusions These findings suggest that body avoidance, rather than increased body focus, contribute to the development of HSR. Future studies should consider the potential clinical benefits of reducing bodily avoidance, via techniques that promote adaptive engagement with bodily sensations.

Chronic pain is exacerbated by maladaptive cognition such as pain catastrophizing (PC). Biomarkers of PC mechanisms may aid precision medicine for chronic pain. Here, we investigate EEG biomarkers using mass univariate and multivariate (machine learning) approaches. We test theoretical notions that PC results from a combination of augmented aversive-value encoding (“magnification”) and persistent expectations of pain (“rumination”). Healthy individuals with high or low levels of PC underwent an experimental pain model involving nociceptive laser stimuli preceded by cues predicting forthcoming pain intensity. Analysis of EEG acquired during the cue and laser stimulation provided event-related potentials (ERPs) identifying spatially and temporally-extended neural representations associated with pain catastrophizing. Specifically, differential neural responses to cues predicting high vs. low intensity pain (i.e. aversive value encoding) were larger in the high PC group, largely originating from mid-cingulate and superior parietal cortex. Multivariate spatiotemporal EEG patterns evoked from cues with high aversive value selectively and significantly differentiated the high PC from low PC group (64.6% classification accuracy). Regression analyses revealed that neural patterns classifying groups could be partially predicted (R2 = 28%) from those neural patterns classifying the aversive value of cues. In contrast, behavioural and EEG analyses did not provide evidence that PC modifies more persistent effects of prior expectation on pain perception and nociceptive responses. These findings support the hypothesis of magnification of aversive value encoding but not persistent expression of expectation in pain catastrophizers. Multivariate patterns of aversive value encoding provide promising biomarkers of maladaptive cognitive responses to chronic pain that have future potential for psychological treatment development and clinical stratification.

Aims and methodTo develop and pilot a clinician-rated outcome scale to evaluate symptomatic outcomes in liaison psychiatry services. Three hundred and sixty patient contacts with 207 separate individuals were rated using six subscales (mood, psychosis, cognition, substance misuse, mind–body problems and behavioural disturbance) plus two additional items (side-effects of medication and capacity to consent for medical treatment). Each item was rated on a five-point scale from 0 to 5 (nil, mild, moderate, severe and very severe).ResultsThe liaison outcome measure was acceptable and easy to use. All subscales showed acceptable interrater reliability, with the exception of the mind–body subscale. Overall, the measure appears to show stability and sensitivity to change.Clinical implicationsThe measure provides a useful and robust way to determine symptomatic change in a liaison mental health setting, although the mind–body subscale requires modification.Declaration of interestNone.

It is well known that the efficacy of treatment effects, including those of placebos, is heavily dependent on positive expectations regarding treatment outcomes. For example, positive expectations about pain treatments are essential for pain reduction. Such positive expectations not only depend on the properties of the treatment itself, but also on the context in which the treatment is presented. However, it is not clear how the preceding threat of pain will bias positive expectancy effects. One hypothesis is that threatening contexts trigger fearful and catastrophic thinking, reducing the pain-relieving effects of positive expectancy. In this study, we investigated the disruptive influence of threatening contexts on positive expectancy effects while 41 healthy volunteers experienced laser-induced heat pain. A threatening context was induced using pain-threatening cues that preceded the induction of positive expectancies via subsequent pain-safety cues. We also utilised electroencephalography (EEG) to investigate potential neural mechanisms underlying these effects. Lastly, we used the Fear of Pain Questionnaire to address whether the disruptive effect of negative contexts on cued pain relief was related to the degree of fear of pain. As predicted, participants responded less to pain-safety cues (i.e., experienced more pain) when these were preceded by pain-threatening cues. In this threatening context, an enhancement of the N2 component of the laser-evoked potential was detected, which was more pronounced in fearful individuals. This effect was localised to the midcingulate cortex, an area thought to integrate negative affect with pain experience to enable adaptive behaviour in aversive situations. These results suggest that threatening contexts disrupt the effect of pain relief cues via an aversive priming mechanism that enhances neural responses in the early stages of sensory processing.

Background: Mucopolysaccharidosis type IH (MPS-IH) [Hurlers Syndrome] is a developmental genetic disorder characterised by severe physical symptoms and cognitive decline. This study aimed to investigate the behavioural phenotype of MPS-IH treated by haematopoietic cell transplantation, focusing on social functioning and sleep. Parental stress was also measured.\ud \ud Methods: Participants were 22 children with MPS-IH (mean age 9 years 1 month), of whom 10 were male (45%). Parents completed the Social Responsiveness Scale (SRS), Child Behaviour Checklist (CBCL), Children’s Sleep Habit Questionnaire and Parent Stress Index, Short Form (PSI-SF).\ud \ud Results: Twenty-three per cent of children with MPS-IH scored in the severe range of the SRS, suggesting significant difficulties in social functioning. Children with MPS-IH were more than 30 times more likely to receive scores in the severe range than typically developing children. Thirty-six per cent scored in the mild-to-moderate range, suggesting milder, but marked, difficulties in social interaction. Although children with MPS-IH did not show significantly higher rates of internalising, externalising or total behaviour problems than the normative sample, they received scores that were significantly higher on social, thought and attention problems and rule-breaking behaviour, and all the competence areas of the CBCL. Parents of children with MPS-IH did not score significantly higher on parental stress than parents in a normative sample.\ud \ud Conclusions: Parents of children with MPS-IH rate their children as having problems with social functioning and various areas of competence more frequently than previously thought, with implications for clinical support.

Non-clinical participants viewed pictures of either neutral or stressful interpersonal scenes before completing a voice-detection task. Exposure to stress did not influence voice detection, but scores on a measure of depersonalisation were positively correlated with voices.

Psychological therapy is generally considered the treatment of choice for psychogenic nonepileptic seizures (PNES), but there is a paucity of research on patients' attitudes towards psychological referral. We conducted semistructured interviews with twelve patients with PNES awaiting psychological treatment in order to understand their perceived treatment needs. Data were analyzed inductively according to the principles of thematic analysis. The results indicated that our patients had clear ideas about their treatment needs and a desire to recover by 'returning to normality'. Many participants felt 'caught in limbo' following their PNES diagnosis, however, because of uncertainties about their condition and a lack of support from professionals. This linked with participants feeling unsure whether psychological treatment would meet their needs; there was also apprehension for some participants about the potential negative consequences of therapy. The clinical implications of these findings are discussed, and recommendations for future research are made.

Psychogenic Nonepileptic Seizures (PNES) are one of the commonest differential diagnoses of epilepsy. This paper provides a narrative review of what has been learnt in the last 25 years regarding the visible manifestations, physiological features, subjective experiences and interactional aspects of PNES. We then explore how current insights into PNES semiology and phenomenology map onto the Integrative Cognitive Model (ICM), a new account of these phenomena that unifies previous approaches within a single explanatory framework. We discuss to what extent recent psychological and neurophysiological research is consistent with the ICM and indicate how the more detailed analysis of physiological data, connectivity analyses of EEG and functional or structural MRI data may provide greater insights into the biopsychosocial underpinnings of a disabling and under-researched disorder.

Conversion disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) describes neurological symptoms, including weakness, numbness and events resembling epilepsy or syncope, which can be positively identified as not being due to recognised neurological disease. This review combines perspectives from psychiatry, psychology and neurology to identify and discuss key problems with the current diagnostic DSM-IV criteria for conversion disorder and to make the following proposals for DSM-5: (a) abandoning the label "conversion disorder" and replacing it with an alternative term that is both theoretically neutral and potentially more acceptable to patients and practitioners; (b) relegating the requirements for "association of psychological factors" and the "exclusion of feigning" to the accompanying text; (c) adding a criterion requiring clinical findings of internal inconsistency or incongruity with recognised neurological or medical disease and altering the current 'disease exclusion' criteria to one in which the symptom must not be 'better explained' by a disease if present, (d) adding a 'cognitive symptoms' subtype. We also discuss whether conversion symptoms are better classified with other somatic symptom disorders or with dissociative disorders and how we might address the potential heterogeneity of conversion symptoms in classification.

The current study aimed to obtain health anxious students’ perspectives on their reasons for using the Internet to obtain health information, and the nature and effects of such usage. Data were gathered using semi-structured interviews with 20 postgraduate and undergraduate students identified as highly health anxious, and were examined using thematic analysis. Results suggested that themes were organized by different stages of the search process. Reasons for searching included curiosity, anxiety/worry about undiagnosed symptoms, and remedy-seeking. Both positive (e.g. reassurance) and negative (e.g. uncertainty) outcomes were reported. Findings from the current study suggest that the Internet constitutes an important resource for obtaining health information by health anxious individuals, with the potential to both reduce and exacerbate health anxiety.

Reason for withdrawal from publication Protocol withdrawn. Cochrane Oral Health was unable to maintain contact with the contact author. The co-authors are unable to take over this protocol.

Dissociation has been cited as a possible psychologic mechanism underpinning functional neurologic disorders (FND) since the 19th century. Since that time, changes in psychiatric classification have created confusion about what the term dissociation actually means. The available evidence suggests that it now refers to at least two qualitatively distinct types of phenomena: detachment (an altered state of consciousness characterized by a sense of separation from the self or world) and compartmentalization (a reversible loss of voluntary control over apparently intact processes and functions), as well as their underlying mechanisms. This chapter considers some of the problems with conflating these phenomena under a single heading as well as the relationship between detachment, compartmentalization, and FND. It is argued that FNDs are fundamentally compartmentalization disorders, but that detachment is often part of the clinical picture and may contribute to the development and maintenance of functional symptoms in many cases. By this view, understanding compartmentalization requires an appreciation of the mechanisms involved in controlling and accessing mental processes and contents. Two possible mechanisms in this regard are described and the evidence for these is considered, followed by a discussion of clinical and empiric implications.

When asked to judge the presence or absence of near-threshold tactile stimuli, participants often report touch experiences when no tactile stimulation has been delivered ('false alarms'). The simultaneous presentation of a light flash during the stimulation period can increase the frequency of touch reports, both when touch is and is not present. Using fMRI, we investigated the BOLD response during both light-present and light-absent false alarms, testing predictions concerning two possible neural mechanisms underlying these illusory touch experiences: activation of a tactile representation in primary somatosensory cortex (SI) and/or activation of a tactile representation in late processing areas outside of sensory-specific cortex, such as medial prefrontal cortex (MPC). Our behavioural results showed that participants made false alarms in light-present and light-absent trials, both of which activated regions of the medial parietal and medial prefrontal cortex including precuneus, posterior cingulate and paracingulate cortex, suggesting the same underlying mechanism. However, only a non-significant increase in SI activity was measured in response to false alarm vs. correct rejection trials. We argue that our results provide evidence for the role of top-down regions in somatic misperception, consistent with findings from studies in humans and non-human primates.

The diagnostic criteria and related features of conversion disorder are under revision for DSM-5, including the requirement that psychological factors accompany the symptoms or deficits in question (Criterion B) and whether conversion disorder should be re-labeled as a dissociative, rather than a somatoform, condition. We examined the cross-cultural evidence on the prevalence, characteristics, and associated features of pseudoneurological symptoms more generally, and conversion disorder in particular, in order to inform the ongoing re-evaluation of the conversion disorder category. We also examined the relationship between these constructs and dissociative symptoms and disorders across cultural groups. Searches were conducted of the mental health literature, particularly since 1994, regarding culture, race, or ethnicity factors related to conversion disorder. Many proposed DSM-5 revisions were supported, such as the elimination of Criterion B. We also found cross-cultural variability in predominant symptoms, disorder prevalence, and relationship with cultural syndromes. Additional information that may contribute to DSM-5 includes the elevated rates across cultures of traumatic exposure and psychiatric comorbidity in conversion disorder. Cross-culturally, conversion disorder is associated strongly with both dissociative and somatoform presentations, revealing no clear basis on which to locate the disorder in DSM-5. Careful consideration should be given to the possible alternatives.

This review by three established clinicians/researchers and two 'rising stars' in the field of psychogenic nonepileptic seizures (PNES) describes recent progress in this area and highlights priorities for future research. Empirically testable models of PNES are emerging but many questions about the aetiology of PNES remain unanswered at present. Video-EEG has made it possible for doctors to make secured diagnoses of PNES in more cases. However, unacceptable diagnostic delays and misdiagnoses are still common. Non-specific EEG changes are often misinterpreted as evidence of epilepsy. A better understanding of the symptomatology of PNES may allow earlier and more accurate diagnoses using self-report questionnaires. The communication of the diagnosis and the engagement of patient in psychological treatment can be difficult. A recent pilot RCT has demonstrated the effectiveness of a psychological treatment in reducing seizures in the short term, but longer-term effectiveness is yet to be demonstrated.

Diabet. Med. 28, 1028–1033 (2011) Abstract Aim Maturity-onset diabetes of the young is a monogenic form of familial, young-onset diabetes. It is rare (∼1% diabetes) and may be misdiagnosed as Type 1 diabetes and inappropriately treated with insulin. Type 1 diabetes is characterized by the presence of islet autoantibodies, including glutamate decarboxylase (GAD) and islet antigen-2 (IA-2) antibodies. The prevalence of islet autoantibodies is unknown in maturity-onset diabetes of the young and may have the potential to differentiate this form of diabetes from Type 1 diabetes. The aim of this study was to determine the prevalence of GAD and IA-2 antibodies in patients with maturity-onset diabetes of the young and Type 1 diabetes. Methods We measured plasma GAD and IA-2 antibodies in 508 patients with the most common forms of maturity-onset diabetes of the young (GCK: n = 227; HNF1A: n = 229; HNF4A: n = 52) and 98 patients with newly diagnosed Type 1 diabetes (diagnosed

I have often argued that the construct of dissociation lacks clarity and that the term dissociation is widely used without consideration for its varied meanings and implications. I agree that more ...

Research suggests that attention has a significant effect on somatic perception in both healthy people and those who suffer from somatic disturbance. The current study investigates the effects of attending to the body on somatic awareness and a particular type of somatic disturbance: erroneous reports of touch sensation, as measured by the Somatic Signal Detection Task (SSDT). During the SSDT, participants are required to detect near-threshold tactile stimulation at their fingertip. Previous research has found that healthy participants erroneously report touch sensations in the absence of a stimulus on this task and that such false alarms are increased when a simultaneous light flash is presented next to their fingertip. Thirty-seven participants completed the SSDT under two conditions: non-informative vision of the hand and no vision of the hand. False alarms were significantly higher in light trials in the non-informative vision condition compared to light trials in the no-vision condition. However, hit rates, sensitivity (d') and response criterion (c) were not affected by non-informative vision of the hand. Using the SSDT, we found that viewing the body increased somatic interference, possibly due to raised awareness of internal bodily sensations. This work provides evidence that viewing the body can have a detrimental effect on simple detection of near-threshold tactile stimulation.

Digital image-based elasto-tomography technology relies on obtaining high-resolution images of a breasts surface under high-frequency actuation, typically in the range of 50-100 Hz. Off-the-shelf digital cameras and imaging elements are unable to capture images directly at these speeds. A method based on strobe imaging is presented for obtaining the required high-speed image capture at a resolution of 1280 times 1024 pixels and actuation frequency of 100 Hz. The final working system produced images that enabled effective 3-D motion tracking of the surface of a silicon phantom. The motion is tracked accurately using a novel Euclidean Invariant signature method.

Contains fulltext : 81193.pdf (Publisher’s version ) (Closed access) BACKGROUND: The syndrome of fixed dystonia includes both CRPS-dystonia and psychogenic dystonia. The underlying mechanisms are unclear, but a high prevalence of neuropsychiatric illness has previously been reported. METHODS: Clinical and neuropsychiatric follow-up study by telephone and self-administered instruments (HADS, SDQ-20, DES II, EQ-5D), on 41 patients with fixed dystonia after a mean of 7.6 (+/-3.6) years. RESULTS: We obtained information on clinical outcome in 35 (85.4%) patients and neuropsychiatric questionnaire data in 22 (53.7%). Eighty-three percent were women. Thirty-one percent had worsened, 46% were the same and 23% had improved, of whom 6% had major remissions. At follow-up, mean duration of illness was 11.8 (+/-4.9) years and mean age 43.2 (+/-14.8) years. Except for 1 patient who was re-diagnosed with corticobasal degeneration, the diagnosis remained unchanged in others. Forty-one percent had scores indicating anxiety and 18% indicating depression; 18% scored within the range of dissociative/somatoform disorders on DES II and 19% on SDQ-20. The mean EQ-5D index and VAS scores were 0.34 and 56.1%. Comparison between the 3 outcome groups revealed significant difference only in the EQ-5D (p=0.003). Only baseline CRPS predicted a worse outcome (chi(2)=0.006). CONCLUSIONS: Our findings revealed that the prognosis of this syndrome is poor, with improvement in less than 25% of patients, major remission in only 6% and continued worsening in a third. A high rate of neuropsychiatric findings was noted and new neuropsychiatric features had occurred in some. Average health status was poor. Of the baseline parameters, only CRPS predicted poorer outcome.

The effects of ultraviolet light exposure on scar pigmentation are well documented. There is a commonly held belief among physicians that sun exposure may also worsen the appearance of fresh scars and result in excess collagen deposition. However, few studies have documented a relationship between ultraviolet light exposure and hypertrophic scarring. This study sought to evaluate the effect of ultraviolet light exposure on scar hypertrophy in an established rabbit model of cutaneous scarring.Four 7-mm ulcers were created on the ventral ears of eight rabbits. Starting on postoperative day 15, half of the wounds were exposed to ultraviolet-B radiation daily for either 7 or 14 days. Ultraviolet-B-exposed (n = 16) and control (n = 16) scars were harvested on postoperative day 32 for histologic and reverse-transcriptase polymerase chain reaction analysis.Exposure to ultraviolet-B radiation for 7 or 14 days was associated with a 52 percent (p0.01) or 74 percent (p0.05) reduction in scar volume, respectively, compared with controls. In wounds subjected to ultraviolet-B radiation for 14 days, collagen type I-alpha2 mRNA expression was 29 percent lower than in controls (p0.05). There was no difference in the mRNA expression of transforming growth factor-beta1.: These short-term observations demonstrate that ultraviolet-B radiation exposure reduces scar hypertrophy in this clinically relevant animal model. A reduction in collagen production or increase in collagen breakdown may account for this result. However, sunscreen should still be used as primary protection when skin is exposed to direct sunlight.

Non-epileptic attack disorder (NEAD) poses a significant clinical problem but is poorly understood. Attachment theory provides a framework for understanding the development and maintenance of NEAD and the contribution of childhood abuse and neglect to these processes. A cross-sectional design was used to study attachment style and early traumatic experiences in individuals with NEAD (N=17) compared to those with epilepsy (N=26). A significant difference in predominant attachment style between the two groups was found, with fearful attachment occurring more frequently in the NEAD group. Abuse and neglect were also significantly more common in the NEAD patients. Both early traumatic experiences and fearful attachment added significantly to the predictive power of a logistic regression equation after controlling for anxiety and dysthymia. The findings suggest a link between disturbed attachment and NEAD and have clinical implications for therapeutic intervention with this group.

OBJECTIVE: High suggestibility is widely regarded as an important feature of patients with medically unexplained symptoms (MUS), particularly those with multiple MUS [i.e. somatization disorder (SD)], although there are few empirical data attesting to this assumption. A study was therefore conducted to compare levels of non-hypnotic suggestibility in patients with SD and medical controls. METHOD: A modified version of the Barber Suggestibility Scale was administered to 19 patients with SD and 17 controls with an established organic dystonia. RESULTS: Patients with SD were no more suggestible than control patients. Dystonia controls were more likely to deliberately comply with suggestions than the SD patients. CONCLUSION: Contrary to popular belief, high suggestibility is not necessarily a feature of SD.

This paper outlines a method for accurately tracking surface motion on an actuated breast as part of a Digital Image-based Elasto-Tomography (DIET) breast cancer screening project. The tracking method is validated in both simulation and experiment on a silicon breast phantom which has similar elasticity characteristics to human breast tissue. Given mean reprojection error ranges between 0.3 and 0.5 pixels for 2M pixel cameras the end result is sub-millimetre surface tracking of a silicon phantom actuated at 100 Hz. This highly accurate, fast and low cost method of tracking is thus well suited to a DIET system.

OBJECTIVE: This study aimed to develop an experimental paradigm, using healthy controls, to measure change in tactile sensitivity and response bias for subsequent testing of patients with medically unexplained symptoms (MUS). METHODS: Participants judged whether or not they detected a weak tactile pulse (presented in 50% of trials). Performance in two conditions (tactile pulses presented with or without a concomitant light) was compared using signal detection analysis to assess whether a task-irrelevant light can invoke the sensation of touch, even in its absence. RESULTS: The results showed that the presence of a concurrent light significantly improved participants' detection of the tactile stimulus by 13.7% [t(18)=4.24, P

Pseudoneurological symptoms (i.e., conversion disorder), historically subsumed within the "hysteria" concept alongside phenomena such as psychogenic amnesia and multiple personality disorder, have been classified as somatoform disorders since DSM-III. Since then, there have been repeated calls to reclassify conversion disorder with the dissociative disorders, as in ICD-10. The authors review issues such as the high correlations between pseudoneurological and dissociative symptoms, the high rates of trauma reported for both groups, and the position that these phenomena share underlying processes. Although reintegrating pseudoneurological symptoms with the dissociative disorders is not without complications, there is a strong case for such a reclassification.

Blood flow through a vessel depends upon compliance and resistance. Resistance changes dynamically due to vasoconstriction and vasodilation as a result of metabolic activity, thus allowing for more or less flow to a particular area. The structure responsible for directing blood to the different areas of the brain and supplying the increase flow is the cerebral arterial circle (CAC). A series of 1D equations were utilized to model propagating flow and pressure waves from the left ventricle of the heart to the CAC. The focus of the current research was to understand the collateral capability of the circle. This was done by decreasing the peripheral resistance in each of the efferent arteries, up to 10% both unilaterally and bilaterally. The collateral patterns were then analyzed. After the initial 60 simulations, it became apparent that flow could increase beyond the scope of a 10% reduction and still be within in vivo conditions. Simulations with higher percentage decreases were performed such that the same amount of flow increase would be induced through each of the efferent arteries separately, same flow tests (SFTs), as well as those that were found to allow for the maximum flow increase through the stimulated artery, maximum flow tests (MFTs). The collateral pattern depended upon which efferent artery was stimulation and if the stimulation was unilaterally or bilaterally induced. With the same amount of flow increase through each of the efferent arteries, the MCAs (middle cerebral arteries) had the largest impact on the collateral capability of the circle, both unilaterally and bilaterally.

A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K(+) and the smooth muscle cell (SMC) Ca(2+) pathway termed a neurovascular unit (NVU). Luminal agonists acting on P2Y receptors on the endothelial cell (EC) surface provide a flux of inositol trisphosphate (IP3) into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between EC and SMC providing a source of sarcoplasmic derived Ca(2+) in the SMC. The model is able to relate a neuronal input signal to the corresponding vessel reaction (contraction or dilation). A tissue slice consisting of blocks, each of which contain an NVU is connected to a space filling H-tree, simulating a perfusing arterial tree (vasculature) The model couples the NVUs to the vascular tree via a stretch mediated Ca(2+) channel on both the EC and SMC. The SMC is induced to oscillate by increasing an agonist flux in the EC and hence increased IP3 induced Ca(2+) from the SMC stores with the resulting calcium-induced calcium release (CICR) oscillation inhibiting NVC thereby relating blood flow to vessel contraction and dilation following neuronal activation. The coupling between the vasculature and the set of NVUs is relatively weak for the case with agonist induced where only the Ca(2+) in cells inside the activated area becomes oscillatory however, the radii of vessels both inside and outside the activated area oscillate (albeit small for those outside). In addition the oscillation profile differs between coupled and decoupled states with the time required to refill the cytosol with decreasing Ca(2+) and increasing frequency with coupling. The solution algorithm is shown to have excellent weak and strong scaling. Results have been generated for tissue slices containing up to 4096 blocks.

Background Agitation is a common experience for people living with dementia, particularly as day-to-day function and cognition start to decline more. At the present time there are limited pharmacological options for relieving agitation and little is known about the safety and efficacy of opioid drugs in this setting. Objectives To determine the clinical efficacy and safety of opioids for agitation in people with dementia. Search methods We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 13 June 2014 using the terms: narcotic OR opioid OR opium OR morphine OR buprenorphine OR codeine OR dextromoramide OR diphenoxylate OR dipipanone OR dextropropoxyphene OR propoxyphene OR diamorphine OR dihydrocodeine OR alfentanil OR fentanyl OR remifentanil OR meptazinol OR methadone OR nalbuphine OR oxycodone OR papaveretum OR pentazocine OR meperidine OR pethidine OR phenazocine OR hydrocodone OR hydromorphone OR levorphanol OR oxymorphone OR butorphanol OR dezocine OR sufentanil OR ketobemidone. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases such as MEDLINE, EMBASE and PscyINFO, as well as numerous trial registries and grey literature sources. Selection criteria Randomised, controlled trials of opioids compared to placebo for agitation in people with dementia. Data collection and analysis Two authors independently assessed the studies identified by the search against the inclusion criteria. Main results There are currently no completed randomised, placebo controlled trials of opioids for agitation in dementia. There are two potentially relevant trials still in progress. Authors' conclusions We found insufficient evidence to establish the clinical efficacy and safety of opioids for agitation in people with dementia. There remains a lack of data to determine if or when opioids either relieve or exacerbate agitation. More evidence is needed to guide the effective, appropriate and safe use of opioids in dementia.