Treatment outcomes in the inpatient management of severe functional neurological disorder: a retrospective cohort study.

Background: Functional neurological disorder (FND) is a heterogeneous condition; severe forms can be disabling. Multidisciplinary treatment and rehabilitation are recommended for severe FND, but there remains a lack of evidence for its efficacy and lack of understanding of the predictors and components of recovery. Methods: We report clinical outcome data for an inpatient cohort with severe FND. Clinical Global Impression Improvement with treatment is the primary outcome measure. Admission and discharge measures (Euroqol quality of life measures, Beck Depression Inventory, Spielberger Trait Anxiety Inventory, Cambridge Depersonalisation Scale, Illness Perception Questionnaire (Revised) and Functional Mobility Scale) are reported as secondary outcomes. Results: We describe an FND cohort (n=52) with chronic illness (mean symptom duration 9.7 years). At admission, there were clinically relevant levels of depression, anxiety and depersonalisation derealisation. At the time of discharge, most (43/52) patients' global condition had improved. Measures of mobility, depression and quality of life also significantly improved while at discharge, symptoms were experienced as more understandable and less distressing than at admission. An admission measure of patient confidence in treatment was predictive of eventual clinical outcome. Conclusions: The most frequent outcome of inpatient rehabilitation is global improvement, even when symptoms are chronic and severe, reflected in measurable changes in both physical and psychological functioning. Significant levels of depersonalisation derealisation seen in this patient group suggest that routine enquiry into such experiences could help personalise FND treatment approaches. Patient confidence in treatment is key in determining clinical outcomes.

Reflections on the CODES trial for adults with dissociative seizures: what we found and considerations for future studies.

The COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures multicentre randomised controlled trial is the largest, fully-powered study to test the clinical and cost-effectiveness of a psychotherapeutic intervention in this population. We also explored predictors or moderators of outcomes and investigated mechanisms of change in therapy. In this current review of findings, we discuss issues related to the design of the trial and consider the study's nested qualitative studies which were undertaken not only to shed light on the original research questions but to provide insights and recommendations for other researchers in the field of functional neurological disorder. Finally, we consider issues relating to the possible clinical application of our study findings.

Behavioural, autonomic, and neural responsivity in depersonalisation-derealisation disorder: A systematic review of experimental evidence.

Depersonalisation-derealisation disorder (DDD) is characterised by distressing experiences of separation from oneself and/or one's surroundings, potentially resulting from alterations in affective, cognitive, and physiological functions. This systematic review aimed to synthesise current experimental evidence of relevance to proposed mechanisms underlying DDD, to appraise existing theoretical models, and to inform future research and theoretical developments. Studies were included if they tested explicit hypotheses in DDD samples, with experimental manipulations of at least one independent variable, alongside behavioural, subjective, neurological, affective and/or physiological dependent variables. Some evidence for diminished subjective responsivity to aversive images and sounds, and hyperactivation in neurocircuits associated with emotional regulation when viewing aversive images emerged, corroborating neurobiological models of DDD. Inconsistencies were present regarding behavioural and autonomic responsivity to facial expressions, emotional memory, and self-referential processing. Common confounds included small sample sizes, medication, and comorbidities. Alterations in affective reactivity and regulation appear to be present in DDD; however, further research employing more rigorous research designs is required to provide stronger evidence for these possible mechanisms.

Predictive Utility of Diffusion MRI After Mild Traumatic Brain Injury in Civilian Populations: A Systematic Review.

OBJECTIVE: A considerable number of people experience persisting symptoms and functional limitations after mild traumatic brain injury (mTBI). It is unclear whether subtle white matter changes contribute to this phenomenon. In this systematic review, the authors evaluated whether microstructural white matter indices on advanced MRI are related to clinical dysfunction among patients without abnormalities on standard brain computed tomography (CT) or MRI (uncomplicated mTBI). METHODS: A search of multiple databases was performed. Studies with individuals who experienced blast-related, sports-related, or multiple mTBIs were excluded. Diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI) metrics and cognitive, neuropsychiatric, or functional outcome measures were extracted from each study. RESULTS: Thirteen studies were selected (participants with mTBI, N=553; healthy control group, N=438). Seven DTI studies evaluated cognitive function, with five reporting significant correlations between reduced white matter integrity and deficits in attention, processing speed, and executive function at 6-12 months after injury (three studies included only individuals with uncomplicated mTBI). Four studies found significant correlations between DTI metrics and persistent postconcussive symptoms after 3-12 months (one study included only individuals with uncomplicated mTBI). Two SWI studies reported conflicting findings regarding the relationship between the presence of microbleeds and postconcussive symptoms. CONCLUSIONS: The results revealed that indices of microstructural white matter integrity may relate to clinical presentation 3-12 months after injury in uncomplicated mTBI. However, analysis methods and brain regions studied varied across studies. Further research is needed to identify relationships between white matter indices in specific brain regions and symptom persistence beyond 12 months.

Case report: Clinical lycanthropy in Huntington's disease.

We describe the case of a patient diagnosed with Huntington's disease (HD), who, following a two-year history of anxiety with obsessional preoccupations, developed psychosis with clinical lycanthropy: a prominent delusional idea that he was a werewolf. Although there was no benefit from various antidepressants and antipsychotics, there was remarkable improvement of his symptoms following prescription of Clozapine. His choreiform movement disorder also improved as his mental state settled. Although some reported cases of clinical lycanthropy are related to neurological conditions, this is the first case in a patient with HD. We also discuss the relevance of cultural and personal factors in the expression of a delusion that incorporates disgust, and the potential role of somatosensory aberrations and misidentification of self.

Six-month outcomes of the CODES randomised controlled trial of cognitive behavioural therapy for dissociative seizures: A secondary analysis.

PURPOSE: The CODES Trial for adults with dissociative seizures had a predesignated 12-month post-randomisation follow-up point for outcome evaluation. We undertook an exploratory, unplanned, secondary analysis to evaluate the effectiveness of cognitive behavioural therapy plus standardised medical care (CBT+SMC) compared to SMC alone at 6 months post-randomisation, i.e., closer to the end of treatment. METHODS: The analysis of 6-month data followed our previous method of using multiple imputation and an intention-to-treat approach to analyse variables 12 months post-randomisation. RESULTS: The original trial primary outcome of monthly seizure frequency showed greater benefit from CBT+SMC than SMC-alone at 6 months (at p < 0.05). Of 13 comparable previously-defined secondary outcomes, 12 showed a significant between group effect (p < 0.05) in favour of the CBT intervention at 6 months. The average effect size of the comparable previously-defined primary and secondary continuous outcomes was 0.33 at 6 months vs 0.26 at 12 months. The estimated Incidence Rate Ratio (IRR) quantifying monthly seizure reduction was IRR = 0.72 (95%CI from 0.55 to 0.93) at 6 months compared to IRR = 0.78 at 12 months. CONCLUSION: DS-specific CBT (plus SMC) produced evidence of significant benefits at 6 months post- randomisation (around which time CBT was complete) compared to SMC alone; for the majority of these outcomes, better results following CBT (plus SMC) had previously been reported at 12 months. Our pattern of results suggests that short- and longer-term follow-ups are necessary to understand treatment effects in this disorder. Studies only providing short-term follow-up data should be interpreted with caution.

Cognitive-behavioural therapy compared with standardised medical care for adults with dissociative non-epileptic seizures: the CODES RCT.

BACKGROUND: Dissociative (non-epileptic) seizures are potentially treatable by psychotherapeutic interventions; however, the evidence for this is limited. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of dissociative seizure-specific cognitive-behavioural therapy for adults with dissociative seizures. DESIGN: This was a pragmatic, multicentre, parallel-arm, mixed-methods randomised controlled trial. SETTING: This took place in 27 UK-based neurology/epilepsy services, 17 liaison psychiatry/neuropsychiatry services and 18 cognitive-behavioural therapy services. PARTICIPANTS: Adults with dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous year and meeting other eligibility criteria were recruited to a screening phase from neurology/epilepsy services between October 2014 and February 2017. After psychiatric assessment around 3 months later, eligible and interested participants were randomised between January 2015 and May 2017. INTERVENTIONS: Standardised medical care consisted of input from neurologists and psychiatrists who were given guidance regarding diagnosis delivery and management; they provided patients with information booklets. The intervention consisted of 12 dissociative seizure-specific cognitive-behavioural therapy 1-hour sessions (plus one booster session) that were delivered by trained therapists, in addition to standardised medical care. MAIN OUTCOME MEASURES: The primary outcome was monthly seizure frequency at 12 months post randomisation. The secondary outcomes were aspects of seizure occurrence, quality of life, mood, anxiety, distress, symptoms, psychosocial functioning, clinical global change, satisfaction with treatment, quality-adjusted life-years, costs and cost-effectiveness. RESULTS: In total, 698 patients were screened and 368 were randomised (standardised medical care alone, n = 182; and cognitive-behavioural therapy plus standardised medical care, n = 186). Primary outcome data were obtained for 85% of participants. An intention-to-treat analysis with multivariate imputation by chained equations revealed no significant between-group difference in dissociative seizure frequency at 12 months [standardised medical care: median of seven dissociative seizures (interquartile range 1-35 dissociative seizures); cognitive-behavioural therapy and standardised medical care: median of four dissociative seizures (interquartile range 0-20 dissociative seizures); incidence rate ratio 0.78, 95% confidence interval 0.56 to 1.09; p = 0.144]. Of the 16 secondary outcomes analysed, nine were significantly better in the arm receiving cognitive-behavioural therapy at a p-value < 0.05, including the following at a p-value ≤ 0.001: the longest dissociative seizure-free period in months 7-12 inclusive post randomisation (incidence rate ratio 1.64, 95% confidence interval 1.22 to 2.20; p = 0.001); better psychosocial functioning (Work and Social Adjustment Scale, standardised treatment effect -0.39, 95% confidence interval -0.61 to -0.18; p < 0.001); greater self-rated and clinician-rated clinical improvement (self-rated: standardised treatment effect 0.39, 95% confidence interval 0.16 to 0.62; p = 0.001; clinician rated: standardised treatment effect 0.37, 95% confidence interval 0.17 to 0.57; p < 0.001); and satisfaction with treatment (standardised treatment effect 0.50, 95% confidence interval 0.27 to 0.73; p < 0.001). Rates of adverse events were similar across arms. Cognitive-behavioural therapy plus standardised medical care produced 0.0152 more quality-adjusted life-years (95% confidence interval -0.0106 to 0.0392 quality-adjusted life-years) than standardised medical care alone. The incremental cost-effectiveness ratio (cost per quality-adjusted life-year) for cognitive-behavioural therapy plus standardised medical care versus standardised medical care alone based on the EuroQol-5 Dimensions, five-level version, and imputed data was £120,658. In sensitivity analyses, incremental cost-effectiveness ratios ranged between £85,724 and £206,067. Qualitative and quantitative process evaluations highlighted useful study components, the importance of clinical experience in treating patients with dissociative seizures and potential benefits of our multidisciplinary care pathway. LIMITATIONS: Unlike outcome assessors, participants and clinicians were not blinded to the interventions. CONCLUSIONS: There was no significant additional benefit of dissociative seizure-specific cognitive-behavioural therapy in reducing dissociative seizure frequency, and cost-effectiveness over standardised medical care was low. However, this large, adequately powered, multicentre randomised controlled trial highlights benefits of adjunctive dissociative seizure-specific cognitive-behavioural therapy for several clinical outcomes, with no evidence of greater harm from dissociative seizure-specific cognitive-behavioural therapy. FUTURE WORK: Examination of moderators and mediators of outcome. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05681227 and ClinicalTrials.gov NCT02325544. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 43. See the NIHR Journals Library website for further project information.

Dissociative seizures resemble epileptic seizures or faints, but can be distinguished from them by trained doctors. Dissociation is the medical word for a 'trance-like' or 'switching off' state. People with dissociative seizures commonly have other psychological or physical problems. Quality of life may be low. The condition accounts for about one in every six patients seen in hospitals because of seizures. We wanted to find out if people with dissociative seizures receiving standardised treatment would also benefit from a talking therapy, called cognitive­behavioural therapy, made specific to this disorder. We did a randomised controlled trial to find out if people with dissociative seizures given standardised treatment and cognitive­behavioural therapy (talking therapy) would do better than those given standardised treatment alone. Standardised treatment of dissociative seizures began with careful diagnosis from a neurologist and then further assessment and treatment from a psychiatrist. In total, 368 people with dissociative seizures participated, with half receiving standardised treatment alone and half having talking therapy plus standardised treatment. We measured seizures and psychological and physical health in both trial groups. We also investigated whether or not cognitive­behavioural therapy was good value for money. After 12 months, patients in both trial groups seemed to have fewer monthly seizures, but there was no advantage in the talking therapy group. Patients in the talking therapy group had more consecutive days without seizures, reporting less impact from them in everyday situations. Patients in the talking therapy group, and their doctors, considered improvements to be better, and patients in this group reported greater satisfaction with treatment. However, the talking therapy was expensive and not as cost-effective as hoped. Interviews with patients and study clinicians showed that they valued aspects of both treatments and of the care provided by the multidisciplinary teams. Overall, cognitive­behavioural therapy designed for dissociative seizures plus standardised treatment was not better at reducing the total numbers of seizures reported, but did produce several positive benefits for participants compared with standardised treatment alone.

Psychological and demographic characteristics of 368 patients with dissociative seizures: data from the CODES cohort.

BACKGROUND: We examined demographic, clinical, and psychological characteristics of a large cohort (n = 368) of adults with dissociative seizures (DS) recruited to the CODES randomised controlled trial (RCT) and explored differences associated with age at onset of DS, gender, and DS semiology. METHODS: Prior to randomisation within the CODES RCT, we collected demographic and clinical data on 368 participants. We assessed psychiatric comorbidity using the Mini-International Neuropsychiatric Interview (M.I.N.I.) and a screening measure of personality disorder and measured anxiety, depression, psychological distress, somatic symptom burden, emotional expression, functional impact of DS, avoidance behaviour, and quality of life. We undertook comparisons based on reported age at DS onset (<40 v. ⩾40), gender (male v. female), and DS semiology (predominantly hyperkinetic v. hypokinetic). RESULTS: Our cohort was predominantly female (72%) and characterised by high levels of socio-economic deprivation. Two-thirds had predominantly hyperkinetic DS. Of the total, 69% had ⩾1 comorbid M.I.N.I. diagnosis (median number = 2), with agoraphobia being the most common concurrent diagnosis. Clinical levels of distress were reported by 86% and characteristics associated with maladaptive personality traits by 60%. Moderate-to-severe functional impairment, high levels of somatic symptoms, and impaired quality of life were also reported. Women had a younger age at DS onset than men. CONCLUSIONS: Our study highlights the burden of psychopathology and socio-economic deprivation in a large, heterogeneous cohort of patients with DS. The lack of clear differences based on gender, DS semiology and age at onset suggests these factors do not add substantially to the heterogeneity of the cohort.

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency. METHODS: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544. FINDINGS: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0-20] in the CBT plus standardised medical care group vs 7 seizures [1-35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events. INTERPRETATION: CBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach. FUNDING: National Institute for Health Research, Health Technology Assessment programme.

Characteristics of 698 patients with dissociative seizures: A UK multicenter study.

OBJECTIVE: We aimed to characterize the demographics of adults with dissociative (nonepileptic) seizures, placing emphasis on distribution of age at onset, male:female ratio, levels of deprivation, and dissociative seizure semiology. METHODS: We collected demographic and clinical data from 698 adults with dissociative seizures recruited to the screening phase of the CODES (Cognitive Behavioural Therapy vs Standardised Medical Care for Adults With Dissociative Non-Epileptic Seizures) trial from 27 neurology/specialist epilepsy clinics in the UK. We described the cohort in terms of age, age at onset of dissociative seizures, duration of seizure disorder, level of socioeconomic deprivation, and other social and clinical demographic characteristics and their associations. RESULTS: In what is, to date, the largest study of adults with dissociative seizures, the overall modal age at dissociative seizure onset was 19 years; median age at onset was 28 years. Although 74% of the sample was female, importantly the male:female ratio varied with age at onset, with 77% of female but only 59% of male participants developing dissociative seizures by the age of 40 years. The frequency of self-reported previous epilepsy was 27%; nearly half of these epilepsy diagnoses were retrospectively considered erroneous by clinicians. Patients with predominantly hyperkinetic dissociative seizures had a shorter disorder duration prior to diagnosis in this study than patients with hypokinetic seizures (P < .001); dissociative seizure type was not associated with gender. Predominantly hyperkinetic seizures were most commonly seen in patients with symptom onset in their late teens. Thirty percent of the sample reported taking antiepileptic drugs; this was more common in men. More than 50% of the sample lived in areas characterized by the highest levels of deprivation, and more than two-thirds were unemployed. SIGNIFICANCE: Females with dissociative seizures were more common at all ages, whereas the proportion of males increased with age at onset. This disorder was associated with socioeconomic deprivation. Those with hypokinetic dissociative seizures may be at risk for delayed diagnosis and treatment.

The role of dissociation and abuse among adolescents who self-harm.

OBJECTIVES: Retrospective recall of dissociative symptoms has been found to mediate the association between childhood abuse and deliberate self-harm (DSH) in later life. To disentangle the effect of recall bias, we tested whether dissociation symptoms ascertained during an acute DSH presentation mediates this link. METHOD: All participants with DSH were recruited during emergency presentation. Seventy-one individuals aged 11-17 years with overdose (OD) and/or self-injury (SI) participated in semi-structured interviews and psychiatric assessment to measure abuse and dissociation. An age- and gender-matched comparison group of 42 non-psychiatric patients admitted to the same service were also assessed. RESULTS: The DSH groups reported significantly higher levels of abuse and dissociation compared to comparison group. Dissociation significantly mediated the association between abuse and DSH. Of the four dissociation subtypes, 'depersonalisation' was the primary mediator. Adolescents with chronic patterns of DSH and the 'OD + SI' self-harm type reported more severe dissociation. CONCLUSION: Exposure to abuse significantly increased the risk of DSH in adolescence. This association was mediated by dissociation. Our findings suggest a possible dose-response relationship between dissociation with DSH chronicity and the 'OD + SI' self-harm type, implicating the importance of evaluating dissociation and depersonalisation symptoms as well as abuse exposure in DSH management.

Impairment of perceptual metacognitive accuracy and reduced prefrontal grey matter volume in first-episode psychosis.

INTRODUCTION: Metacognition, or "thinking about thinking", is a higher-order thought process that allows for the evaluation of perceptual processes for accuracy. Metacognitive accuracy is associated with the grey matter volume (GMV) in the prefrontal cortex (PFC), an area also impacted in schizophrenia. The present study set out to investigate whether deficits in metacognitive accuracy are present in the early stages of psychosis. METHODS: Metacognitive accuracy in first-episode psychosis (FEP) was assessed on a perceptual decision-making task and their performance compared to matched healthy control participants (N = 18). A novel signal detection theory approach was used to model metacognitive sensitivity independently from objective perceptual performance. A voxel-based morphometry investigation was also conducted on GMV. RESULTS: We found that the FEP group demonstrated significantly worse metacognitive accuracy compared to controls (p = .039). Importantly, GMV deficits were also observed in the superior frontal gyrus. The findings suggest a specific deficit in this processing domain to exist at first episode; however, no relationship was found between GMV and metacognitive accuracy. CONCLUSIONS: Our findings support the notion that an inability to accurately scrutinise perception may underpin functional deficits observed in later schizophrenia; however, the exact neural basis of metacognitive deficits in FEP remains elusive.

COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): statistical and economic analysis plan for a randomised controlled trial.

BACKGROUND: Dissociative seizures (DSs), also called psychogenic non-epileptic seizures, are a distressing and disabling problem for many patients in neurological settings with high and often unnecessary economic costs. The COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES) trial is an evaluation of a specifically tailored psychological intervention with the aims of reducing seizure frequency and severity and improving psychological well-being in adults with DS. The aim of this paper is to report in detail the quantitative and economic analysis plan for the CODES trial, as agreed by the trial steering committee. METHODS: The CODES trial is a multicentre, pragmatic, parallel group, randomised controlled trial performed to evaluate the clinical effectiveness and cost-effectiveness of 13 sessions of cognitive behavioural therapy (CBT) plus standardised medical care (SMC) compared with SMC alone for adult outpatients with DS. DISCUSSION: The objectives and design of the trial are summarised, and the aims and procedures of the planned analyses are illustrated. The proposed analysis plan addresses statistical considerations such as maintaining blinding, monitoring adherence with the protocol, describing aspects of treatment and dealing with missing data. The formal analysis approach for the primary and secondary outcomes is described, as are the descriptive statistics that will be reported. This paper provides transparency to the planned inferential analyses for the CODES trial prior to the extraction of outcome data. It also provides an update to the previously published trial protocol and guidance to those conducting similar trials. TRIAL REGISTRATION: ISRCTN registry ISRCTN05681227 (registered on 5 March 2014); ClinicalTrials.gov NCT02325544 (registered on 15 December 2014).

Deficits in Neurite Density Underlie White Matter Structure Abnormalities in First-Episode Psychosis.

BACKGROUND: Structural abnormalities across multiple white matter tracts are recognized in people with early psychosis, consistent with dysconnectivity as a neuropathological account of symptom expression. We applied advanced neuroimaging techniques to characterize microstructural white matter abnormalities for a deeper understanding of the developmental etiology of psychosis. METHODS: Thirty-five first-episode psychosis patients, and 19 healthy controls, participated in a quantitative neuroimaging study using neurite orientation dispersion and density imaging, a multishell diffusion-weighted magnetic resonance imaging technique that distinguishes white matter fiber arrangement and geometry from changes in neurite density. Fractional anisotropy (FA) and mean diffusivity images were also derived. Tract-based spatial statistics compared white matter structure between patients and control subjects and tested associations with age, symptom severity, and medication. RESULTS: Patients with first-episode psychosis had lower regional FA in multiple commissural, corticospinal, and association tracts. These abnormalities predominantly colocalized with regions of reduced neurite density, rather than aberrant fiber bundle arrangement (orientation dispersion index). There was no direct relationship with active symptoms. FA decreased and orientation dispersion index increased with age in patients, but not control subjects, suggesting accelerated effects of white matter geometry change. CONCLUSIONS: Deficits in neurite density appear fundamental to abnormalities in white matter integrity in early psychosis. In the first application of neurite orientation dispersion and density imaging in psychosis, we found that processes compromising axonal fiber number, density, and myelination, rather than processes leading to spatial disruption of fiber organization, are implicated in the etiology of psychosis. This accords with a neurodevelopmental origin of aberrant brain-wide structural connectivity predisposing individuals to psychosis.

Emotional Experience and Awareness of Self: Functional MRI Studies of Depersonalization Disorder.

This paper presents functional MRI work on emotional processing in depersonalization disorder (DPD). This relatively neglected disorder is hallmarked by a disturbing change in the quality of first-person experience, almost invariably encompassing a diminished sense of self and an alteration in emotional experience such that the sufferer feels less emotionally reactive, with emotions experienced as decreased or "damped down," so that emotional life seems to lack spontaneity and subjective validity. Here we explored responses to emotive visual stimuli to examine the functional neuroanatomy of emotional processing in DPD before and after pharmacological treatment. We also employed concurrent skin conductance measurement as an index of autonomic arousal. In common with previous studies we demonstrated that in DPD, there is attenuated psychophysiological response to emotional material, reflected in altered patterns of (i) regional brain response, (ii) autonomic responses. By scanning participants before and after treatment we were able to build on previous findings by examining the changes in functional MRI response in patients whose symptoms had improved at time 2. The attenuation of emotional experience was associated with reduced activity of the insula, whereas clinical improvement in DPD symptoms was associated with increased insula activity. The insula is known to be implicated in interoceptive awareness and the generation of feeling states. In addition an area of right ventrolateral prefrontal cortex emerged as particularly implicated in what may be "top-down" inhibition of emotional responses. The relevance of these findings to the wider study of emotion, self-related processes, and interoception is discussed.

COgnitive behavioural therapy vs standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): a multicentre randomised controlled trial protocol.

BACKGROUND: The evidence base for the effectiveness of psychological interventions for patients with dissociative non-epileptic seizures (DS) is currently extremely limited, although data from two small pilot randomised controlled trials (RCTs), including from our group, suggest that Cognitive Behavioural Therapy (CBT) may be effective in reducing DS occurrence and may improve aspects of psychological status and psychosocial functioning. METHODS/DESIGN: The study is a multicentre, pragmatic parallel group RCT to evaluate the clinical and cost-effectiveness of specifically-tailored CBT plus standardised medical care (SMC) vs SMC alone in reducing DS frequency and improving psychological and health-related outcomes. In the initial screening phase, patients with DS will receive their diagnosis from a neurologist/epilepsy specialist. If patients are eligible and interested following the provision of study information and a booklet about DS, they will consent to provide demographic information and fortnightly data about their seizures, and agree to see a psychiatrist three months later. We aim to recruit ~500 patients to this screening stage. After a review three months later by a psychiatrist, those patients who have continued to have DS in the previous eight weeks and who meet further eligibility criteria will be told about the trial comparing CBT + SMC vs SMC alone. If they are interested in participating, they will be given a further booklet on DS and study information. A research worker will see them to obtain their informed consent to take part in the RCT. We aim to randomise 298 people (149 to each arm). In addition to a baseline assessment, data will be collected at 6 and 12 months post randomisation. Our primary outcome is monthly seizure frequency in the preceding month. Secondary outcomes include seizure severity, measures of seizure freedom and reduction, psychological distress and psychosocial functioning, quality of life, health service use, cost effectiveness and adverse events. We will include a nested qualitative study to evaluate participants' views of the intervention and factors that acted as facilitators and barriers to participation. DISCUSSION: This study will be the first adequately powered evaluation of CBT for this patient group and offers the potential to provide an evidence base for treating this patient group. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05681227 ClinicalTrials.gov NCT02325544.

Neuroanatomical substrates for the volitional regulation of heart rate.

The control of physiological arousal can assist in the regulation of emotional state. A subset cortical and subcortical brain regions are implicated in autonomic control of bodily arousal during emotional behaviors. Here, we combined human functional neuroimaging with autonomic monitoring to identify neural mechanisms that support the volitional regulation of heart rate, a process that may be assisted by visual feedback. During functional magnetic resonance imaging (fMRI), 15 healthy adults performed an experimental task in which they were prompted voluntarily to increase or decrease cardiovascular arousal (heart rate) during true, false, or absent visual feedback. Participants achieved appropriate changes in heart rate, without significant modulation of respiratory rate, and were overall not influenced by the presence of visual feedback. Increased activity in right amygdala, striatum and brainstem occurred when participants attempted to increase heart rate. In contrast, activation of ventrolateral prefrontal and parietal cortices occurred when attempting to decrease heart rate. Biofeedback enhanced activity within occipito-temporal cortices, but there was no significant interaction with task conditions. Activity in regions including pregenual anterior cingulate and ventral striatum reflected the magnitude of successful task performance, which was negatively related to subclinical anxiety symptoms. Measured changes in respiration correlated with posterior insula activation and heart rate, at a more lenient threshold, change correlated with insula, caudate, and midbrain activity. Our findings highlight a set of brain regions, notably ventrolateral prefrontal cortex, supporting volitional control of cardiovascular arousal. These data are relevant to understanding neural substrates supporting interaction between intentional and interoceptive states related to anxiety, with implications for biofeedback interventions, e.g., real-time fMRI, that target emotional regulation.

Grey-matter texture abnormalities and reduced hippocampal volume are distinguishing features of schizophrenia.

Neurodevelopmental processes are widely believed to underlie schizophrenia. Analysis of brain texture from conventional magnetic resonance imaging (MRI) can detect disturbance in brain cytoarchitecture. We tested the hypothesis that patients with schizophrenia manifest quantitative differences in brain texture that, alongside discrete volumetric changes, may serve as an endophenotypic biomarker. Texture analysis (TA) of grey matter distribution and voxel-based morphometry (VBM) of regional brain volumes were applied to MRI scans of 27 patients with schizophrenia and 24 controls. Texture parameters (uniformity and entropy) were also used as covariates in VBM analyses to test for correspondence with regional brain volume. Linear discriminant analysis tested if texture and volumetric data predicted diagnostic group membership (schizophrenia or control). We found that uniformity and entropy of grey matter differed significantly between individuals with schizophrenia and controls at the fine spatial scale (filter width below 2mm). Within the schizophrenia group, these texture parameters correlated with volumes of the left hippocampus, right amygdala and cerebellum. The best predictor of diagnostic group membership was the combination of fine texture heterogeneity and left hippocampal size. This study highlights the presence of distributed grey-matter abnormalities in schizophrenia, and their relation to focal structural abnormality of the hippocampus. The conjunction of these features has potential as a neuroimaging endophenotype of schizophrenia.

Dissociative symptoms and epilepsy.

This article considers the relationship between various types of dissociative symptoms, including symptoms of depersonalization, derealization, and conversion disorders, and epilepsy. After introductory remarks concerning dissociation, this relationship is discussed through two main themes: firstly, the phenomenology and mechanisms of so-called 'dreamy states' in epilepsy and their closest analogs in psychiatric disorders, and secondly, the similarities and differences between epileptic seizures and psychogenic nonepileptic attacks. Although epileptic and dissociative symptoms may appear similar to observers, they arise through different mechanisms and have different experiential qualities.

Self-regulation of the anterior insula: Reinforcement learning using real-time fMRI neurofeedback.

The anterior insula (AI) plays a key role in affective processing, and insular dysfunction has been noted in several clinical conditions. Real-time functional MRI neurofeedback (rtfMRI-NF) provides a means of helping people learn to self-regulate activation in this brain region. Using the Blood Oxygenated Level Dependant (BOLD) signal from the right AI (RAI) as neurofeedback, we trained participants to increase RAI activation. In contrast, another group of participants was shown 'control' feedback from another brain area. Pre- and post-training affective probes were shown, with subjective ratings and skin conductance response (SCR) measured. We also investigated a reward-related reinforcement learning model of rtfMRI-NF. In contrast to the controls, we hypothesised a positive linear increase in RAI activation in participants shown feedback from this region, alongside increases in valence ratings and SCR to affective probes. Hypothesis-driven analyses showed a significant interaction between the RAI/control neurofeedback groups and the effect of self-regulation. Whole-brain analyses revealed a significant linear increase in RAI activation across four training runs in the group who received feedback from RAI. Increased activation was also observed in the caudate body and thalamus, likely representing feedback-related learning. No positive linear trend was observed in the RAI in the group receiving control feedback, suggesting that these data are not a general effect of cognitive strategy or control feedback. The control group did, however, show diffuse activation across the putamen, caudate and posterior insula which may indicate the representation of false feedback. No significant training-related behavioural differences were observed for valence ratings, or SCR. In addition, correlational analyses based on a reinforcement learning model showed that the dorsal anterior cingulate cortex underpinned learning in both groups. In summary, these data demonstrate that it is possible to regulate the RAI using rtfMRI-NF within one scanning session, and that such reward-related learning is mediated by the dorsal anterior cingulate.