A cross-sectional study of auditory verbal hallucinations experienced by people with a diagnosis of borderline personality disorder.

BACKGROUND: The presence of auditory verbal hallucinations (AVHs) does not currently feature in the main diagnostic criteria for borderline personality disorder (BPD). However, there is accumulating evidence that a high proportion of BPD patients report longstanding and frequent AVHs which constitute a significant risk factor for suicide plans and attempts, and hospitalization. AIM: This study addressed questions about the validity and phenomenology of AVHs in the context of BPD. The longer-term aim is to facilitate the development and translation of treatment approaches to address the unmet need of this population. METHOD: This was a cross-sectional study, combining phenomenological and psychological assessments administered in person and online. We explored the experiences of 48 patients with a diagnosis of BPD who were hearing AVHs. RESULTS: Participants gave 'consistent' reports on the measure of AVH phenomenology, suggesting that these experiences were legitimate. Similar to AVHs in a psychosis context, AVHs were experienced as distressing and appraised as persecutory. AVHs were found to be weakly associated with BPD symptoms. AVHs were also rated highly as a treatment priority by the majority of participants. CONCLUSION: The findings suggest that AVH is a legitimate and distressing symptom of BPD and a treatment priority for some patients. The relative independence of AVHs from other BPD symptoms and emotional states suggests that psychological treatment may need to be targeted specifically at the symptom of AVHs. This treatment could be adapted from cognitive behaviour therapy, the psychological intervention that is recommended for the treatment of AVHs in the context of psychosis.

Voice Hearing in Borderline Personality Disorder Across Perceptual, Subjective, and Neural Dimensions.

BACKGROUND: Auditory verbal hallucinations (AVH) commonly occur in the context of borderline personality disorder (BPD) yet remain poorly understood. AVH are often perceived by patients with BPD as originating from inside the head and hence viewed clinically as "pseudohallucinations," but they nevertheless have a detrimental impact on well-being. METHODS: The current study characterized perceptual, subjective, and neural expressions of AVH by using an auditory detection task, experience sampling and questionnaires, and functional neuroimaging, respectively. RESULTS: Perceptually, reported AVH correlated with a bias for reporting the presence of a voice in white noise. Subjectively, questionnaire measures indicated that AVH were significantly distressing and persecutory. In addition, AVH intensity, but not perceived origin (i.e., inside vs outside the head), was associated with greater concurrent anxiety. Neurally, fMRI of BPD participants demonstrated that, relative to imagining or listening to voices, periods of reported AVH induced greater blood oxygenation level-dependent activity in anterior cingulate and bilateral temporal cortices (regional substrates for language processing). AVH symptom severity was associated with weaker functional connectivity between anterior cingulate and bilateral insular cortices. CONCLUSION: In summary, our results indicate that AVH in participants with BPD are (1) underpinned by aberrant perceptual-cognitive mechanisms for signal detection, (2) experienced subjectively as persecutory and distressing, and (3) associated with distinct patterns of neural activity that inform proximal mechanistic understanding. Our findings are like analogous observations in patients with schizophrenia and validate the clinical significance of the AVH experience in BPD, often dismissed as "pseudohallucinations." These highlight a need to reconsider this experience as a treatment priority.

Altering Dynamics of Autonomic Processing Therapy (ADAPT) trial: a novel, targeted treatment for reducing anxiety in joint hypermobility.

BACKGROUND: Hypermobility is a poorly recognised and understood musculoskeletal disorder thought to affect around 20% of the population. Hypermobility is associated with reduced physiological and psychological functioning and quality of life and is a known risk factor for the development of an anxiety disorder. To date, no evidence-based, targeted treatment for anxiety in the context of hypermobility exists. The present intervention (ADAPT-Altering Dynamics of Autonomic Processing Therapy) is a novel therapy combining bio-behavioural training with cognitive approaches from clinical health psychology targeting the catastrophisation of internal sensations, with aim to improve autonomic trait prediction error. METHOD: Eighty individuals with diagnosed hypermobility will be recruited and the efficacy of ADAPT to treat anxiety will be compared to an Emotion-Focused Supportive Therapy (EFST) comparator therapy in a randomised controlled trial. The primary treatment target will be post therapy score on the Beck Anxiety Inventory, and secondary outcomes will also be considered in relation to interoception, depression, alexithymia, social and work adjustment, panic symptoms and dissociation. Due to COVID restrictions, the intervention will be moved to online delivery and qualitative assessment of treatment tolerance to online therapy will also be assessed. DISCUSSION: Online delivery of an intervention targeting anxiety would improve the quality of life for those experiencing anxiety disorder and help to reduce the £11.7 billion that anxiety disorders cost the UK economy annually. TRIAL REGISTRATION: World Health Organization ISRCTN17018615 . Registered on 20th February 2019; trial protocol version 2.

Cognitive impairment in schizophrenia: relationships with cortical thickness in fronto-temporal regions, and dissociability from symptom severity.

Cognitive impairments are a core and persistent characteristic of schizophrenia with implications for daily functioning. These show only limited response to antipsychotic treatment and their neural basis is not well characterised. Previous studies point to relationships between cortical thickness and cognitive performance in fronto-temporal brain regions in schizophrenia patients (SZH). There is also evidence that these relationships might be independent of symptom severity, suggesting dissociable disease processes. We set out to explore these possibilities in a sample of 70 SZH and 72 age and gender-matched healthy controls (provided by the Center of Biomedical Research Excellence (COBRE)). Cortical thickness within fronto-temporal regions implicated by previous work was considered in relation to performance across various cognitive domains (from the MATRICS Cognitive Battery). Compared to controls, SZH had thinner cortices across most fronto-temporal regions and significantly lower performance on all cognitive domains. Robust relationships with cortical thickness were found: visual learning and attention performance correlated with bilateral superior and middle frontal thickness in SZH only. Correlations between attention performance and right transverse temporal thickness were also specific to SZH. Findings point to the importance of these regions for cognitive performance in SZH, possibly reflecting compensatory processes and/or aberrant connectivity. No links to symptom severity were observed in these regions, suggesting these relationships are dissociable from underlying psychotic symptomology. Findings enhance understanding of the brain structural underpinnings and possible aetiology of cognitive impairment in SZH.

Brain structural correlates of functional capacity in first-episode psychosis.

Impaired functional capacity is a core feature of schizophrenia and presents even in first-episode psychosis (FEP) patients. Impairments in daily functioning tend to persist despite antipsychotic therapy but their neural basis is less clear. Previous studies suggest that volume loss in frontal cortex might be an important contributor, but findings are inconsistent. We aimed to comprehensively investigate the brain structural correlates of functional capacity in FEP using MRI and a reliable objective measure of functioning [University of California, San Diego Performance-Based Skills Assessment (UPSA)]. In a sample of FEP (n = 39) and a well-matched control group (n = 21), we measured cortical thickness, gray matter volume, and white matter tract integrity (fractional anisotropy, FA) within brain regions implicated by previous work. The FEP group had thinner cortex in various frontal regions and fusiform, and reduced FA in inferior longitudinal fasciculus (ILF). In FEP, poorer functional capacity correlated with reduced superior frontal volume and lower FA in left ILF. Importantly, frontal brain volumes and integrity of the ILF were identified as the structural correlates of functional capacity in FEP, controlling for other relevant factors. These findings enhance mechanistic understanding of functional capacity deficits in schizophrenia by specifying the underlying neural correlates. In future, this could help inform intervention strategies.

A systematic review of structural MRI investigations within borderline personality disorder: Identification of key psychological variables of interest going forward.

Existing models of Borderline Personality Disorder (BPD) suggest that a combination of genetic vulnerability, childhood trauma, and disrupted attachment can lead to the marked emotional lability, impulsivity and interpersonal difficulties observed clinically. Brain structural differences in frontal, limbic and hippocampal regions have been reported in BPD. Less clear is how specific psychological factors relate to these structural differences, and how consistently this is found across studies. This was the focus of the present review. Eighteen studies published between 2004 and 2018 met inclusion criteria encompassing 990 participants. Study quality was assessed using the Nottingham-Ottawa Scale. We also introduce a newly devised scale to assess MRI reporting quality. The most frequently investigated psychological variable were impulsivity (9 studies), depression (8), trauma (6), aggression (6), severity of symptoms (3), global functioning, abuse and dissociation (2). Study quality varied, however, a trend was observed where newer studies were higher in reporting quality. Impulsivity demonstrated greater association with frontal structures, trauma related to the hypothalamus and limbic systems, and aggression with hippocampal and frontal structures. The present review recommends greater exploration of neurocognitive and psychosis-related features such as delusions, paranoia and voice-hearing in future studies, and to investigate cortical changes in longitudinal designs.

A meta-analytic review of the relationship between neurocognition, metacognition and functional outcome in schizophrenia.

Previous research has identified that neurocognition predicts functional outcome in schizophrenia to a greater extent than psychopathology. More contemporary authors have begun to explore the role of metacognition as a mediating variable between neurocognition and functional outcome. The present review sought to extend the known work by synthesising the results reported in individual studies to see if these results are consistently found across samples. Relevant search strategies were entered into Medline (PubMed), PsychINFO and Embase. The present meta-analysis encompassed 17 studies (N = 1060) investigating the relationship between neurocognition and metacognition and seven studies investigating the relationship between metacognition and functional outcome (N = 645). A small-to-moderate mean effect size was found between neurocognition and metacognition (effect size range: 0.13-0.58) and a small-to-moderate effect size was found between metacognition and functional outcome (range: 0.17-0.57). Study findings suggest that relationships between variables are consistently found across samples and that future research should focus on investigating this relationship at earlier stages of illness, in female cohorts and across cognitive domains. Greater investigation is required in functional outcome, differentiating the impact of metacognition on functional capacity and other domains of functional outcome.

Brain Structural Correlates of Metacognition in First-Episode Psychosis.

Metacognition is impaired in schizophrenia and is an important predictor of functional outcome, but the underlying neuropathology is not clear. Studies have implicated frontal regions and there is also some evidence that the hippocampus might play a pivotal role, but findings are inconsistent. We set out to more comprehensively investigate the neural underpinnings of insight in first-episode psychosis (FEP) using 2 metacognitive measures (the Beck Cognitive Insight Scale [BCIS]) and a perceptual metacognitive accuracy task alongside structural magnetic resonance imaging (MRI). We measured cortical thickness in insula and frontal regions, hippocampal (including subfield) volumes, hippocampal microstructure (using neurite orientation dispersion and density imaging [NODDI]), and fractional anisotropy in fornix. Relative to controls, FEP showed poorer metacognitive accuracy, thinner cortex in frontal regions and lower fornix integrity. In healthy controls (but not FEP), metacognitive accuracy correlated with cortical thickness in frontal cortex and insula. Conversely, in FEP (but not controls), metacognitive accuracy correlated with hippocampal volume and microstructural indices. Subicular hippocampal subregions were particularly implicated. No structural correlates of BCIS were found. These findings suggest that the neural bases of metacognition might differ in FEP: hippocampal (rather than frontal) integrity seems to be critical. Further, the use of objectively measured metacognitive indices seems to be a more powerful method for understanding the neurocircuitry of metacognition in FEP, which has the potential to inform therapeutic strategies and improve outcome in these patients.

Three-Year Follow-Up Study Exploring Metacognition and Function in Individuals With First Episode Psychosis.

Introduction: Research has demonstrated that functional outcome in psychosis is predicted by factors such as neurocognition, functional capacity, symptoms and, more recently, metacognition. Metacognitive ability has been demonstrated to mediate between neurocognition and functional outcome in First Episode Psychosis (FEP). Whether metacognition also predicts longer-term recovery in first episode psychosis is unknown. This study assessed whether neurocognition, functional capacity and metacognitive ability in FEP predicted functional outcome three years later. Methods: Eighty individuals with First Episode Psychosis were re-contacted after an average 3 years (range: 26-45 month follow-up) from baseline. Twenty-six participants (33%) completed completed measures of neurocognition, metacognition, functional capacity, functional outcome (hours spent in structured activity per week) and psychopathology at baseline and at follow-up. Results: Individual regression analyses demonstrated neurocognition, functional capacity, and metacognitive ability at baseline significantly predicted functional outcome at three years. However, when baseline functional outcome was controlled, only metacognitive ability was a significant predictor of change in functional outcome from baseline to follow-up, p < 0.001. This model explained 72% (adjusted r 2 = 0.69) of the variance in functional outcome at follow-up. Negative symptoms did not change the model. Discussion: This study demonstrated that better metacognitive ability significantly predicted improvement in functioning in FEP across a 3-year period. This highlights the potential value of clinical interventions that focus on improving metacognitive ability at first point of illness to maximize recovery.

Self-defining Memories Predict Engagement in Structured Activity in First Episode Psychosis, Independent of Neurocognition and Metacognition.

BACKGROUND: Self-defining memories (SDMs) are vivid personal memories, related to narrative identity. Individuals with schizophrenia report less specific, more negative, and extract less meaning from these memories compared to control groups. SDMs have been shown to be predicted by neurocognition, associated with metacognition, and linked to goal outcomes in healthy controls. As neurocognition and metacognition are known predictors of poor functioning in psychosis, SDMs may also be a predictor. No study has assessed the relationship to functioning or pattern of SDMs in first episode psychosis (FEP). METHODS: This was a cross-sectional study involving 71 individuals with FEP and 57 healthy controls who completed an SDM questionnaire. FEP participants completed measures of neurocognition, metacognition (Metacognitive Assessment Interview), functional capacity (The University of California, San Diego [UCSD] Performance-Based Skills Assessment), and functional outcome (Time-Use Survey). RESULTS: SDMs reported by individuals with FEP were less integrated compared to healthy controls. Within the FEP sample, holding less specific memories was associated with engagement in significantly fewer hours of structured activity per week and specificity of SDMs mediated the relationship between neurocognition and functional outcome, independent of metacognition. CONCLUSION: This is the first study to assess SDMs in FEP and to explore the important role of SDMs on clinical outcomes, compared to healthy controls. This study suggests that elaborating on specific SDMs is a valid therapeutic target and may be considered a tool to improve daily functioning in FEP.

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.

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.

Metacognition as a Mediating Variable Between Neurocognition and Functional Outcome in First Episode Psychosis.

Background: Neurocognitive and functional outcome deficits have long been acknowledged in schizophrenia and neurocognition has been found to account for functional disability to a greater extent than psychopathology. Much of the variance in functional outcome however still remains unexplained and metacognition may mediate the relationship between neurocognition, functional capacity, and self-reported social and occupational function. Method: Eighty first episode psychosis participants were recruited and completed measures of neurocognition (memory, executive function, and intelligence quotient), metacognition (Beck Cognitive Insight Scale, Metacognitive Awareness Interview), psychopathology (PANSS), and both functional capacity (UPSA) and real-life social and occupational function (The Time Use Survey). Path analyses investigated the relationships between variables through structural equation modeling. Results: A series of path models demonstrated that metacognition partially mediates the relationship between neurocognition and functional capacity, and fully mediates the relationship between functional capacity and social and occupational function. Conclusion: The present study findings identify that metacognition may be critical to translating cognitive and functional skills into real-world contexts, and this relationship is found at early stages of illness. Understanding how individuals translate cognitive and functional skills into the real-world (the competence-performance gap) may offer valuable guidance to intervention programs. This finding is important to models of recovery as it suggests that intervention programs that focus on enhancing metacognition abilities may have a greater impact than traditional rehabilitation programs focusing on cognitive abilities, on social and occupational outcomes.

Penetration of voriconazole, 1%, eyedrops into human aqueous humor: a prospective open-label study.

OBJECTIVE: To determine the therapeutic efficacy of adjuvant use of voriconazole, 1%, eyedrops in the treatment of refractory fungal keratitis. METHODS: A prospective open-label trial was conducted to determine voriconazole levels obtained in human aqueous humor after administration of a 1% solution, preserved with 0.01% benzalkonium chloride, every 6 hours for 3 days, or hourly for 4 doses. Ten participants were selected among patients scheduled to undergo elective anterior segment surgery, and samples were tested using validated high-performance liquid chromatography. RESULTS: The mean (SD) voriconazole concentrations after hourly dosing (n = 5) was 1.90 (1.12) microg/mL and after a single dosing every 6 hours (n = 5) was 0.94 (1.21) microg/mL, respectively. The mean (SD) sampling times after the last administration of eyedrops were 1.1 (0.5) hours after hourly dosing and 2.1 (0.6) hours after a single dosing every 6 hours. CONCLUSIONS: Voriconazole, 1%, eyedrops are well tolerated and penetrate into human aqueous humor when administered at hourly or 6-hourly intervals. They are effective in treating Candida and Aspergillus keratitis, are substantially more affordable than oral therapy, and have less potential to cause systemic adverse effects.