The relationship between white matter architecture and language lateralisation in the healthy brain.

Interhemispheric anatomical differences have long been thought to be related to language lateralisation. Previous studies have explored whether asymmetries in the diffusion characteristics of white matter language tracts are consistent with language lateralisation. These studies, typically with smaller cohorts, yielded mixed results. This study investigated whether connectomic analysis of quantitative anisotropy (QA) and shape features of white matter tracts across the whole brain are associated with language lateralisation. We analysed 1040 healthy individuals (562 females) from the Human Connectome Project database. Hemispheric language dominance for each participant was quantified using a laterality quotient (LQ) derived from fMRI activation in regions of interest (ROIs) associated with a language comprehension task compared against a math task. A linear regression model was used to examine the relationship between structural asymmetry and functional lateralisation. Connectometry revealed a significant negative correlation between LQs and QA of corpus callosum tracts, indicating that higher QA in these regions is associated with bilateral and right-hemisphere language representation in frontal and temporal regions, respectively. Left language laterality in temporal lobe was significantly associated with longer right inferior fronto-occipital fasciculus (IFOF) and forceps minor tracts. These results suggest that diffusion measures of microstructural architecture as well as geometrical features of reconstructed white matter tracts play a role in language lateralisation. People with increased dependence on right or both frontal hemispheres for language processing may have more developed commissural fibres, which may support more efficient interhemispheric communication.Significance statement The left cerebral hemisphere is dominant for language functions in most people. In some healthy people, language functions are lateralised to the right hemisphere or distributed across both hemispheres. The anatomy underlying patterns of hemispheric language dominance are not well established. Emerging evidence suggests that white matter connectivity and architecture is an important feature of cortical functional organisation. In this work, we report that people who have language functions distributed across both hemispheres have greater inter-hemispheric connectivity compared to lateralised people. Our findings provide further insights into the anatomical basis of language function and may have wider clinical implications.

Brain alterations in regions associated with end-organ diabetic microvascular disease in diabetes mellitus: A UK Biobank study.

BACKGROUND: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC). METHODS: This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts. RESULTS: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001). INTERPRETATION: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM.

From basic sciences and engineering to epileptology: A translational approach.

Collaborative efforts between basic scientists, engineers, and clinicians are enabling translational epileptology. In this article, we summarize the recent advances presented at the International Conference for Technology and Analysis of Seizures (ICTALS 2022): (1) novel developments of structural magnetic resonance imaging; (2) latest electroencephalography signal-processing applications; (3) big data for the development of clinical tools; (4) the emerging field of hyperdimensional computing; (5) the new generation of artificial intelligence (AI)-enabled neuroprostheses; and (6) the use of collaborative platforms to facilitate epilepsy research translation. We highlight the promise of AI reported in recent investigations and the need for multicenter data-sharing initiatives.

Children's engagement and caregivers' use of language-boosting strategies during shared book reading: A mixed methods approach.

For shared book reading to be effective for language development, the adult and child need to be highly engaged. The current paper adopted a mixed-methods approach to investigate caregiver's language-boosting behaviours and children's engagement during shared book reading. The results revealed there were more instances of joint attention and caregiver's use of prompts during moments of higher engagement. However, instances of most language-boosting behaviours were similar across episodes of higher and lower engagement. Qualitative analysis assessing the link between children's engagement and caregiver's use of speech acts, revealed that speech acts do seem to contribute to high engagement, in combination with other aspects of the interaction.

Event-based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data.

OBJECTIVE: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. METHODS: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. RESULTS: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI. SIGNIFICANCE: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.

Automated subcortical volume estimation from 2D MRI in epilepsy and implications for clinical trials.

PURPOSE: Most techniques used for automatic segmentation of subcortical brain regions are developed for three-dimensional (3D) MR images. MRIs obtained in non-specialist hospitals may be non-isotropic and two-dimensional (2D). Automatic segmentation of 2D images may be challenging and represents a lost opportunity to perform quantitative image analysis. We determine the performance of a modified subcortical segmentation technique applied to 2D images in patients with idiopathic generalised epilepsy (IGE). METHODS: Volume estimates were derived from 2D (0.4 × 0.4 × 3 mm) and 3D (1 × 1x1mm) T1-weighted acquisitions in 31 patients with IGE and 39 healthy controls. 2D image segmentation was performed using a modified FSL FIRST (FMRIB Integrated Registration and Segmentation Tool) pipeline requiring additional image reorientation, cropping, interpolation and brain extraction prior to conventional FIRST segmentation. Consistency between segmentations was assessed using Dice coefficients and volumes across both approaches were compared between patients and controls. The influence of slice thickness on consistency was further assessed using 2D images with slice thickness increased to 6 mm. RESULTS: All average Dice coefficients showed excellent agreement between 2 and 3D images across subcortical structures (0.86-0.96). Most 2D volumes were consistently slightly lower compared to 3D volumes. 2D images with increased slice thickness showed lower agreement with 3D images with lower Dice coefficients (0.55-0.83). Significant volume reduction of the left and right thalamus and putamen was observed in patients relative to controls across 2D and 3D images. CONCLUSION: Automated subcortical volume estimation of 2D images with a resolution of 0.4 × 0.4x3mm using a modified FIRST pipeline is consistent with volumes derived from 3D images, although this consistency decreases with an increased slice thickness. Thalamic and putamen atrophy has previously been reported in patients with IGE. Automated subcortical volume estimation from 2D images is feasible and most reliable at using in-plane acquisitions greater than 1 mm x 1 mm and provides an opportunity to perform quantitative image analysis studies in clinical trials.

Fiber ball white matter modeling in focal epilepsy.

Multicompartment diffusion magnetic resonance imaging (MRI) approaches are increasingly being applied to estimate intra-axonal and extra-axonal diffusion characteristics in the human brain. Fiber ball imaging (FBI) and its extension fiber ball white matter modeling (FBWM) are such recently described multicompartment approaches. However, these particular approaches have yet to be applied in clinical cohorts. The modeling of several diffusion parameters with interpretable biological meaning may offer the development of new, noninvasive biomarkers of pharmacoresistance in epilepsy. In the present study, we used FBI and FBWM to evaluate intra-axonal and extra-axonal diffusion properties of white matter tracts in patients with longstanding focal epilepsy. FBI/FBWM diffusion parameters were calculated along the length of 50 white matter tract bundles and statistically compared between patients with refractory epilepsy, nonrefractory epilepsy and controls. We report that patients with chronic epilepsy had a widespread distribution of extra-axonal diffusivity relative to controls, particularly in circumscribed regions along white matter tracts projecting to cerebral cortex from thalamic, striatal, brainstem, and peduncular regions. Patients with refractory epilepsy had significantly greater markers of extra-axonal diffusivity compared to those with nonrefractory epilepsy. The extra-axonal diffusivity alterations in patients with epilepsy observed in the present study could be markers of neuroinflammatory processes or a reflection of reduced axonal density, both of which have been histologically demonstrated in focal epilepsy. FBI is a clinically feasible MRI approach that provides the basis for more interpretive conclusions about the microstructural environment of the brain and may represent a unique biomarker of pharmacoresistance in epilepsy.

Illness Perception Mediates the Relationship Between the Severity of Symptoms and Perceived Health Status in Patients With Behçet Disease.

OBJECTIVE: The aim of this study was to investigate the relationship between psychological representations of illness, perceived health status, and self-assessment of symptom severity in patients with Behçet disease, a rare long-term incurable condition with unclear etiology. METHODS: Using cross-sectional survey design, data on self-administered questionnaires on illness perception, health status, symptoms severity, and demographic characteristics were collected from 273 patients with Behçet disease (age range, 18-65 years). The data were subjected to mediation analysis to test whether cognitive and emotional components of illness perception mediate the relationship between the severity of symptoms and heath status. RESULTS: The results support our hypotheses that cognitive components of illness perception (perceived consequences and identity of the illness) mediate the link between symptom activity and pain, whereas emotional components of the illness (emotional representations about the illness) mediate the relationship between disease activity and perceived energy level. CONCLUSIONS: The robustness of these mediation effects suggests potential directions for clinical psychologists and health care practitioners in developing support programs. We supplement our study with Open Access database containing information about type of medication, comorbid mood disorder, and detailed measurement of the severity of BD symptoms for sharing and accumulating multidisciplinary knowledge aiming to support the development of interventions. Addressing psychological aspects of BD will help to manage complex patients effectively.

I Am There but Not Quite: An Unfaithful Mirror That Reduces Feelings of Ownership and Agency.

The experience of seeing one's own face in a mirror is a common experience in daily life. Visual feedback from a mirror is linked to a sense of identity. We developed a procedure that allowed individuals to watch their own face, as in a normal mirror, or with specific distortions (lag) for active movement or passive touch. By distorting visual feedback while the face is being observed on a screen, we document an illusion of reduced embodiment. Participants made mouth movements, while their forehead was touched with a pen. Visual feedback was either synchronous (simultaneous) with reality, as in a mirror, or asynchronous (delayed). Asynchronous feedback was exclusive to touch or movement in different conditions and incorporated both in a third condition. Following stimulation, participants rated their perception of the face in the mirror, and perception of their own face, on questions that tapped into agency and ownership. Results showed that perceptions of both agency and ownership were affected by asynchrony. Effects related to agency, in particular, were moderated by individual differences in depersonalisation and auditory hallucination-proneness, variables with theoretical links to embodiment. The illusion presents a new way of investigating the extent to which body representations are malleable.

Ambiguity between self and other: Individual differences in action attribution.

Individuals differ in their ability to attribute actions to self or other. This variance is thought to explain, in part, the experience of voice-hearing. Misattribution can also be context-driven. For example, causal ambiguity can arise when the actions of two or more individuals are coordinated and produce similar effects (e.g., music-making). Experience in such challenging contexts may refine skills of action attribution. Forty participants completed a novel finger-tapping task which parametrically manipulated the proportion of control that 'self' versus 'other' possessed over resulting auditory tones. Results showed that action misattribution peaked in the middle of the self-to-other continuum and was biased towards other. This pattern was related to both high hallucination-proneness and to low musical-experience. Findings suggest not only that causal ambiguity plays a key role in agency but also that action attribution abilities may improve with practice, potentially providing an avenue for remediation of the positive symptoms of schizophrenia.

'Looking before and after': Can simple eye tracking patterns distinguish poetic from prosaic texts?

Introduction: The study of 'serious' literature has recently developed into an emerging field called neurocognitive poetics that applies cognitive neuroscientific techniques to examine how we understand and appreciate poetry. The current research used eye-tracking techniques on a small sample of young adults to see if and how the reading of short pieces of poetry differed from the reading of matched prosaic texts. Methods: With 'proof of concept' intentions reflecting arguments first proposed by 19th Century literary figures, there was a particular focus on the differences between the reading of poetry and prose in terms number and frequency of fixations and regressive eye movements back and forth within the texts in this two-by-two experimental design (poetry vs. prose x need vs. no need for final line reappraisal). Results: It was found that poetic pieces compared to prosaic pieces were associated with more and longer fixations and more regressive eye movements throughout the text. The need to reappraise meaning at the prompt of a final line was only significantly associated with more regressive eye movements. Comparisons examining the 4 text conditions (poetic reappraisal, poetic non-reappraisal, prosaic reappraisal, and prosaic non-reappraisal) showed that the poetic reappraisal condition was characterised by significantly more regressive eye movements as well as longer fixations compared to the prosaic non-reappraisal condition. No significant correlations were found between self-reported literary familiarity and eye tracking patterns. Discussion: Despite limitations, this proof-of-concept study provides insights into reading patterns that can help to define objectively the nature of poetic material as requiring slower reading particularly characterised by more and longer fixations and eye movements backwards through the texts compared to the faster, more linear reading of prose. Future research using these, and other psychophysiological metrics can begin to unpack the putative cognitive benefits of reading literary material.

Advanced Brain Age and Chronic Poststroke Aphasia Severity.

BACKGROUND AND OBJECTIVES: Chronic poststroke language impairment is typically worse in older individuals or those with large stroke lesions. However, there is unexplained variance that likely depends on intact tissue beyond the lesion. Brain age is an emerging concept, which is partially independent from chronologic age. Advanced brain age is associated with cognitive decline in healthy older adults; therefore, we aimed to investigate the relationship with stroke aphasia. We hypothesized that advanced brain age is a significant factor associated with chronic poststroke language impairments, above and beyond chronologic age, and lesion characteristics. METHODS: This cohort study retrospectively evaluated participants from the Predicting Outcomes of Language Rehabilitation in Aphasia clinical trial (NCT03416738), recruited through local advertisement in South Carolina (US). Primary inclusion criteria were left hemisphere stroke and chronic aphasia (≥12 months after stroke). Participants completed baseline behavioral testing including the Western Aphasia Battery-Revised (WAB-R), Philadelphia Naming Test (PNT), Pyramids and Palm Trees Test (PPTT), and Wechsler Adult Intelligence Scale Matrices subtest, before completing 6 weeks of language therapy. The PNT was repeated 1 month after therapy. We leveraged modern neuroimaging techniques to estimate brain age and computed a proportional difference between chronologic age and estimated brain age. Multiple linear regression models were used to evaluate the relationship between proportional brain age difference (PBAD) and behavior. RESULTS: Participants (N = 93, 58 males and 35 females, average age = 61 years) had estimated brain ages ranging from 14 years younger to 23 years older than chronologic age. Advanced brain age predicted performance on semantic tasks (PPTT) and language tasks (WAB-R). For participants with advanced brain aging (n = 47), treatment gains (improvement on the PNT) were independently predicted by PBAD (T = -2.0474, p = 0.0468, 9% of variance explained). DISCUSSION: Through the application of modern neuroimaging techniques, advanced brain aging was associated with aphasia severity and performance on semantic tasks. Notably, therapy outcome scores were also associated with PBAD, albeit only among participants with advanced brain aging. These findings corroborate the importance of brain age as a determinant of poststroke recovery and underscore the importance of personalized health factors in determining recovery trajectories, which should be considered during the planning or implementation of therapeutic interventions.

Protocol for an observational cohort study investigating biomarkers predicting seizure recurrence following a first unprovoked seizure in adults.

INTRODUCTION: A first unprovoked seizure is a common presentation, reliably identifying those that will have recurrent seizures is a challenge. This study will be the first to explore the combined utility of serum biomarkers, quantitative electroencephalogram (EEG) and quantitative MRI to predict seizure recurrence. This will inform patient stratification for counselling and the inclusion of high-risk patients in clinical trials of disease-modifying agents in early epilepsy. METHODS AND ANALYSIS: 100 patients with first unprovoked seizure will be recruited from a tertiary neuroscience centre and baseline assessments will include structural MRI, EEG and a blood sample. As part of a nested pilot study, a subset of 40 patients will have advanced MRI sequences performed that are usually reserved for patients with refractory chronic epilepsy. The remaining 60 patients will have standard clinical MRI sequences. Patients will be followed up every 6 months for a 24-month period to assess seizure recurrence. Connectivity and network-based analyses of EEG and MRI data will be carried out and examined in relation to seizure recurrence. Patient outcomes will also be investigated with respect to analysis of high-mobility group box-1 from blood serum samples. ETHICS AND DISSEMINATION: This study was approved by North East-Tyne & Wear South Research Ethics Committee (20/NE/0078) and funded by an Association of British Neurologists and Guarantors of Brain clinical research training fellowship. Findings will be presented at national and international meetings published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NIHR Clinical Research Network's (CRN) Central Portfolio Management System (CPMS)-44976.

Association Between Anatomical Location of Surgically Induced Lesions and Postoperative Seizure Outcome in Temporal Lobe Epilepsy.

BACKGROUND AND OBJECTIVES: To determine the association between surgical lesions of distinct gray and white structures and connections with favorable postoperative seizure outcomes. METHODS: Patients with drug-resistant temporal lobe epilepsy (TLE) from 3 epilepsy centers were included. We employed a voxel-based and connectome-based mapping approach to determine the association between favorable outcomes and surgery-induced temporal lesions. Analyses were conducted controlling for multiple confounders, including total surgical resection/ablation volume, hippocampal volumes, side of surgery, and site where the patient was treated. RESULTS: The cohort included 113 patients with TLE (54 women; 86 right-handed; mean age at seizure onset 16.5 years [SD 11.9]; 54.9% left) who were 61.1% free of disabling seizures (Engel Class 1) at follow-up. Postoperative seizure freedom in TLE was associated with (1) surgical lesions that targeted the hippocampus as well as the amygdala-piriform cortex complex and entorhinal cortices; (2) disconnection of temporal, frontal, and limbic regions through loss of white matter tracts within the uncinate fasciculus, anterior commissure, and fornix; and (3) functional disconnection of the frontal (superior and middle frontal gyri, orbitofrontal region) and temporal (superior and middle pole) lobes. DISCUSSION: Better postoperative seizure freedom is associated with surgical lesions of specific structures and connections throughout the temporal lobes. These findings shed light on the key components of epileptogenic networks in TLE and constitute a promising source of new evidence for future improvements in surgical interventions. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with TLE, postoperative seizure freedom is associated with surgical lesions of specific temporal lobe structures and connections.

Altered Structural Brain Networks in Refractory and Nonrefractory Idiopathic Generalized Epilepsy.

Introduction: Idiopathic generalized epilepsy (IGE) is a collection of generalized nonlesional epileptic network disorders. Around 20-40% of patients with IGE are refractory to antiseizure medication, and mechanisms underlying refractoriness are poorly understood. Here, we characterize structural brain network alterations and determine whether network alterations differ between patients with refractory and nonrefractory IGE. Methods: Thirty-three patients with IGE (10 nonrefractory and 23 refractory) and 39 age- and sex-matched healthy controls were studied. Network nodes were segmented from T1-weighted images, while connections between these nodes (edges) were reconstructed from diffusion magnetic resonance imaging (MRI). Diffusion networks of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and streamline count (Count) were studied. Differences between all patients, refractory, nonrefractory, and control groups were computed using network-based statistics. Nodal volume differences between groups were computed using Cohen's d effect size calculation. Results: Patients had significantly decreased bihemispheric FA and Count networks and increased MD and RD networks compared with controls. Alterations in network architecture, with respect to controls, differed depending on treatment outcome, including predominant FA network alterations in refractory IGE and increased nodal volume in nonrefractory IGE. Diffusion MRI networks were not influenced by nodal volume. Discussion: Although a nonlesional disorder, patients with IGE have bihemispheric structural network alterations that may differ between patients with refractory and nonrefractory IGE. Given that distinct nodal volume and FA network alterations were observed between treatment outcome groups, a multifaceted network analysis may be useful for identifying imaging biomarkers of refractory IGE.

Association of Epilepsy Surgery With Changes in Imaging-Defined Brain Age.

OBJECTIVE: To determine whether surgery in patients with mesial temporal lobe epilepsy (mTLE) is associated with reduced brain-predicted age as a neural marker overall brain health, we compared brain-predicted and chronologic age difference (brain age gap estimation [BrainAGE]) in patients before and after surgery with healthy controls. METHODS: We acquired 3D T1-weighted MRI scans for 48 patients with mTLE before and after temporal lobe surgery to estimate brain age using a gaussian processes regression model. We examined BrainAGE before and after surgery controlling for brain volume change, comparing patients to 37 age- and sex-matched controls. RESULTS: Preoperatively, patients showed an increased BrainAGE of more than 7 years compared to controls. However, surgery was associated with a mean BrainAGE reduction of 5 years irrespective of whether or not surgery resulted in complete seizure freedom. We observed a lateralization effect as patients with left mTLE had BrainAGE values that more closely resembled control group values following surgery. CONCLUSIONS: Our findings suggest that while morphologic brain alterations linked to accelerated aging have been observed in mTLE, surgery may be associated with changes that reverse such alterations in some patients. This work highlights the advantages of resective surgery on overall brain health in patients with refractory focal epilepsy.

The Pragmatics of Pragmatic Language and the Curse of Ambiguity: An fMRI Study.

In pragmatic language, there is an intentional distinction between the literal meaning of what is said, and what the speaker actually means. Previous neuroimaging investigations of pragmatic language have contrasted it with literal language; however, such contrasts may have been confounded by the higher levels of ambiguity in pragmatic language. Here, we used functional magnetic resonance imaging (fMRI) to compare pragmatic sentences (specifically requiring the interpretation of nonliteral meaning in the form of hints) with unintentionally ambiguous scenarios. Analysis showed that ambiguous language activated brain areas recognized to play a role in generating a theory of mind (ToM) that have previously been argued to support understanding of pragmatic language, specifically medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and temporoparietal junction (TPJ). In contrast, the pragmatic scenarios drew on anterior temporal, superior parietal lobule, in addition to precuneus. While no effect of gender was found for unintentionally ambiguous stimuli, females showed greater activity than males within mPFC and inferior frontal gyrus (IFG) for pragmatic scenarios - regions thought to be involved in cognitive and affective empathy, respectively. Findings suggest that while areas underpinning ToM are sufficient to support meaning derivation in the context of ambiguity, reasoning about pragmatic intent is more reliant on access to self-referential memory.

Investigating imaging network markers of cognitive dysfunction and pharmacoresistance in newly diagnosed epilepsy: a protocol for an observational cohort study in the UK.

INTRODUCTION: Epilepsy is one of the most common serious brain disorders, characterised by seizures that severely affect a person's quality of life and, frequently, their cognitive and mental health. Although most existing work has examined chronic epilepsy, newly diagnosed patients present a unique opportunity to understand the underlying biology of epilepsy and predict effective treatment pathways. The objective of this prospective cohort study is to examine whether cognitive dysfunction is associated with measurable brain architectural and connectivity impairments at diagnosis and whether the outcome of antiepileptic drug treatment can be predicted using these measures. METHODS AND ANALYSIS: 107 patients with newly diagnosed focal epilepsy from two National Health Service Trusts and 48 healthy controls (aged 16-65 years) will be recruited over a period of 30 months. Baseline assessments will include neuropsychological evaluation, structural and functional Magnetic Resonance Imaging (MRI), Electroencephalography (EEG), and a blood and saliva sample. Patients will be followed up every 6 months for a 24-month period to assess treatment outcomes. Connectivity- and network-based analyses of EEG and MRI data will be carried out and examined in relation to neuropsychological evaluation and patient treatment outcomes. Patient outcomes will also be investigated with respect to analysis of molecular isoforms of high mobility group box-1 from blood and saliva samples. ETHICS AND DISSEMINATION: This study was approved by the North West, Liverpool East Research Ethics Committee (19/NW/0384) through the Integrated Research Application System (Project ID 260623). Health Research Authority (HRA) approval was provided on 22 August 2019. The project is sponsored by the UoL (UoL001449) and funded by a UK Medical Research Council (MRC) research grant (MR/S00355X/1). Findings will be presented at national and international meetings and conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: IRAS Project ID 260623.

The Necessity of Ambiguity in Self-Other Processing: A Psychosocial Perspective With Implications for Mental Health.

While distinguishing between the actions and physical boundaries of self and other (non-self) is usually straightforward there are contexts in which such differentiation is challenging. For example, self-other ambiguity may occur when actions of others are similar or complementary to those of the self. Even in the absence of such situational challenges, individuals experiencing hallucinations have difficulties with this distinction, often experiencing thoughts or actions of self as belonging to other agents. This paper explores the role of ambiguity in self-other differentiation, drawing from developmental, psychodynamic, and neurocognitive perspectives. A key proposal is that engagement in contexts that make distinctions between self and other challenging yet necessary allow reality-testing skills related to agency to develop. Attunement in typical caregiver-infant interactions is framed as a safe but inherently ambiguous environment that provides optimal condition for the infant to develop a coherent self-other sense. Vulnerability to psychosis may be related to limited access to such an environment in early development. However, the perceptual, cognitive, and social skills that contribution to attribution are likely to be malleable following infancy and improve though opportunities for boundary play in similarly ambiguous settings. Using music-making to illustrate, we postulate that engagement in intricate joint-actions that blurs agentic boundaries can contribute to the continued development of an adaptive sense of self and other essential to healthy social functioning. Increased insight into the self-other ambiguity may enhance our understanding of mechanisms underlying "self-disorders" such as schizophrenia and eventually extend the range of social and arts-based therapeutic possibilities.

Perceived neighbourhood affluence, mental health and wellbeing influence judgements of threat and trust on our streets: An urban walking study.

This study aimed to understand how people respond to different urban neighbourhoods. We explored whether participants' mental health and wellbeing, judgements of resident wealth, family SES and sentiments reflected in descriptions of place features predicted in situ sense of threat and trust. Forty-six student participants walked in groups through 2 urban neighbourhoods, separated by a park, in the North West of England, noting responses at pre-determined stops. Significant differences existed in participants' sense of trust and threat between the 2 neighbourhoods along with differences in perceived resident wealth and sentiments expressed. Participants' levels of persecutory ideas and their sense of residents' wealth predicted in situ trust in both neighbourhoods while level of personal resilience predicted the extent of threat felt in the more deprived neighbourhood. Demonstrating the value of the method, these findings have implications for the governance of urban neighbourhoods whereby obvious cues signalling a harsh environment need to be minimised to create more positive psychological responses to places.