Individual differences in excitation and inhibition in visual cortex

The formation of a visual percept in the human brain involves multiple processes, the extent of which may be related to each other within individuals but may show variability between participants. The aim of this thesis was to investigate the relationships between individual variability in various measures of visual processing. The non-invasive neuroimaging methods of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), magnetoencephalography (MEG) and functional MRI (fMRI) were employed to measure brain structure, neurotransmitter concentration, neuronal oscillations and haemodynamic activity, respectively. Reductions in haemodynamic activity in non-stimulated areas of visual cortex (negative blood oxygen level-dependent responses) were shown to hold useful information about the stimulus, in addition to the responses in stimulated cortex. In general, there were no strong relationships between increased or decreased functional responses in visual cortex and measures of brain structure or of neurotransmitter concentration. Age was the major determinant of individual variability in the frequency of neuronal oscillations. These findings do not replicate results from previous studies that have shown links between individual differences in these measures. This discrepancy was not due to poor repeatability of MRS measures, since methods for optimisation of MRS were identified in this thesis. Simulations were also conducted to determine the sample sizes required in correlational studies involving neuroimaging measures with associated measurement noise. The lack of replication of relationships between neuroimaging measures of individual differences in visual processing is likely to be influenced by low statistical power, due to the small sample sizes and weak relationships tested. Such studies should therefore be conducted and interpreted cautiously, bearing in mind issues of power, demographic mediators of relationships and the likely strength of relationships inferred from the physiological mechanisms linking the variables tested

The relationship between MEG and fMRI

In recent years functional neuroimaging techniques such as fMRI, MEG, EEG and PET have provided researchers with a wealth of information on human brain function. However none of these modalities can measure directly either the neuro-electrical or neuro-chemical processes that mediate brain function. This means that metrics directly reflecting brain ‘activity’ must be inferred from other metrics (e.g. magnetic fields (MEG) or haemodynamics (fMRI)). To overcome this limitation, many studies seek to combine multiple complementary modalities and an excellent example of this is the combination of MEG (which has high temporal resolution) with fMRI (which has high spatial resolution). However, the full potential of multi-modal approaches can only be truly realised in cases where the relationship between metrics is known. In this paper, we explore the relationship between measurements made using fMRI and MEG. We describe the origins of the two signals as well as their relationship to electrophysiology. We review multiple studies that have attempted to characterise the spatial relationship between fMRI and MEG, and we also describe studies that exploit the rich information content of MEG to explore differing relationships between MEG and fMRI across neural oscillatory frequency bands. Monitoring the brain at “rest” has become of significant recent interest to the neuroimaging community and we review recent evidence comparing MEG and fMRI metrics of functional connectivity. A brief discussion of the use of magnetic resonance spectroscopy (MRS) to probe the relationship between MEG/fMRI and neurochemistry is also given. Finally, we highlight future areas of interest and offer some recommendations for the parallel use of fMRI and MEG

Researching heritage values in social media environments:Understanding variabilities and (in)visibilities

This article adopts a reflexive methodology, called rapid logging, to examine how heritage values relating to the same heritage ‘thing’ are variously crafted by the mutual agencies of human and non-human actors on and with social media. In the process, it also explores the (in)visibilities produced through the heritage value assemblages co-curated by researchers with other actors including social media platforms and data, past objects, places and practices. The analysis focuses on the values associated with a specific case study, the area once occupied by the Old Gas Works, in North Canongate, Edinburgh, UK. Our conclusions demonstrate the importance of multi-platform and reflexive research to develop contextual and critical understandings of heritage value assemblages that can lead to fairer decision-making in heritage and more just societies

Quantifying the core deficit in classical schizophrenia

In the classical descriptions of schizophrenia, Kraepelin and Bleuler recognised disorganization and impoverishment of mental activity as fundamental symptoms. Their classical descriptions also included a tendency to persisting disability. The psychopathological processes underlying persisting disability in schizophrenia remain poorly understood. The delineation of a core deficit underlying persisting disability would be of value in predicting outcome and enhancing treatment. We tested the hypothesis that mental disorganization and impoverishment are associated with persisting impairments of cognition and role-function, and together reflect a latent core deficit that is discernible in cases diagnosed by modern criteria. We used Confirmatory Factor Analysis to determine whether measures of disorganisation, mental impoverishment, impaired cognition and role functioning in 40 patients with schizophrenia represent a single latent variable. Disorganization scores were computed from the variance shared between disorganization measures from three commonly used symptom scales. Mental impoverishment scores were computed similarly. A single factor model exhibited a good fit, supporting the hypothesis that these measures reflect a core deficit.Persisting brain disorders are associated with a reduction in Post Motor Beta Rebound (PMBR), the characteristic increase in electrophysiological beta amplitude that follows a motor response. Patients had significantly reduced PMBR compared with healthy controls. PMBR was negatively correlated with core deficit score.While the symptoms constituting impoverished and disorganised mental activity are dissociable in schizophrenia, nonetheless, the variance that these two symptom domains share with impaired cognition and role function, appears to reflect a pathophysiological process that might be described as the core deficit of classical schizophrenia

A multi-layer network approach to MEG connectivity analysis

Recent years have shown the critical importance of inter-regional neural network connectivity in supporting healthy brain function. Such connectivity is measurable using neuroimaging techniques such as MEG, however the richness of the electrophysiological signal makes gaining a complete picture challenging. Specifically, connectivity can be calculated as statistical interdependencies between neural oscillations within a large range of different frequency bands. Further, connectivity can be computed between frequency bands. This pan-spectral network hierarchy likely helps to mediate simultaneous formation of multiple brain networks, which support ongoing task demand. However, to date it has been largely overlooked, with many electrophysiological functional connectivity studies treating individual frequency bands in isolation. Here, we combine oscillatory envelope based functional connectivity metrics with a multi-layer network framework in order to derive a more complete picture of connectivity within and between frequencies. We test this methodology using MEG data recorded during a visuomotor task, highlighting simultaneous and transient formation of motor networks in the beta band, visual networks in the gamma band and a beta to gamma interaction. Having tested our method, we use it to demonstrate differences in occipital alpha band connectivity in patients with schizophrenia compared to healthy controls. We further show that these connectivity differences are predictive of the severity of persistent symptoms of the disease, highlighting their clinical relevance. Our findings demonstrate the unique potential of MEG to characterise neural network formation and dissolution. Further, we add weight to the argument that dysconnectivity is a core feature of the neuropathology underlying schizophrenia

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

The impact of the prevent duty on schools: a review of the evidence

The UK has emerged as an influential global player in developing policy to counter violent extremism, and therefore it is important to consider the emerging evidence about the impact of this policy in education. The Prevent Duty came into force in the UK in 2015, placing a legal responsibility on schools and teachers to implement anti-terrorist legislation and prevent young people from being drawn into extremism or radicalisation. This article reviews all of the material based on empirical studies in England involving school teachers and students published between 2015 (when the Duty was introduced) and the beginning of 2019 (27 articles and reports in total) to consider the impact of the policy on schools. The key themes emerging from our analysis of this evidence base are related (1) to the ways the policy is interpreted within Islamophobic discourses, (2) the emergence of Britishness as a key feature of fundamental British values, and (3) the implications of framing Prevent as a safeguarding issue. We argue that the evidence gives support to those who have been critical of the Prevent Duty in schools, and that it seems to be generating a number of unintended and negative side effects. However, the evidence also illustrates how teachers have agency in relation to the policy, and may thus be able to enact the policy in ways which reduce some of the most harmful effects