Establishing, versus Maintaining, Brain Function: A Neuro-computational Model of Cortical Reorganization after Injury to the Immature Brain

The effect of age at injury on outcome after acquired brain injury (ABI) has been the subject of much debate. Many argue that young brains are relatively tolerant of injury. A contrasting viewpoint due to Hebb argues that greater system integrity may be required for the initial establishment of a function than for preservation of an already-established function. A neuro-computational model of cortical map formation was adapted to examine effects of focal and distributed injury at various stages of development. This neural network model requires a period of training during which it self-organizes to establish cortical maps. Injuries were simulated by lesioning the model at various stages of this process and network function was monitored as "development" progressed to completion. Lesion effects are greater for larger, earlier, and distributed (multifocal) lesions. The mature system is relatively robust, particularly to focal injury. Activities in recovering systems injured at an early stage show changes that emerge after an asymptomatic interval. Early injuries cause qualitative changes in system behavior that emerge after a delay during which the effects of the injury are latent. Functions that are incompletely established at the time of injury may be vulnerable particularly to multifocal injury

The effect of functional roles on perceived group efficiency during computer-supported collaborative learning

In this article, the effect of functional roles on group performance and collaboration during computer-supported collaborative learning (CSCL) is investigated. Especially the need for triangulating multiple methods is emphasised: Likert-scale evaluation questions, quantitative content analysis of e-mail communication and qualitative analysis of open-ended questions were used. A comparison of fourty-one questionnaire observations, distributed over thirteen groups in two research conditions – groups with prescribed functional roles (n = 7, N = 18) and nonrole groups (n = 6, N = 23) – revealed no main effect for performance (grade). Principal axis factoring of the Likert-scales revealed a latent variable that was interpreted as perceived group efficiency (PGE). Multilevel modelling (MLM) yielded a positive marginal effect of PGE. Most groups in the role condition report a higher degree of PGE than nonrole groups. Content analysis of e-mail communication of all groups in both conditions (role n = 7, N = 25; nonrole n = 6, N = 26) revealed that students in role groups contribute more ‘coordination’ focussed statements. Finally, results from cross case matrices of student responses to open-ended questions support the observed marginal effect that most role groups report a higher degree of perceived group efficiency than nonrole groups

Development of a consensus classification of physiotherapy interventions in paediatric neurorehabilitation

Background and Aims Physiotherapy within paediatric neurorehabilitation is a complex process whereby the relationship between treatments delivered and resultant severity-adjusted patient outcomes have been difficult to demonstrate. An essential prerequisite for analysing physiotherapy input at the point of its delivery to the patient is to have clear descriptions and categories of physiotherapy interventions. Recent work in this area has focussed on grouping treatments based on their common essential ingredients. The aim of this work is to develop an expert-lead consensus classification of physiotherapy interventions used in paediatric neurorehabilitation, categorised according to their essential ingredients, actions and mediators. Method Comprehensive literature searches of five electronic databases (MEDLINE, EMBASE, AMED, CINAHL and PsychINFO) together with supplementary hand searching identified 4,194 studies which were separated into 34 different interventions following cross-referencing with other sources. These were then divided into eight distinct categories according to their essential treatment ingredients. A panel of 13 expert physiotherapists specialising in the field of paediatric neurorehabilitation were consulted in two rounds of an online modifiedDelphi survey (a method commonly used to glean expert consensus). Results In modified-Delphi survey rounds 1 and 2 respectively, eight (62%) and nine (69%) of the experts responded. Utilising a threshold of ≥75% agreement set a priori to represent expert consensus, there was agreement that the eight categories are comprehensive (complete) and unambiguous (easily understood). What remains less clear is the extent to which these categories are independent of one another. Discussion This categorisation of physiotherapy interventions within paediatric neurorehabilitation is the first of its kind to group treatments according to their essential treatment ingredients. Such work adds the potential for gleaning greater understanding regarding how physiotherapy leads to improved patient outcomes within paediatric neurorehabilitation. Further work is required in this area to better understand the extent to which different categories are truly independent or where similarities exist between them

Computer modelling of connectivity change suggests epileptogenesis mechanisms in idiopathic generalised epilepsy

Patients with idiopathic generalised epilepsy (IGE) typically have normal conventional magnetic resonance imaging (MRI), hence MRI based diagnosis is challenging. Anatomical abnormalities underlying brain dysfunctions in IGE are unclear and their relation to the pathomechanisms of epileptogenesis is poorly understood. In this study, we applied connectometry, an advanced quantitative neuroimaging technique for investigating localised changes in white-matter tissue. Analysing white matter structures of 32 subjects we incorporated our findings in a computational model of seizure dynamics to suggest a plausible mechanism of epileptogenesis. Patients with IGE have significant bilateral alterations in major white-matter fascicles. In the cingulum, fornix, and superior longitudinal fasciculus, tract integrity is compromised, whereas in specific parts of tracts between thalamus and the precentral gyrus, tract integrity is enhanced in patients. Combining these alterations in a logistic regression model, we computed the decision boundary that discriminated patients and controls. The computational model, informed with the findings on the tract abnormalities, specifically highlighted the importance of enhanced cortico-reticular connections along with impaired cortico-cortical connections in inducing pathological seizure-like dynamics. We emphasise taking directionality of brain connectivity into consideration towards understanding the pathological mechanisms; this is possible by combining neuroimaging and computational modelling. Our imaging evidence of structural alterations suggest the loss of cortico-cortical and enhancement of cortico-thalamic fibre integrity in IGE. We further suggest that impaired connectivity from cortical regions to the thalamic reticular nucleus offers a therapeutic target for selectively modifying the brain circuit for reversing the mechanisms leading to epileptogenesis

Complement factor I deficiency: a potentially treatable cause of fulminant cerebral inflammation

Objective To raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation. Methods Case report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature. Results We present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function. Conclusions Our case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role

Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic die

Selecting outcome measures to validate prognostic biomarkers of paediatric mild traumatic brain injury: challenges and priorities

Outcomes following paediatric mild traumatic brain injury (mTBI) are extremely heterogenous. While emerging biomarkers promise enhanced prognostic accuracy, a critical question remains unanswered—which outcome measures provide the most accurate assessment of injury impact? In this article, we highlight barriers to selecting appropriate outcome measures, including variability in how outcomes are defined and the wide range of assessment tools used. With reference to the most recent literature, we summarise current evidence of adverse outcomes following paediatric mTBI and highlight emerging candidate biomarkers of these outcomes. We emphasise the unique challenges associated with interpreting outcome measures in younger patients, from the impact of developmental stage and assessment timing to the influence of injury-independent factors. We assert the need to consider these obstacles when designing and interpreting mTBI biomarker studies. To realise the potential of prognostic biomarkers, future research should prioritise establishing consensus definitions, compiling a set of accessible and comprehensive outcome measures, and capturing injury-independent factors through longitudinal study designs

Protocol for the EACH trial: a multicentre phase II study evaluating the safety and antitumour activity of the combination of avelumab, an anti-PD-L1 agent, and cetuximab, as any line treatment for patients with recurrent/metastatic head and neck squamous cell cancer (HNSCC) in the UK

INTRODUCTION: Head and neck cancer is the eighth most common cancer in the UK. Current standard of care treatment for patients with recurrent/metastatic squamous cell head and neck carcinoma (HNSCC) is platinum-based chemotherapy combined with the anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, cetuximab. However, most patients will have poor median overall survival (OS) of 6-9 months despite treatment. HNSCC tumours exhibit an immune landscape poised to respond to immunotherapeutic approaches, with most tumours expressing the immunosuppressive receptor programmed death-ligand 1 (PD-L1). We undertook the current study to determine the safety and efficacy of avelumab, a monoclonal antibody targeting the interaction between PD-L1 and its receptor on cytotoxic T-cells, in combination with cetuximab. METHODS AND ANALYSIS: This is a multi-centre, single-arm dose de-escalation phase II safety and efficacy study of avelumab combined with cetuximab; the study was to progress to a randomised phase II trial, however, the study will now complete after the safety run-in component. Up to 16 participants with histologically/cytologically recurrent/metastatic squamous cell carcinoma (including HNSCC) who have not received cetuximab previously will be recruited. All patients will receive 10 mg/kg avelumab and cetuximab (500, 400 or 300 mg/m2 depending on the cohort open at time of registration) on days 1 and 15 of 4-week cycles for up to 1 year, (avelumab not given cycle 1 day 1). A modified continual reassessment method will be used to determine dose de-escalation. The primary objective is to establish the safety of the combination and to determine the optimum dose of cetuximab. Secondary objectives include assessing evidence of antitumour activity by evaluating response rates and disease control rates at 6 and 12 months as well as progression-free and OS. ETHICS AND DISSEMINATION: Approval granted by City and East REC (18/LO/0021). Findings will be published in peer-reviewed journals and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT03494322

Compositional controls on oceanic plates : geophysical evidence from the MELT area

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature 437 (2005): 249-252, doi:10.1038/nature04014.Magnetotelluric (MT) and seismic data, collected during the MELT experiment at the Southern East Pacific Rise (SEPR) constrain the distribution of melt beneath this mid-ocean-ridge spreading center and also the evolution of the oceanic lithosphere during its early cooling history. In this paper, we focus on structure imaged at distances ~100 to 350 km east of the ridge crest, corresponding to seafloor ages of ~1.3 to 4.5 Ma, where the seismic and electrical conductivity structure is nearly constant, independent of age. Beginning at a depth of about 60 km, there is a large increase in electrical conductivity and a change from isotropic to transversely anisotropic electrical structure with higher conductivity in the direction of fast propagation for seismic waves. Because conductive cooling models predict structure that increases in depth with age, extending to about 30 km at 4.5 Ma, we infer that the structure of young oceanic plates is instead controlled by a decrease in water content above 60 km induced by the melting process beneath the spreading center.US participation in the MELT experiment and subsequent analysis was funded by NSF grants through the Marine Geology and Geophysics Program, Ocean Sciences Division