Bridging experiments, models and simulations : an integrative approach to validation in computational cardiac electrophysiology

Computational models in physiology often integrate functional and structural information from a large range of spatio-temporal scales from the ionic to the whole organ level. Their sophistication raises both expectations and scepticism concerning how computational methods can improve our understanding of living organisms and also how they can reduce, replace and refine animal experiments. A fundamental requirement to fulfil these expectations and achieve the full potential of computational physiology is a clear understanding of what models represent and how they can be validated. The present study aims at informing strategies for validation by elucidating the complex interrelations between experiments, models and simulations in cardiac electrophysiology. We describe the processes, data and knowledge involved in the construction of whole ventricular multiscale models of cardiac electrophysiology. Our analysis reveals that models, simulations, and experiments are intertwined, in an assemblage that is a system itself, namely the model-simulation-experiment (MSE) system. Validation must therefore take into account the complex interplay between models, simulations and experiments. Key points for developing strategies for validation are: 1) understanding sources of bio-variability is crucial to the comparison between simulation and experimental results; 2) robustness of techniques and tools is a pre-requisite to conducting physiological investigations using the MSE system; 3) definition and adoption of standards facilitates interoperability of experiments, models and simulations; 4) physiological validation must be understood as an iterative process that defines the specific aspects of electrophysiology the MSE system targets, and is driven by advancements in experimental and computational methods and the combination of both.

Cerebellar grey-matter deficits, cannabis use and first-episode schizophrenia in adolescents and young adults

Epidemiological data link adolescent cannabis use to psychosis and schizophrenia, but its contribution to schizophrenia neuropathology remains controversial. First-episode schizophrenia (FES) patients show regional cerebral grey- and white-matter changes as well as a distinct pattern of regional grey-matter loss in the vermis of the cerebellum. The cerebellum possesses a high density of cannabinoid type 1 receptors involved in the neuronal diversification of the developing brain. Cannabis abuse may interfere with this process during adolescent brain maturation leading to ‘schizophrenia-like’ cerebellar pathology. Magnetic resonance imaging and cortical pattern matching techniques were used to investigate cerebellar grey and white matter in FES patients with and without a history of cannabis use and non-psychiatric cannabis users. In the latter group we found lifetime dose-dependent regional reduction of grey matter in the right cerebellar lobules and a tendency for more profound grey-matter reduction in lobule III with younger age at onset of cannabis use. The overall regional grey-matter differences in cannabis users were within the normal variability of grey-matter distribution. By contrast, FES subjects had lower total cerebellar grey-matter : total cerebellar volume ratio and marked grey-matter loss in the vermis, pedunculi, flocculi and lobules compared to pair-wise matched healthy control subjects. This pattern and degree of grey-matter loss did not differ from age-matched FES subjects with comorbid cannabis use. Our findings indicate small dose-dependent effects of juvenile cannabis use on cerebellar neuropathology but no evidence of an additional effect of cannabis use on FES cerebellar grey-matter pathology.

Gray matter deficits, mismatch negativity, and outcomes in schizophrenia

Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients’ levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl’s gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl’s gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.

Cerebellar grey matter deficits in first-episode schizophrenia mapped using cortical pattern matching

Cerebellar dysfunction has been proposed to lead to “cognitive dysmetria” in schizophrenia via the cortico-cerebellar-thalamic-cortical circuit, contributing to a range of cognitive and clinical symptoms of the disorder. Here we investigated total cerebellar grey and white matter volumes and cerebellar regional grey matter abnormalities in 13 remitted first-episode schizophrenia patients with less than 2 years’ duration of illness. Patient data were compared to 13 pair-wise age, gender, and handedness-matched healthy volunteers using cortical pattern averaging on high-resolution magnetic resonance images. Total cerebellar volume and total grey matter volumes in first-episode schizophrenia patients did not differ from healthy control subjects, but total cerebellar white matter was increased and total grey to white matter ratios were reduced in patients. Four clusters of cerebellar grey matter reduction were identified: (i) in superior vermis; (ii) in the left lobuli VI; (iii) in right-inferior lobule IX, extending into left lobule IX; and (iv) bilaterally in the areas of lobuli III, peduncle and left flocculus. Grey matter deficits were particularly prominent in right lobuli III and IX, left flocculus and bilateral pedunculi. These cerebellar areas have been implicated in attention control, emotional regulation, social functioning, initiation of smooth pursuit eye movements, eye-blink conditioning, language processing, verbal memory, executive function and the processing of spatial and emotional information. Consistent with common clinical, cognitive, and pathophysiological signs of established illness, our findings demonstrate cerebellar pathology as early as in first-episode schizophrenia.

Health and guardianship law : guardianship and administration application in the matter of MDC [2014] QCAT 338

The recent decision of the Queensland Civil and Administrative Tribunal (QCAT) in Guardianship and administration application in the matter of MDC [2014] QCAT 338, provides an important ruling on the limits of who can be appointed as an enduring power of attorney under the Powers of Attorney Act 1998 (Qld). In particular, the tribunal adopted a broad interpretation of the term "health provider" when considering the limits on who can be appointed as an enduring power of attorney under the legislation...

Review-evaluating the molecular assays for measuring the oxidative potential of particulate matter

Several cell-free assays are currently used to quantify and detect the Reactive Oxygen Species (ROS). All of them have certain limitations, do not provide direct comparison of results and, to date, none of these assays have been acknowledged as the most suitable acellular assay and none has yet been adopted for investigation of potential PM toxicity. These assays include DTT, ascorbic acid, DCFHDA and PFN assays which have been used in measurements of the particles generated from various combustion sources such as diesel engine, wood smoke (or biomass burning) and cigarette smoke, as well as for outdoor measurements. All the probes use different units for expressing redox properties of PM. Also, their reactivity is being triggered by different types of ROS. This limits the direct comparison of the results that are reporting the toxicity of the same aerosol type measured with various probes. This study is evaluating and comparing the various assays in order to develop deeper understanding of their capabilities, selectivity as well as improve understanding of the underlying chemical mechanisms. Keywords: DTT, DCFH-DA, PFN, BPEA-nit, Ascorbic acid, oxidative potential

ACE research vignette 038 : Cracking the start-up code : does it matter when you do what?

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international Entrepreneurship researchers. This vignette deals with the process of new venture creation, and specifically the sequence in which different ‘start-up activities’ are undertaken.

Making stories matter: Using participatory new media storytelling and evaluation to serve marginalised and regional communities

In this chapter, we draw on our experiences facilitating community storytelling workshops in regional Queensland in partnership with the Queensland branch of Oral History Association of Australia (OHAA Qld) in order to develop a best practice model for promoting creative approaches to recording oral narratives using digital tools, informed by creative writing practice and embedded evaluation (Klaebe 2012 & 2013). These experiences offer an insight into how creative approaches to training can facilitate the sharing and preservation of stories in regional communities.

Large Scale Simulations of Hippocampal-Neocortical Interactions in a Parallel Version of Genesis

A hippocampal-CA3 memory model was constructed with PGENESIS, a recently developed version of GENESIS that allows for distributed processing of a neural network simulation. A number of neural models of the human memory system have identified the CA3 region of the hippocampus as storing the declarative memory trace. However, computational models designed to assess the viability of the putative mechanisms of storage and retrieval have generally been too abstract to allow comparison with empirical data. Recent experimental evidence has shown that selective knock-out of NMDA receptors in the CA1 of mice leads to reduced stability of firing specificity in place cells. Here a similar reduction of stability of input specificity is demonstrated in a biologically plausible neural network model of the CA3 region, under conditions of Hebbian synaptic plasticity versus an absence of plasticity. The CA3 region is also commonly associated with seizure activity. Further simulations of the same model tested the response to continuously repeating versus randomized nonrepeating input patterns. Each paradigm delivered input of equal intensity and duration. Non-repeating input patterns elicited a greater pyramidal cell spike count. This suggests that repetitive versus non-repeating neocortical inpus has a quantitatively different effect on the hippocampus. This may be relevant to the production of independent epileptogenic zones and the process of encoding new memories.

Plasmonic effect of annealed gold islands for improving efficiency of organic solar cells

Embedding metallic nanoparticles in organic solar cells can enhance the photoabsorption through light trapping processes. This paper investigates how gold islands obtained by annealing 1–5 nm thick Au layers affect the photoabsorption. Using finite-difference time-domain simulations, the cell efficiency for various island geometries and thicknesses are analyzed and the properties of the islands for maximal photocurrent are discussed. It is shown that a careful choice of size and concentration of gold islands could contribute to enhance the power conversion efficiencies when compared to standard organic solar cell devices. The conclusions are then compared to experimental data for thermally annealed gold islands in bulk heterojunction solar cells. The results of this paper will contribute to the optimization of plasmonic organic solar cell systems and will pave the way for the development of highly efficient organic solar cell devices.