Inter-individual variability in optimal current direction for transcranial magnetic stimulation of the motor cortex

We evaluated inter-individual variability in optimal current direction for biphasic transcranial magnetic stimulation (TMS) of the motor cortex. Motor threshold for first dorsal interosseus was detected visually at eight coil orientations in 45° increments. Each participant (n = 13) completed two experimental sessions. One participant with low test–retest correlation (Pearson's r < 0.5) was excluded. In four subjects, visual detection of motor threshold was compared to EMG detection; motor thresholds were very similar and highly correlated (0.94–0.99). Similar with previous studies, stimulation in the majority of participants was most effective when the first current pulse flowed towards postero-lateral in the brain. However, in four participants, the optimal coil orientation deviated from this pattern. A principal component analysis using all eight orientations suggests that in our sample the optimal orientation of current direction was normally distributed around the postero-lateral orientation with a range of 63° (S.D. = 13.70°). Whenever the intensity of stimulation at the target site is calculated as a percentage from the motor threshold, in order to minimize intensity and side-effects it may be worthwhile to check whether rotating the coil 45° from the traditional posterior–lateral orientation decreases motor threshold.

Estimating ECAP threshold from the variability of the response

Electrical compound action potentials (ECAPs) of the cochlear nerve are used clinically for quick and efficient cochlear implant parameter setting. The ECAP is the aggregate response of nerve fibres at various distances from the recording electrode, and the magnitude of the ECAP is therefore related to the number of fibres excited by a particular stimulus. Current methods, such as the masker-probe or alternating polarity methods, use the ECAP magnitude at various stimulus levels to estimate the neural threshold, from which the parameters are calculated. However, the correlation between ECAP threshold and perceptual threshold is not always good, with ECAP threshold typically being much higher than perceptual threshold. The lower correlation is partly due to the very different pulse rates used for ECAPs (below 100 Hz) and clinical programs (hundreds of Hz up to several kHz). Here we introduce a new method of estimating ECAP threshold for cochlear implants based upon the variability of the response. At neural threshold, where some but not all fibers respond, there is a different response each trial. This inter-trial variability can be detected overlaying the constant variability of the system noise. The large stimulus artefact, which requires additional trials for artefact rejection in the standard ECAP magnitude methods, is not consequential, as it has little variability. The variability method therefore consists of simply presenting a pulse and recording the ECAP, and as such is quicker than other methods. It also has the potential to be run at high rates like clinical programs, potentially improving the correlation with behavioural threshold. Preliminary data is presented that shows a detectable variability increase shortly after probe offset, at probe levels much lower than those producing a detectable ECAP magnitude. Care must be taken, however, to avoid saturation of the recording amplifier saturation; in our experiments we found a gain of 300 to be optimal.

Examination variability in short-wavelength automated perimetry

The study evaluated sources of within- and between-subject variability in standard white-on-white (W-W) perimetry and short-wavelength automated perimetry (SWAP). The Influence of staircase strategy on the fatigue effect in W-W perimetry was investigated for a 4 dB single step, single reversal strategy; a variable step size, single reversal dynamic strategy; and the standard 4-2 dB double reversal strategy. The fatigue effect increased as the duration of the examination Increased and was greatest in the second eye for all strategies. The fatigue effect was lowest for the 4dB strategy, which exhibited the shortest examination time and was greatest for the 4-2 dB strategy, which exhibited the longest examination time. Staircase efficiency was lowest for the 4 dB strategy and highest for the dynamic strategy which thus offers a reduced examination time and low inter-subject variability. The normal between-subject variability of SWAP was determined for the standard 4-2 dB double reversal strategy and the 3 dB single reversal FASTPAC strategy and compared to that of W-W perimetry, The decrease in sensitivity with Increase in age was greatest for SWAP. The between-subject variability of SWAP was greater than W-W perimetry. Correction for the Influence of ocular media absorption reduced the between-subject variability of SWAP, The FASTPAC strategy yielded the lowest between-subject variability In SWAP, but the greatest between-subject variability In WoW perimetry. The greater between-subject variability of SWAP has profound Implications for the delineation of visual field abnormality, The fatigue effect for the Full Threshold strategy in SWAP was evaluated with conventional opaque, and translucent occlusion of the fellow eye. SWAP exhibited a greater fatigue effect than W-W perimetry. Translucent occlusion reduced the between-subject variability of W-W perimetry but Increased the between-subject variability of SWAP. The elevation of sensitivity was greater with translucent occlusion which has implications for the statistical analysis of W-W perimetry and SWAP. The influence of age-related cataract extraction and IOL implantation upon the visual field derived by WoW perimetry and SWAP was determined. Cataract yielded a general reduction In sensitivity which was preferentially greater in SWAP, even after the correction of SWAP for the attenuation of the stimulus by the ocular media. There was no correlation between either backward or forward light scatter and the magnitude of the attenuation of W-W or SWAP sensitivity. The post-operative mean deviation in SWAP was positive and has ramifications for the statistical Interpretation of SWAP. Short-wavelength-sensitive pathway isolation was assessed as a function of stimulus eccentricity using the two-colour Increment threshold method. At least 15 dB of SWS pathway Isolation was achieved for 440 nm, 450 nm and 460 nm stimuli at a background luminance of 100 cdm-2, There was a slight decrease In SWS pathway Isolation for all stimulus wavelengths with increasing eccentricity which was not of clinical significance. Adopting a 450 nm stimulus may reduce between-subject variability In SWAP due to a reduction In ocular media absorption and macular pigment absorption.

Accuracy and applications of group MEG studies using cortical source locations estimated from participants' scalp surfaces

We contend that powerful group studies can be conducted using magnetoencephalography (MEG), which can provide useful insights into the approximate distribution of the neural activity detected with MEG without requiring magnetic resonance imaging (MRI) for each participant. Instead, a participant's MRI is approximated with one chosen as a best match on the basis of the scalp surface from a database of available MRIs. Because large inter-individual variability in sulcal and gyral patterns is an inherent source of blurring in studies using grouped functional activity, the additional error introduced by this approximation procedure has little effect on the group results, and offers a sufficiently close approximation to that of the participants to yield a good indication of the true distribution of the grouped neural activity. T1-weighted MRIs of 28 adults were acquired in a variety of MR systems. An artificial functional image was prepared for each person in which eight 5 × 5 × 5 mm regions of brain activation were simulated. Spatial normalisation was applied to each image using transformations calculated using SPM99 with (1) the participant's actual MRI, and (2) the best matched MRI substituted from those of the other 27 participants. The distribution of distances between the locations of points using real and substituted MRIs had a modal value of 6 mm with 90% of cases falling below 12.5 mm. The effects of this -approach on real grouped SAM source imaging of MEG data in a verbal fluency task are also shown. The distribution of MEG activity in the estimated average response is very similar to that produced when using the real MRIs. © 2003 Wiley-Liss, Inc.

Evaluation of the auto-refraction function of the Nidek OPD-Scan III

Background: The aim was to evaluate the validity and repeatability of the auto-refraction function of the Nidek OPD-Scan III (Nidek Technologies, Gamagori, Japan) compared with non-cycloplegic subjective refraction. The Nidek OPD-Scan III is a new aberrometer/corneal topographer workstation based on the skiascopy principle. It combines a wavefront aberrometer, topographer, autorefractor, auto keratometer and pupillometer/pupillographer. Methods: Objective refraction results obtained using the Nidek OPD-Scan III were compared with non-cycloplegic subjective refraction for 108 eyes of 54 participants (29 female) with a mean age of 23.7±9.5 years. Intra-session and inter-session variability were assessed on 14 subjects (28 eyes). Results: The Nidek OPD-Scan III gave slightly more negative readings than results obtained by subjective refraction (Nidek mean difference -0.19±0.36 DS, p<0.01 for sphere; -0.19±0.35 DS, p<0.01 for mean spherical equivalent; -0.002±0.23 DC, p=0.91 for cylinder; -0.06±0.38 DC, p=0.30 for J0 and -0.36±0.31 DC for J45, p=0.29). Auto-refractor results for 74 per cent of spherical readings and 60 per cent of cylindrical powers were within±0.25 of subjective refraction. There was high intra-session and inter-session repeatability for all parameters; 90 per cent of inter-session repeatability results were within 0.25 D. Conclusion: The Nidek OPD-Scan III gives valid and repeatable measures of objective refraction when compared with non-cycloplegic subjective refraction. © 2013 The Authors. Clinical and Experimental Optometry © 2013 Optometrists Association Australia.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

Aims - To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. Methods - The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. Results - The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)0.35 x EXP (-0.0058 x TPT) x EXP (0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h−1 kg−1 (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Conclusion Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.

Measurement of scleral thickness in humans using anterior segment optical coherent tomography

Anterior segment optical coherent tomography (AS-OCT, Visante; Zeiss) is used to examine meridional variation in anterior scleral thickness (AST) and its association with refractive error, ethnicity and gender. Scleral cross-sections of 74 individuals (28 males; 46 females; aged between 18-40 years (27.7±5.3)) were sampled twice in random order in 8 meridians: [superior (S), inferior (I), nasal (N), temporal (T), superior-temporal (ST), superior-nasal (SN), inferior-temporal (IT) and inferior-nasal (IN)]. AST was measured in 1mm anterior-toposterior increments (designated the A-P distance) from the scleral spur (SS) over a 6mm distance. Axial length and refractive error were measured with a Zeiss IOLMaster biometer and an open-view binocular Shin-Nippon autorefractor. Intra- And inter-observer variability of AST was assessed for each of the 8 meridians. Mixed repeated measures ANOVAs tested meridional and A-P distance differences in AST with refractive error, gender and ethnicity. Only right eye data were analysed. AST (mean±SD) across all meridians and A-P distances was 725±46μm. Meridian SN was the thinnest (662±57μm) and I the thickest (806 ±60μm). Significant differences were found between all meridians (p<0.001), except S:ST, IT:IN, IT:N and IN:N. Significant differences between A-P distances were found except between SS and 6 mm and between 2 and 4mm. AST measurements at 1mm (682±48 μm) were the thinnest and at 6mm (818±49 μm) the thickest (p<0.001); a significant interaction occurred between meridians and A-P distances (p<0.001). AST was significantly greater (p<0.001) in male subjects but no significant differences were found between refractive error or ethnicity. Significant variations in AST occur with regard to meridian and distance from the SS and may have utility in selecting optimum sites for pharmaceutical or surgical intervention.

Source localization methods

One of the most pressing demands on electrophysiology applied to the diagnosis of epilepsy is the non-invasive localization of the neuronal generators responsible for brain electrical and magnetic fields (the so-called inverse problem). These neuronal generators produce primary currents in the brain, which together with passive currents give rise to the EEG signal. Unfortunately, the signal we measure on the scalp surface doesn't directly indicate the location of the active neuronal assemblies. This is the expression of the ambiguity of the underlying static electromagnetic inverse problem, partly due to the relatively limited number of independent measures available. A given electric potential distribution recorded at the scalp can be explained by the activity of infinite different configurations of intracranial sources. In contrast, the forward problem, which consists of computing the potential field at the scalp from known source locations and strengths with known geometry and conductivity properties of the brain and its layers (CSF/meninges, skin and skull), i.e. the head model, has a unique solution. The head models vary from the computationally simpler spherical models (three or four concentric spheres) to the realistic models based on the segmentation of anatomical images obtained using magnetic resonance imaging (MRI). Realistic models – computationally intensive and difficult to implement – can separate different tissues of the head and account for the convoluted geometry of the brain and the significant inter-individual variability. In real-life applications, if the assumptions of the statistical, anatomical or functional properties of the signal and the volume in which it is generated are meaningful, a true three-dimensional tomographic representation of sources of brain electrical activity is possible in spite of the ‘ill-posed’ nature of the inverse problem (Michel et al., 2004). The techniques used to achieve this are now referred to as electrical source imaging (ESI) or magnetic source imaging (MSI). The first issue to influence reconstruction accuracy is spatial sampling, i.e. the number of EEG electrodes. It has been shown that this relationship is not linear, reaching a plateau at about 128 electrodes, provided spatial distribution is uniform. The second factor is related to the different properties of the source localization strategies used with respect to the hypothesized source configuration.

Costs and benefits of orthographic inconsistency in reading:evidence from a cross-linguistic comparison

We compared reading acquisition in English and Italian children up to late primary school analyzing RTs and errors as a function of various psycholinguistic variables and changes due to experience. Our results show that reading becomes progressively more reliant on larger processing units with age, but that this is modulated by consistency of the language. In English, an inconsistent orthography, reliance on larger units occurs earlier on and it is demonstrated by faster RTs, a stronger effect of lexical variables and lack of length effect (by fifth grade). However, not all English children are able to master this mode of processing yielding larger inter-individual variability. In Italian, a consistent orthography, reliance on larger units occurs later and it is less pronounced. This is demonstrated by larger length effects which remain significant even in older children and by larger effects of a global factor (related to speed of orthographic decoding) explaining changes of performance across ages. Our results show the importance of considering not only overall performance, but inter-individual variability and variability between conditions when interpreting cross-linguistic differences.

Localising the auditory N1m with event-related beamformers:localisation accuracy following bilateral and unilateral stimulation

The auditory evoked N1m-P2m response complex presents a challenging case for MEG source-modelling, because symmetrical, phase-locked activity occurs in the hemispheres both contralateral and ipsilateral to stimulation. Beamformer methods, in particular, can be susceptible to localisation bias and spurious sources under these conditions. This study explored the accuracy and efficiency of event-related beamformer source models for auditory MEG data under typical experimental conditions: monaural and diotic stimulation; and whole-head beamformer analysis compared to a half-head analysis using only sensors from the hemisphere contralateral to stimulation. Event-related beamformer localisations were also compared with more traditional single-dipole models. At the group level, the event-related beamformer performed equally well as the single-dipole models in terms of accuracy for both the N1m and the P2m, and in terms of efficiency (number of successful source models) for the N1m. The results yielded by the half-head analysis did not differ significantly from those produced by the traditional whole-head analysis. Any localisation bias caused by the presence of correlated sources is minimal in the context of the inter-individual variability in source localisations. In conclusion, event-related beamformers provide a useful alternative to equivalent-current dipole models in localisation of auditory evoked responses.

Sociolinguistic variability in oral narrative.

This thesis begins with a sociolinguistic correlational study of three phonetic variables - (h), (t) and (ing) - as used by four occupational groups - nurses, chefs, hairdressers and taxi-drivers. The groups were selected to incorporate three independent variables: sex (male-dominated versus female-dominated occupations); training (length and specialisation - nurses and chefs being more specialised than hairdressers and taxi-drivers) and location (the populations were selected from two cities - Liverpool and Birmingham). Although the correlational work demonstrates intra-sex and occupation consistency in speakers' choice of linguistic variants (females (particularly nurses) being significantly closer to the prestige norm), it is essentially non-explanatory and cannot accout for narrative dynamics and style shift. Therefore, an in-depth qualitative examination of the data (which draws mainly on Narrative and Discourse Analysis) forms the major part of the analysis. The study first analyses features common to all the narratives, direct speech, expressive phonology and linguistic ambiguity emerging as characteristic of all humorous storytelling. Secondly, three major sources of inter-personal variation are invetigated: narrator perspective, sex and occuptational role. Perspective is found to vary with topic and personality, greater narrator involvement coinciding with a higher proportion of internal evaluation devices. Sex differences include topic choice and bonding in the storytelling sessions. Sex differences are also evident in style shifting, where the narrator mimics the voice of a character in the narrative (aodpting segmental and/or prosodic tokens to signal a change of persona). The research finds that female narrators rarely employ segmental accommodation downwards on the social scale (whereas men do), but are on the other hand adept at using prosodic effects for mimicry. Taxi-drivers emerge as the group with the most distinctive narrative flair, a fact which is related to their occupation. The conclusion stresses a need for both quantitative and qualitative approaches to data; the importance of occupational role, as opposed to sex role per se in determining narrative conventions; the view of narrative as a negotiable entity, which is the product of relationships among participants; and the importance of considering the totality of the communicative act.

Geographical variation in carbon dioxide fluxes from soils in agro-ecosystems and its implications for life-cycle assessment

1. Exchange of carbon dioxide (CO2) from soils can contribute significantly to the global warming potential (GWP) of agro-ecosystems. Due to variations in soil type, climatic onditions and land management practices, exchange of CO2 can differ markedly in different geographical locations. The food industry is developing carbon footprints for their products necessitating integration of CO2 exchange from soils with other CO2 emissions along the food chain. It may be advantageous to grow certain crops in different geographical locations to minimize CO2 emissions from the soil, and this may provide potential to offset other emissions in the food chain, such as transport. 2. Values are derived for the C balance of soils growing horticultural crops in the UK, Spain and Uganda. Net ecosystem production (NEP) is firstly calculated from the difference in net primary production (NPP) and heterotrophic soil respiration (Rh). Both NPP and Rh were estimated from intensive direct field measurements. Secondly, net biome production (NBP) is calculated by subtracting the crop biomass from NEP to give an indication of C balance. The importance of soil exchange is discussed in the light of recent discussions on carbon footprints and within the context of food life-cycle assessment (LCA). 3. The amount of crop relative to the biomass and the Rh prevailing in the different countries were the dominant factors influencing the magnitude of NEP and NBP. The majority of the biomass for lettuce Lactuca sativa and vining peas Pisum sativum, was removed from the field as crop; therefore, NEP and NBP were mainly negative. This was amplified for lettuces grown in Uganda (-16·5 and -17 t C ha-1 year-1 compared to UK and Spain -4·8 to 7·4 and -5·1 to 6·3 t C ha-1 year-1 for NEP and NBP, respectively) where the climate elevated Rh. 4. Synthesis and applications. This study demonstrates the importance of soil emissions in the overall life cycle of vegetables. Variability in such emissions suggests that assigning a single value to food carbon footprints may not be adequate, even within a country. Locations with high heterotrophic soil respiration, such as Spain and Uganda (21·9 and 21·6 t C ha-1 year-1, respectively), could mitigate the negative effects of climate on the C costs of crop production by growth of crops with greater returns of residue to the soil. This would minimize net CO2 emissions from these agricultural ecosystems.