The effect of Gaussian noise on the threshold, dynamic range, and loudness of analogue cochlear implant stimuli

The deliberate addition of Gaussian noise to cochlear implant signals has previously been proposed to enhance the time coding of signals by the cochlear nerve. Potentially, the addition of an inaudible level of noise could also have secondary benefits: it could lower the threshold to the information-bearing signal, and by desynchronization of nerve discharges, it could increase the level at which the information-bearing signal becomes uncomfortable. Both these effects would lead to an increased dynamic range, which might be expected to enhance speech comprehension and make the choice of cochlear implant compression parameters less critical (as with a wider dynamic range, small changes in the parameters would have less effect on loudness). The hypothesized secondary effects were investigated with eight users of the Clarion cochlear implant; the stimulation was analogue and monopolar. For presentations in noise, noise at 95% of the threshold level was applied simultaneously and independently to all the electrodes. The noise was found in two-alternative forced-choice (2AFC) experiments to decrease the threshold to sinusoidal stimuli (100 Hz, 1 kHz, 5 kHz) by about 2.0 dB and increase the dynamic range by 0.7 dB. Furthermore, in 2AFC loudness balance experiments, noise was found to decrease the loudness of moderate to intense stimuli. This suggests that loudness is partially coded by the degree of phase-locking of cochlear nerve fibers. The overall gain in dynamic range was modest, and more complex noise strategies, for example, using inhibition between the noise sources, may be required to get a clinically useful benefit. © 2006 Association for Research in Otolaryngology.

Stimuli of varying spatial scale induce gamma activity with distinct temporal characteristics in human visual cortex

Gamma activity to stationary grating stimuli was studied non-invasively using MEG recordings in humans. Using a spatial filtering technique, we localized gamma activity to primary visual cortex. We tested the hypothesis that spatial frequency properties of visual stimuli may be related to the temporal frequency characteristics of the associated cortical responses. We devised a method to assess temporal frequency differences between stimulus-related responses that typically exhibit complex spectral shapes. We applied this methodology to either single-trial (induced) or time-averaged (evoked) responses in four frequency ranges (0-40, 20-60, 40-80 and 60-100 Hz) and two time windows (either the entire duration of stimulus presentation or the first second following stimulus onset). Our results suggest that stimuli of varying spatial frequency induce responses that exhibit significantly different temporal frequency characteristics. These effects were particularly accentuated for induced responses in the classical gamma frequency band (20-60 Hz) analyzed over the entire duration of stimulus presentation. Strikingly, examining the first second of the responses following stimulus onset resulted in significant loss in stimulus specificity, suggesting that late signal components contain functionally relevant information. These findings advocate a functional role of gamma activity in sensory representation. We suggest that stimulus specific frequency characteristics of MEG signals can be mapped to processes of neuronal synchronization within the framework of coupled dynamical systems.

Changes in inositol lipids and phosphates after stimulation of the MAS-transfected NG115-401L-C3 cell line by mitogenic and non-mitogenic stimuli

A neuronal cell line (NG115-401L-C3) was stimulated by mitogenic (angiotensin) and non-mitogenic (bradykinin) peptides and examined for the time course of changes in the levels of radiolabelled inositol phosphates and phospholipids. Both peptides stimulated the time-dependent production of Ins(1,4,5)P3 and related metabolites. Bradykinin caused a much larger increase in Ins(1,4,5)P3 than did angiotensin. However, both peptides stimulated similar rises in the levels of Ins(1,3,4)P3 and InsP4. Bradykinin but not angiotensin, caused a rapid (within 2 s) fall in the levels of PtdIns(4,5)P2 and PtdIns(4)P. Serum pretreatment of the cells caused a 2-3-fold potentiation of both the responses to bradykinin and angiotensin. Although significant levels of PtdIns(3)P were detected in resting cells neither mitogenic (angiotensin, insulin-like growth factor I, transforming growth factor beta) nor non-mitogenic (bradykinin, nerve growth factor interleukin-1) receptor activation changed its levels, arguing against regulation of either PtdIns 3-kinase or PtdIns(3)P phosphatase. We conclude that, as judged by the levels of its product. PtdIns(3)P, the enzyme PtdIns 3-kinase is not activated. This questions the significance of this activity in the receptor-mediated initiation of DNA synthesis.

Cell passage-associated transient high oxygenation causes a transient decrease in cellular glutathione and affects T cell responses to apoptotic and mitogenic stimuli

Routine cell line maintenance involves removal of waste products and replenishment of nutrients via replacement of cell culture media. Here, we report that routine maintenance of three discrete cell lines (HSB-CCRF-2 and Jurkat T cells, and phaeo-chromocytoma PC12 cells) decreases the principal cellular antioxidant, glutathione, by up to 42% in HSB-CCRF-2 cells between 60 and 120 min after media replenishment. However, cellular glutathione levels returned to baseline within 5 h after passage. The decrease in glutathione was associated with modulation of the response of Jurkat T cells to apoptotic and mitogenic signals. Methotrexate-induced apoptosis over 16 h, measured as accumulation of apoptotic nucleoids, was decreased from 22 to 17% if cells were exposed to cytotoxic agent 30 min after passage compared with cells exposed to MTX in the absence of passage. In contrast, interleukin-2 (IL-2) production over 24 h in response to the toxin phytohaemagglutinin (PHA), was increased by 34% if cells were challenged 2 h after passage compared with PHA treatment in the absence of passage. This research highlights the presence of a window of time after cell passage of non-adherent cells that may lead to over- or under-estimation of subsequent cell responses to toxins, which is dependent on cellular antioxidant capacity or redox state. © 2007 Elsevier B.V. All rights reserved.

The influence of diet on protein oxidation

Protein oxidation can be perceived as essential for the control of intracellular signalling and gene expression on the one hand, but in contrast, a potentially cytotoxic hazard of aerobic life. Reduction and oxidation of thiol groups on specific cysteine residues can act as critical molecular switches, in modulating response to growth factors, apoptotic and inflammatory stimuli to name a few. Such oxidative reactions are likely to be transient and represent low levels of oxidative modification to a protein. Sustained oxidative stress conditions through absence of essential dietary antioxidant or low activity of endogenous enzyme scavengers can cause irreversible damage and loss of function. Such modifications are believed to be important in many diseases associated with ageing. Therefore, it has been postulated that diet may exert an influence on the steady state of protein oxidation and thus offer potential health benefits through preservation of normal protein function. In the present paper, the current evidence from in vivo studies on the effects of dietary antioxidants and oxidants on protein oxidation will be evaluated, and needs for future research will be highlighted.

Three-factor models versus time series models:quantifying time-dependencies of interactions between stimuli in cell biology and psychobiology for short longitudinal data

Signal integration determines cell fate on the cellular level, affects cognitive processes and affective responses on the behavioural level, and is likely to be involved in psychoneurobiological processes underlying mood disorders. Interactions between stimuli may subjected to time effects. Time-dependencies of interactions between stimuli typically lead to complex cell responses and complex responses on the behavioural level. We show that both three-factor models and time series models can be used to uncover such time-dependencies. However, we argue that for short longitudinal data the three factor modelling approach is more suitable. In order to illustrate both approaches, we re-analysed previously published short longitudinal data sets. We found that in human embryonic kidney 293 cells cells the interaction effect in the regulation of extracellular signal-regulated kinase (ERK) 1 signalling activation by insulin and epidermal growth factor is subjected to a time effect and dramatically decays at peak values of ERK activation. In contrast, we found that the interaction effect induced by hypoxia and tumour necrosis factor-alpha for the transcriptional activity of the human cyclo-oxygenase-2 promoter in HEK293 cells is time invariant at least in the first 12-h time window after stimulation. Furthermore, we applied the three-factor model to previously reported animal studies. In these studies, memory storage was found to be subjected to an interaction effect of the beta-adrenoceptor agonist clenbuterol and certain antagonists acting on the alpha-1-adrenoceptor / glucocorticoid-receptor system. Our model-based analysis suggests that only if the antagonist drug is administer in a critical time window, then the interaction effect is relevant.

Signaling pathways initiated by beta-hydroxy-beta-methylbutyrate to attenuate the depression of protein synthesis in skeletal muscle in response to cachectic stimuli

To investigate the mechanism by which beta-hydroxy-beta-methylbutyrate (HMB) attenuates the depression of protein synthesis in the skeletal muscle of cachectic mice, a study has been carried out in murine myotubes in the presence of proteolysis-inducing factor (PIF). PIF inhibited protein synthesis by 50% within 4 h, and this was effectively attenuated by HMB (25-50 muM). HMB (50 muM) alone stimulated protein synthesis, and this was attenuated by rapamycin (27 nM), an inhibitor of mammalian target of rapamycin (mTOR). Further evidence for an involvement of this pathway was shown by an increased phosphorylation of mTOR, the 70-kDa ribosomal S6 kinase (p70(S6k)), and initiation factor 4E-binding protein (4E-BP1) and an increased association of eukaryotic initiation factor 2 (eIF4E) with eIF4G. PIF alone induced a transient (1-2 h) stimulation of phosphorylation of mTOR and p70(S6k). However, in the presence of HMB, phosphorylation of mTOR, p70(S6k), and 4E-BP1 was increased, and inactive 4E-BP1-eIF4E complex was reduced, whereas the active eIF4G.eIF4E complex was increased, suggesting continual stimulation of protein synthesis. HMB alone reduced phosphorylation of elongation factor 2, but this effect was not seen in the presence of PIF. PIF induced autophosphorylation of the double-strand RNA-dependent protein kinase (PKR), leading to phosphorylation of eIF2 on the alpha-subunit, which would inhibit protein synthesis. However, in the presence of HMB, phosphorylation of PKR and eIF2alpha was attenuated, and this was also observed in skeletal muscle of cachectic mice administered HMB (0.25 g/kg). These results suggest that HMB attenuates the depression of protein synthesis by PIF in myotubes through multiple mechanisms.

Estimation of functional connectivity from electromagnetic signals and the amount of empirical data required

An increasing number of neuroimaging studies are concerned with the identification of interactions or statistical dependencies between brain areas. Dependencies between the activities of different brain regions can be quantified with functional connectivity measures such as the cross-correlation coefficient. An important factor limiting the accuracy of such measures is the amount of empirical data available. For event-related protocols, the amount of data also affects the temporal resolution of the analysis. We use analytical expressions to calculate the amount of empirical data needed to establish whether a certain level of dependency is significant when the time series are autocorrelated, as is the case for biological signals. These analytical results are then contrasted with estimates from simulations based on real data recorded with magnetoencephalography during a resting-state paradigm and during the presentation of visual stimuli. Results indicate that, for broadband signals, 50-100 s of data is required to detect a true underlying cross-correlations coefficient of 0.05. This corresponds to a resolution of a few hundred milliseconds for typical event-related recordings. The required time window increases for narrow band signals as frequency decreases. For instance, approximately 3 times as much data is necessary for signals in the alpha band. Important implications can be derived for the design and interpretation of experiments to characterize weak interactions, which are potentially important for brain processing.

Spatial coherence does not affect contrast discrimination for multiple Gabor stimuli

Gestalt grouping rules imply a process or mechanism for grouping together local features of an object into a perceptual whole. Several psychophysical experiments have been interpreted as evidence for constrained interactions between nearby spatial filter elements and this has led to the hypothesis that element linking might be mediated by these interactions. A common tacit assumption is that these interactions result in response modulation which disturbs a local contrast code. We addressed this possibility by performing contrast discrimination experiments using two-dimensional arrays of multiple Gabor patches arranged either (i) vertically, (ii) in circles (coherent conditions), or (iii) randomly (incoherent condition), as well as for a single Gabor patch. In each condition, contrast increments were applied to either the entire test stimulus (experiment 1) or a single patch whose position was cued (experiment 2). In experiment 3, the texture stimuli were reduced to a single contour by displaying only the central vertical strip. Performance was better for the multiple-patch conditions than for the single-patch condition, but whether the multiple-patch stimulus was coherent or not had no systematic effect on the results in any of the experiments. We conclude that constrained local interactions do not interfere with a local contrast code for our suprathreshold stimuli, suggesting that, in general, this is not the way in which element linking is achieved. The possibility that interactions are involved in enhancing the detectability of contour elements at threshold remains unchallenged by our experiments.

Extrinsic factors in the perception of bistable motion stimuli

When viewing a drifting plaid stimulus, perceived motion alternates over time between coherent pattern motion and a transparent impression of the two component gratings. It is known that changing the intrinsic attributes of such patterns (e.g. speed, orientation and spatial frequency of components) can influence percept predominance. Here, we investigate the contribution of extrinsic factors to perception; specifically contextual motion and eye movements. In the first experiment, the percept most similar to the speed and direction of surround motion increased in dominance, implying a tuned integration process. This shift primarily involved an increase in dominance durations of the consistent percept. The second experiment measured eye movements under similar conditions. Saccades were not associated with perceptual transitions, though blink rate increased around the time of a switch. This indicates that saccades do not cause switches, yet saccades in a congruent direction might help to prolong a percept because i) more saccades were directionally congruent with the currently reported percept than expected by chance, and ii) when observers were asked to make deliberate eye movements along one motion axis, this increased percept reports in that direction. Overall, we find evidence that perception of bistable motion can be modulated by information from spatially adjacent regions, and changes to the retinal image caused by blinks and saccades.

Normative MEG data to flash and pattern reversal stimuli

We have attempted to establish normative values of components of the magnetic evoked field to flash and pattern reversal stimuli prior to clinical use of the MEG. Full visual field, binocular evoked magnetic fields were recorded from 100 subjects 16 to 86 years of age with a single channel dc Squid (BTI) second-order gradiometer at a point 5-6cm above the inion. The majority of subjects showed a large positive component (out going magnetic field) of mean latency 115 ms (SD range 2.5 -11.8 in different decades of life) to the pattern reversal stimulus. In many subjects, this P100M was preceeded and succeeded by negative deflections (in going field). About 6% of subjects showed an inverted response i.e. a PNP wave. Waveforms to flash were more variable in shape with several positive components; the most consistent having a mean latency of 110ms (SD range 6.4-23.2). Responses to both stimuli were consistent when measured on the same subject on six different occasions (SD range 4.8 to 7.3). The data suggest that norms can be established for evoked magnetic field components, in particular for the pattern reversal P100M, which could be used in the diagnosis of neuro-opthalmological disease.

Topography of visual evoked magnetic responses to pattern shift, pattern onset and flash stimuli

Different visual stimuli may activate separate channels in the visual system and produce magnetic responses from the human bran which originate from distinct regions of the visual cortex. To test this hypothesis, we have investigated the distribution of visual evoked magnetic responses to three distinct visual stimuli over the occipital region of the scalp with a DC-SQUID second-order gradiometer in an ubshielded environment. Patterned stimuli were presented full field and to the right half field, while a flash stimulus was presented full field only, in five normal subjects. Magnetic responses were recorded from 20 to 42 positions over the occipital scalp. Topographic maps were prepared of the major positive component within the first 150ms to the three stimuli, i.e., the P100m (pattern shift), C11m (pattern onset) and P2m (flash). For the pattern shift stimulus the data suggested the source of the P100m was close to the midline with the current directed towards the medial surface. The data for the pattern onset C11m suggested a source at a similar depth but with the current directed away from the midline towards the lateral surface. The flash P2m appeared to originate closer to the surface of the occipital pole than both the patterned stimuli. Hence the pattern shift (which may represent movement), and the pattern onset C11m (representing contrast and contour) appear to originate in similar areas of brain but to represent different asepcts of cortical processing. By contrast, the flash P2m (representing luminance change) appears to originate in a distinct area of visual cortex closer to the occipital pole.

Synchronization processes in nonlinear systems and their relation to cortical oscillatory dynamics

This thesis was focused on theoretical models of synchronization to cortical dynamics as measured by magnetoencephalography (MEG). Dynamical systems theory was used in both identifying relevant variables for brain coordination and also in devising methods for their quantification. We presented a method for studying interactions of linear and chaotic neuronal sources using MEG beamforming techniques. We showed that such sources can be accurately reconstructed in terms of their location, temporal dynamics and possible interactions. Synchronization in low-dimensional nonlinear systems was studied to explore specific correlates of functional integration and segregation. In the case of interacting dissimilar systems, relevant coordination phenomena involved generalized and phase synchronization, which were often intermittent. Spatially-extended systems were then studied. For locally-coupled dissimilar systems, as in the case of cortical columns, clustering behaviour occurred. Synchronized clusters emerged at different frequencies and their boundaries were marked through oscillation death. The macroscopic mean field revealed sharp spectral peaks at the frequencies of the clusters and broader spectral drops at their boundaries. These results question existing models of Event Related Synchronization and Desynchronization. We re-examined the concept of the steady-state evoked response following an AM stimulus. We showed that very little variability in the AM following response could be accounted by system noise. We presented a methodology for detecting local and global nonlinear interactions from MEG data in order to account for residual variability. We found crosshemispheric nonlinear interactions of ongoing cortical rhythms concurrent with the stimulus and interactions of these rhythms with the following AM responses. Finally, we hypothesized that holistic spatial stimuli would be accompanied by the emergence of clusters in primary visual cortex resulting in frequency-specific MEG oscillations. Indeed, we found different frequency distributions in induced gamma oscillations for different spatial stimuli, which was suggestive of temporal coding of these spatial stimuli. Further, we addressed the bursting character of these oscillations, which was suggestive of intermittent nonlinear dynamics. However, we did not observe the characteristic-3/2 power-law scaling in the distribution of interburst intervals. Further, this distribution was only seldom significantly different to the one obtained in surrogate data, where nonlinear structure was destroyed. In conclusion, the work presented in this thesis suggests that advances in dynamical systems theory in conjunction with developments in magnetoencephalography may facilitate a mapping between levels of description int he brain. this may potentially represent a major advancement in neuroscience.

Contrast integration over area is extensive: a three-stage model of spatial summation

Classical studies of area summation measure contrast detection thresholds as a function of grating diameter. Unfortunately, (i) this approach is compromised by retinal inhomogeneity and (ii) it potentially confounds summation of signal with summation of internal noise. The Swiss cheese stimulus of T. S. Meese and R. J. Summers (2007) and the closely related Battenberg stimulus of T. S. Meese (2010) were designed to avoid these problems by keeping target diameter constant and modulating interdigitated checks of first-order carrier contrast within the stimulus region. This approach has revealed a contrast integration process with greater potency than the classical model of spatial probability summation. Here, we used Swiss cheese stimuli to investigate the spatial limits of contrast integration over a range of carrier frequencies (1–16 c/deg) and raised plaid modulator frequencies (0.25–32 cycles/check). Subthreshold summation for interdigitated carrier pairs remained strong (~4 to 6 dB) up to 4 to 8 cycles/check. Our computational analysis of these results implied linear signal combination (following square-law transduction) over either (i) 12 carrier cycles or more or (ii) 1.27 deg or more. Our model has three stages of summation: short-range summation within linear receptive fields, medium-range integration to compute contrast energy for multiple patches of the image, and long-range pooling of the contrast integrators by probability summation. Our analysis legitimizes the inclusion of widespread integration of signal (and noise) within hierarchical image processing models. It also confirms the individual differences in the spatial extent of integration that emerge from our approach.

A comparison between static and kinetic visual attention as a means of detecting age-related deterioration of the visual system and driving performance

A critical review of previous research revealed that visual attention tests, such as the Useful Field of View (UFOV) test, provided the best means of detecting age-related changes to the visual system that could potentially increase crash risk. However, the question was raised as to whether the UFOV, which was regarded as a static visual attention test, could be improved by inclusion of kinetic targets that more closely represent the driving task. A computer program was written to provide more information about the derivation of UFOV test scores. Although this investigation succeeded in providing new information, some of the commercially protected UFOV test procedures still remain unknown. Two kinetic visual attention tests (DRTS1 and 2), developed at Aston University to investigate inclusion of kinetic targets in visual attention tests, were introduced. The UFOV was found to be more repeatable than either of the kinetic visual attention tests and learning effects or age did not influence these findings. Determinants of static and kinetic visual attention were explored. Increasing target eccentricity led to reduced performance on the UFOV and DRTS1 tests. The DRTS2 was not affected by eccentricity but this may have been due to the style of presentation of its targets. This might also have explained why only the DRTS2 showed laterality effects (i.e. better performance to targets presented on the left hand side of the road). Radial location, explored using the UFOV test, showed that subjects responded best to targets positioned to the horizontal meridian. Distraction had opposite effects on static and kinetic visual attention. While UFOV test performance declined with distraction, DRTS1 performance increased. Previous research had shown that this striking difference was to be expected. Whereas the detection of static targets is attenuated in the presence of distracting stimuli, distracting stimuli that move in a structured flow field enhances the detection of moving targets. Subjects reacted more slowly to kinetic compared to static targets, longitudinal motion compared to angular motion and to increased self-motion. However, the effects of longitudinal motion, angular motion, self-motion and even target eccentricity were caused by target edge speed variations arising because of optic flow field effects. The UFOV test was more able to detect age-related changes to the visual system than were either of the kinetic visual attention tests. The driving samples investigated were too limited to draw firm conclusions. Nevertheless, the results presented showed that neither the DRTS2 nor the UFOV tests were powerful tools for the identification of drivers prone to crashes or poor driving performance.