Spatial Hearing with Simultaneous Sound Sources: A Psychophysical Investigation

This thesis provides an overview of work conducted to investigate human spatial hearing in situations involving multiple concurrent sound sources. Much is known about spatial hearing with single sound sources, including the acoustic cues to source location and the accuracy of localisation under different conditions. However, more recently interest has grown in the behaviour of listeners in more complex environments. Concurrent sound sources pose a particularly difficult problem for the auditory system, as their identities and locations must be extracted from a common set of sensory receptors and shared computational machinery. It is clear that humans have a rich perception of their auditory world, but just how concurrent sounds are processed, and how accurately, are issues that are poorly understood. This work attempts to fill a gap in our understanding by systematically examining spatial resolution with multiple sound sources. A series of psychophysical experiments was conducted on listeners with normal hearing to measure performance in spatial localisation and discrimination tasks involving more than one source. The general approach was to present sources that overlapped in both frequency and time in order to observe performance in the most challenging of situations. Furthermore, the role of two primary sets of location cues in concurrent source listening was probed by examining performance in different spatial dimensions. The binaural cues arise due to the separation of the two ears, and provide information about the lateral position of sound sources. The spectral cues result from location-dependent filtering by the head and pinnae, and allow vertical and front-rear auditory discrimination. Two sets of experiments are described that employed relatively simple broadband noise stimuli. In the first of these, two-point discrimination thresholds were measured using simultaneous noise bursts. It was found that the pair could be resolved only if a binaural difference was present; spectral cues did not appear to be sufficient. In the second set of experiments, the two stimuli were made distinguishable on the basis of their temporal envelopes, and the localisation of a designated target source was directly examined. Remarkably robust localisation was observed, despite the simultaneous masker, and both binaural and spectral cues appeared to be of use in this case. Small but persistent errors were observed, which in the lateral dimension represented a systematic shift away from the location of the masker. The errors can be explained by interference in the processing of the different location cues. Overall these experiments demonstrated that the spatial perception of concurrent sound sources is highly dependent on stimulus characteristics and configurations. This suggests that the underlying spatial representations are limited by the accuracy with which acoustic spatial cues can be extracted from a mixed signal. Three sets of experiments are then described that examined spatial performance with speech, a complex natural sound. The first measured how well speech is localised in isolation. This work demonstrated that speech contains high-frequency energy that is essential for accurate three-dimensional localisation. In the second set of experiments, spatial resolution for concurrent monosyllabic words was examined using similar approaches to those used for the concurrent noise experiments. It was found that resolution for concurrent speech stimuli was similar to resolution for concurrent noise stimuli. Importantly, listeners were limited in their ability to concurrently process the location-dependent spectral cues associated with two brief speech sources. In the final set of experiments, the role of spatial hearing was examined in a more relevant setting containing concurrent streams of sentence speech. It has long been known that binaural differences can aid segregation and enhance selective attention in such situations. The results presented here confirmed this finding and extended it to show that the spectral cues associated with different locations can also contribute. As a whole, this work provides an in-depth examination of spatial performance in concurrent source situations and delineates some of the limitations of this process. In general, spatial accuracy with concurrent sources is poorer than with single sound sources, as both binaural and spectral cues are subject to interference. Nonetheless, binaural cues are quite robust for representing concurrent source locations, and spectral cues can enhance spatial listening in many situations. The findings also highlight the intricate relationship that exists between spatial hearing, auditory object processing, and the allocation of attention in complex environments

The chronic fatigue syndrome and hyperventilation

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Centaur 1952

Digitised by the Faculty of the Veterinary Scienc

Protein Design Based on a PHD Scaffold

The plant homeodomain (PHD) is a protein domain of ~45�100 residues characterised by a Cys4-His-Cys3 zinc-binding motif. When we commenced our study of the PHD in 2000, it was clear that the domain was commonly found in proteins involved in transcription. Sequence alignments indicate that while the cysteines, histidine and a few other key residues are strictly conserved, the rest of the domain varies greatly in terms of both amino acid composition and length. However, no structural information was available on the PHD and little was known about its function. We were therefore interested in determining the structure of a PHD in the hope that this might shed some light on its function and molecular mechanism of action. Our work began with the structure determination of a representative PHD, Mi2b-P2, and this work is presented in Chapter 3. Through comparison of this structure with the two other PHD structures that were determined during the course of our work, it became clear that PHDs adopt a well-defined globular fold with a superimposable core region. In addition, PHDs contain two loop regions (termed L1 and L3) that display increased flexibility and overlay less well between the three PHD structures available. These L1 and L3 regions correspond to variable regions identified earlier in PHD sequence alignments, indicating that L1 and L3 are probably not crucial for the PHD fold, but are instead likely to be responsible for imparting function(s) to the PHD. Indeed, numerous recent functional studies of PHDs from different proteins have since demonstrated their ability in binding a range of other proteins. In order to ascertain whether or not L1 and L3 were in fact dispensable for folding, we made extensive mutations (including both insertions and substitutions) in the loop regions of Mi2b-P2 and showed that the structure was maintained. We then went on to illustrate that a new function could be imparted to Mi2b-P2 by inserting a five-residue CtBP-binding motif into the L1 region and showed this chimera could fold and bind CtBP. Having established that the PHD could adopt a new binding function, we next sought to use combinatorial methods to introduce other novel functions into the PHD scaffold. Phage display was selected for this purpose, because it is a well-established technique and has been used successfully to engineer zinc-binding domains by other researchers. However, in order to establish this technique in our laboratory, we first chose a control system in which two partner proteins were already known to interact in vitro. We chose the protein complex formed between the transcriptional regulators LMO2 and ldb1 as a test case. We have examined this interaction in detail in our laboratory, and determined its three-dimensional structure. Furthermore, inappropriate formation of this complex is implicated in the onset of T-cell acute lymphoblastic leukemia. We therefore sought to use phage display to engineer ldb1 mimics that could potentially compete against wild-type ldb1 for LMO2, and this work is described in Chapter 4. Using a phage library containing ~3 x 10 7 variants of the LMO2-binding region of ldb1, we isolated mutants that were able to interact with LMO2 with higher affinity and specificity than wild-type ldb1. These ldb1 mutants represent a first step towards finding potential therapeutics for treating LMO-associated diseases. Having established phage display in our laboratory, we went on to search for PHD mutants that could bind selected target proteins. This work is described in Chapter 5. We created three PHD libraries with eight randomized residues in each of L1, L3 or in both loops of the PHD. These PHD libraries were then screened against four target proteins. After four rounds of selection, we were able to isolate a PHD mutant (dubbed L13-FH6) that could bind our test protein Fli-ets. This result demonstrates that a novel function can be imparted to the PHD using combinatorial methods and opens the way for further work in applying the PHD scaffold to other protein design work. In summary, the work detailed in Chapters 3 and 5 demonstrates that the PHD possesses many of the properties that are desirable for a protein scaffold for molecular recognition, including small size, stability, and a well-characterised structure. Moreover, the PHD motif possesses two loops (L1 and L3) of substantial size that can be remodeled for target binding. This may lead to an enhancement of binding affinities and specificities over other small scaffolds that have only one variable loop. In light of the fact that PHDs are mainly found in nuclear proteins, it is reasonable to expect that engineered PHDs could be expressed and function in an intracellular environment, unlike many other scaffolds that can only function in an oxidizing environment. Therefore, our results together with other currently available genomic and functional information indicate PHD is an excellent candidate for a scaffold that could be used to modify cellular processes. Appendices 1 and 2 describe completed bodies of work on unrelated projects that I have carried out during the course of my PhD candidature. The first comprises the invention and application of DNA sequences that contain all N-base sequences in the minimum possible length. This work is presented as a reprint of our recently published paper in Nucleic Acids Research. The second Appendix describes our structural analysis of an antifreeze protein from the shorthorn sculpin, a fish that lives in the Arctic and Antarctic oceans. This work is presented as a manuscript that is currently under review at the Journal of the American Chemical Society

Cognitive behaviour therapy for fatigued cancer survivors: long-term follow-up

An earlier randomised-controlled trial demonstrated the positive effects of cognitive behaviour therapy (CBT), especially designed for fatigued cancer survivors in reducing fatigue, functional impairments and psychological distress. In the current prospective study, we were able to examine the long-term effect of CBT in patients who completed the therapy. Predictors of fatigue severity at follow-up were exploratory investigated. Sixty-eight patients who completed CBT were assessed at pretreatment, post-treatment and at follow-up (mean follow-up 1.9 years (s.d. 1.0), range: 1–4 years). To analyse possible predictors of treatment outcome a linear regression (enter) was carried out. Improvements on fatigue severity, functional impairment and psychological distress after CBT appeared to remain stable during a follow-up period. Patients who were not fatigued anymore at follow-up were not different from a reference group of non-fatigued cancer survivors. The explorative regression analysis showed that fatigue severity, psychological distress and somatic attributions at pretreatment contributed to persistent fatigue severity at follow-up. Cognitive behaviour therapy, especially designed for post-cancer fatigue, is successful in reducing fatigue and functional impairment in cancer survivors. Moreover, these positive effects were maintained at about 2 years after finishing CBT

Dimensional assessment of chronic fatigue syndrome

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Tryptophan depletion in chronic fatigue syndrome, a pilot cross-over study

Background: Chronic fatigue syndrome (CFS) is still an enigmatic disorder. CFS can be regarded as a complex disorder with tremendous impact on lives of CFS-patients. Full recovery without treatment is rare. A somatic explanation for the fatigue is lacking. There is clinical and experimental evidence implicating enhanced serotonergic neurotransmission in CFS. Genetic studies and imaging studies support the hypothesis of upregulated serotonin system in CFS. In line with the hypothesis of an increased serotonergic state in CFS, we performed a randomised clinical trial investigated the effect of 5-HT3 receptor antagonism in CFS. No benefit was found of the 5-HT3 receptor antagonist ondansetron compared to placebo. To further investigate the involvement of serotonin in CFS we performed a placebo controlled cross over pilot study investigating the effect of Acute Tryptophan Depletion. Findings: Five female CFS-patients who met the US Center for Disease Control and Prevention criteria for CFS were recruited. There were two test days, one week apart. Each participant received placebo and ATD. To evaluate the efficacy of the ATD procedure tryptophan and the large neutral amino acids were measured. The outcome measures were fatigue severity, concentration and mood states. ATD resulted in a significant plasma tryptophan to large neutral amino acid ratio reduction of 96%. There were no significant differences in fatigue-, depression and concentration between the placebo- and ATD condition. Conclusions: These first five CFS-patients did not respond to the ATD procedure. However, a much larger sample size is needed to draw final conclusions on the hypothesis of an increased serotonergic state in the pathophysiology of CFS. Trial registration: ISRCTN0751814

The measurement of fatigue in patients with multiple sclerosis. A multidimensional comparison with patients with chronic fatigue syndrome and healthy subjects

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