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

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

Centaur 1952

Digitised by the Faculty of the Veterinary Scienc

Exploring fatigue in cancer patients. From diagnosis until one year after cancer treatment

Contains fulltext : 89943.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 4 juli 2011Promotores : Bleijenberg, G., Graaf, W.T.A. van der Co-promotores : Verhagen, C.A.H.H.V.M., Gielissen, M.F.M.255 p

Psychosocial interventions for reducing fatigue during cancer treatment in adults.

BACKGROUND: Fatigue is a common symptom in cancer patients receiving active treatment. There are a limited number of reviews evaluating interventions for fatigue during active treatment, and they are restricted to patients with advanced cancer, or to patients during radiotherapy. To date there is no systematic review on psychosocial interventions for fatigue during cancer treatment. OBJECTIVES: To evaluate if psychosocial interventions are effective in reducing fatigue in cancer patients receiving active treatment for cancer, and which types of psychosocial interventions are the most effective. SEARCH STRATEGY: In September 2008 we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), PUBMED, MEDLINE, EMBASE, CINAHL and PsycINFO, and checked the reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) were included which evaluated psychosocial interventions in adult cancer patients during treatment, with fatigue as an outcome measure. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data from the selected studies, and assessed the methodological quality using several quality rating scales and additional criteria. MAIN RESULTS: Twenty-seven studies met the inclusion criteria with a total of 3324 participants, and seven studies reported significant effects of the psychosocial intervention on fatigue. In three studies the effect was maintained at follow-up. The quality of the studies was generally moderate. Effect sizes varied between 0.17 to 1.07.The effectiveness of interventions specific for fatigue was significantly higher (80%) compared to interventions not specific for fatigue (14%). In five studies the interventions were specifically focused on fatigue, with four being effective. The five interventions were brief, consisting of three individual sessions, provided by (oncology) nurses. In general, during these interventions participants were educated about fatigue, were taught in self-care or coping techniques, and learned activity management.Of the remaining 22 studies only three were effective in reducing fatigue, and these interventions had a more general approach. These interventions were aimed at psychological distress, mood and physical symptoms, and varied strongly in duration and content. AUTHORS' CONCLUSIONS: There is limited evidence that psychosocial interventions during cancer treatment are effective in reducing fatigue. At present, psychosocial interventions specifically for fatigue are a promising type of intervention. However, there is no solid evidence for the effectiveness of interventions not specific for fatigue. Most aspects of the included studies were heterogeneous, and therefore it could not be established which other types of interventions, or elements were essential in reducing fatigue

Severe fatigue and related factors in cancer patients before the initiation of treatment.

Contains fulltext : 71054.pdf (publisher's version ) (Closed access

Fatigue and its associated psychosocial factors in cancer patients on active palliative treatment measured over time

PURPOSE: Fatigue is a frequently reported symptom by patients with advanced cancer, but hardly any prospective information is available about fatigue while on treatment in the palliative setting. In a previous cross-sectional study, we found several factors contributing to fatigue in these patients. In this study, we investigated the course of fatigue over time and if psychosocial factors were associated with fatigue over time. METHODS: Patients on cancer treatment for incurable solid tumors were observed over 6 months. Patients filled in the Checklist Individual Strength monthly to measure the course of fatigue. Baseline questionnaires were used to measure disease acceptance, anxiety, depressive mood, fatigue catastrophizing, sleeping problems, discrepancies in social support, and self-reported physical activity for their relation with fatigue over time. RESULTS: At baseline 137 patients and after 6 months 89 patients participated. The mean duration of participation was 4.9 months. At most time points, fatigue scores were significantly higher in the group dropouts in comparison with the group participating 6 months (completers). Overall fatigue levels remained stable over time for the majority of participants. In the completers, 42 % never experienced severe fatigue, 29 % persisted being severely fatigued, and others had either an increasing or decreasing level. Of the investigated factors, low reported physical activity and non-acceptance of cancer were associated significantly to fatigue. CONCLUSION: A substantial number of participants never experienced severe fatigue and fatigue levels remained stable over time. For those who do experience severe fatigue, non-acceptance of having incurable cancer and low self-reported physical activity may be fatigue-perpetuating factors

Chronic fatigue in type 1 diabetes: highly prevalent but not explained by hyperglycemia or glucose variability

Item does not contain fulltextOBJECTIVE Fatigue is a classical symptom of hyperglycemia, but the relationship between chronic fatigue and diabetes has not been systematically studied. We investigated prevalence, impact, and potential determinants of chronic fatigue in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS Out of 324 randomly selected T1DM outpatients, 214 participated in this cross-sectional observational study. Participants were compared with age- and sex-matched population-based controls. Chronic fatigue, functional impairments, current health status, comorbidity, diabetes-related factors, and fatigue-related cognitions and behaviors were assessed with questionnaires, and HbA1c values and comorbidity were assessed with medical records. Sixty-six patients underwent continuous glucose monitoring combined with an electronic fatigue diary for 5 days. Acute fatigue and four glucose parameters were determined: mean, variability, and relative time spent in hypoglycemia and hyperglycemia. RESULTS T1DM patients were significantly more often chronically fatigued (40%; 95% CI 34-47%) compared with matched controls (7%; 95% CI 3-10%; P < 0.001). Chronically fatigued patients had significantly more functional impairments. Fatigue was the most troublesome symptom. Age, depression, pain, sleeping problems, low self-efficacy concerning fatigue, and physical inactivity were significantly associated with chronic fatigue. Chronically fatigued patients spent slightly less time in hypoglycemia (proportion 0.07 +/- 0.06 vs. 0.12 +/- 0.10; P = 0.025). Glucose parameters were not related to acute fatigue. CONCLUSIONS Chronic fatigue is highly prevalent and clinically relevant in T1DM. Its significant relationship with cognitive behavioral variables and weak association with blood glucose levels suggests that behavioral interventions could be helpful in managing chronic fatigue in T1DM

Does neuropsychological test performance predict outcome of cognitive behavior therapy for Chronic Fatigue Syndrome and what is the role of underperformance?

Item does not contain fulltextOBJECTIVE: A subgroup of patients with Chronic Fatigue Syndrome (CFS) has cognitive impairments, reflected by deviant neuropsychological test performance. However, abnormal test scores can also be caused by suboptimal effort. We hypothesized that worse neuropsychological test performance and underperformance were related to each other and to a smaller reduction in fatigue, functional impairments, physical limitations and higher dropout rates following cognitive behavior therapy (CBT) for CFS. METHODS: Data were drawn from a previous trial, in which CFS patients were randomized to two conditions; 1) guided self-instruction and additional CBT (n=84) or 2) waiting period followed by regular CBT for CFS (n=85). Underperformance was assessed using the Amsterdam Short Term Memory Test (<84). To test neuropsychological test performance, the Symbol Digit Modalities Task, a simple reaction time task and a choice reaction time task were used. Interaction effects were determined between underperformance and neuropsychological test performance on therapy outcomes. RESULTS: Underperformance was associated to worse neuropsychological test performance, but there were no significant interaction effects of these two factors by therapy on fatigue severity, functional impairments and physical limitations, but there was a significant main effect of underperformance on functional impairments, physical limitations and dropout rates. CONCLUSION: Underperformance or neuropsychological test performance was not related to the change in fatigue, functional impairments, and physical limitations following CBT for CFS. However, underperforming patients did drop out more often. Therapists should pay attention to beliefs and behavioral or environmental factors that might maintain underperformance and increase the risk of dropout