Enhancing BOLD response in the auditory system by neurophysiologically tuned fMRI sequence

Auditory neuroscience has not tapped fMRI's full potential because of acoustic scanner noise emitted by the gradient switches of conventional echoplanar fMRI sequences. The scanner noise is pulsed, and auditory cortex is particularly sensitive to pulsed sounds. Current fMRI approaches to avoid stimulus-noise interactions are temporally inefficient. Since the sustained BOLD response to pulsed sounds decreases with repetition rate and becomes minimal with unpulsed sounds, we developed an fMRI sequence emitting continuous rather than pulsed gradient sound by implementing a novel quasi-continuous gradient switch pattern. Compared to conventional fMRI, continuous-sound fMRI reduced auditory cortex BOLD baseline and increased BOLD amplitude with graded sound stimuli, short sound events, and sounds as complex as orchestra music with preserved temporal resolution. Response in subcortical auditory nuclei was enhanced, but not the response to light in visual cortex. Finally, tonotopic mapping using continuous-sound fMRI demonstrates that enhanced functional signal-to-noise in BOLD response translates into improved spatial separability of specific sound representations.

Practical Object-Oriented Back-in-Time Debugging

Back-in-time debuggers are extremely useful tools for identifying the causes of bugs, as they allow us to inspect the past states of objects no longer present in the current execution stack. Unfortunately the "omniscient" approaches that try to remember all previous states are impractical because they either consume too much space or they are far too slow. Several approaches rely on heuristics to limit these penalties, but they ultimately end up throwing out too much relevant information. In this paper we propose a practical approach to back-in-time debugging that attempts to keep track of only the relevant past data. In contrast to other approaches, we keep object history information together with the regular objects in the application memory. Although seemingly counter-intuitive, this approach has the effect that past data that is not reachable from current application objects (and hence, no longer relevant) is automatically garbage collected. In this paper we describe the technical details of our approach, and we present benchmarks that demonstrate that memory consumption stays within practical bounds. Furthermore since our approach works at the virtual machine level, the performance penalty is significantly better than with other approaches.

Flow-Centric, Back-In-Time Debugging

Conventional debugging tools present developers with means to explore the run-time context in which an error has occurred. In many cases this is enough to help the developer discover the faulty source code and correct it. However, rather often errors occur due to code that has executed in the past, leaving certain objects in an inconsistent state. The actual run-time error only occurs when these inconsistent objects are used later in the program. So-called back-in-time debuggers help developers step back through earlier states of the program and explore execution contexts not available to conventional debuggers. Nevertheless, even back-in-time debuggers do not help answer the question, ``Where did this object come from?'' The Object-Flow Virtual Machine, which we have proposed in previous work, tracks the flow of objects to answer precisely such questions, but this VM does not provide dedicated debugging support to explore faulty programs. In this paper we present a novel debugger, called Compass, to navigate between conventional run-time stack-oriented control flow views and object flows. Compass enables a developer to effectively navigate from an object contributing to an error back-in-time through all the code that has touched the object. We present the design and implementation of Compass, and we demonstrate how flow-centric, back-in-time debugging can be used to effectively locate the source of hard-to-find bugs.

Differences in Time to Disease Progression Do Not Predict for Cancer-specific Survival in Patients Receiving Immediate or Deferred Androgen-deprivation Therapy for Prostate Cancer: Final Results of EORTC Randomized Trial 30891 with 12 Years of Follow-up

BACKGROUND Trials assessing the benefit of immediate androgen-deprivation therapy (ADT) for treating prostate cancer (PCa) have often done so based on differences in detectable prostate-specific antigen (PSA) relapse or metastatic disease rates at a specific time after randomization. OBJECTIVE Based on the long-term results of European Organization for Research and Treatment of Cancer (EORTC) trial 30891, we questioned if differences in time to progression predict for survival differences. DESIGN, SETTING, AND PARTICIPANTS EORTC trial 30891 compared immediate ADT (n=492) with orchiectomy or luteinizing hormone-releasing hormone analog with deferred ADT (n=493) initiated upon symptomatic disease progression or life-threatening complications in randomly assigned T0-4 N0-2 M0 PCa patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Time to first objective progression (documented metastases, ureteric obstruction, not PSA rise) and time to objective castration-resistant progressive disease were compared as well as PCa mortality and overall survival. RESULTS AND LIMITATIONS After a median of 12.8 yr, 769 of the 985 patients had died (78%), 269 of PCa (27%). For patients receiving deferred ADT, the overall treatment time was 31% of that for patients on immediate ADT. Deferred ADT was significantly worse than immediate ADT for time to first objective disease progression (p<0.0001; 10-yr progression rates 42% vs 30%). However, time to objective castration-resistant disease after deferred ADT did not differ significantly (p=0.42) from that after immediate ADT. In addition, PCa mortality did not differ significantly, except in patients with aggressive PCa resulting in death within 3-5 yr after diagnosis. Deferred ADT was inferior to immediate ADT in terms of overall survival (hazard ratio: 1.21; 95% confidence interval, 1.05-1.39; p [noninferiority]=0.72, p [difference] = 0.0085). CONCLUSIONS This study shows that if hormonal manipulation is used at different times during the disease course, differences in time to first disease progression cannot predict differences in disease-specific survival. A deferred ADT policy may substantially reduce the time on treatment, but it is not suitable for patients with rapidly progressing disease.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units. © RSNA, 2014 Online supplemental material is available for this article.