Behavioural performance improvement in visuomotor learning correlates with functional and microstructural brain changes.

A better understanding of practice-induced functional and structural changes in our brains can help us design more effective learning environments that provide better outcomes. Although there is growing evidence from human neuroimaging that experience-dependent brain plasticity is expressed in measurable brain changes that are correlated with behavioural performance, the relationship between behavioural performance and structural or functional brain changes, and particularly the time course of these changes, is not well characterised. To understand the link between neuroplastic changes and behavioural performance, 15 healthy participants in this study followed a systematic eye movement training programme for 30 min daily at home, 5 days a week and for 6 consecutive weeks. Behavioural performance statistics and eye tracking data were captured throughout the training period to evaluate learning outcomes. Imaging data (DTI and fMRI) were collected at baseline, after two and six weeks of continuous training, and four weeks after training ended. Participants showed significant improvements in behavioural performance (faster task completion time, lower fixation number and fixation duration). Spatially overlapping reductions in microstructural diffusivity measures (MD, AD and RD) and functional activation increases (BOLD signal) were observed in two main areas: extrastriate visual cortex (V3d) and the frontal part of the cerebellum/Fastigial Oculomotor Region (FOR), which are both involved in visual processing. An increase of functional activity was also recorded in the right frontal eye field. Behavioural, structural and functional changes were correlated. Microstructural change is a better predictor for long-term behavioural change than functional activation is, whereas the latter is superior in predicting instantaneous performance. Structural and functional measures at week 2 of the training programme also predict performance at week 6 and 10, which suggests that imaging data at an early stage of training may be useful in optimising practice environments or rehabilitative training programmes.

Catching audiovisual mice: predicting the arrival time of auditory-visual motion signals.

We investigated the extent to which auditory and visual motion signals are combined when observers are asked to predict the location of a virtually moving target. In Condition 1, the unimodal and bimodal signals were noisy, but the target object was continuously visible and audible; in Condition 2, the virtually moving object was hidden (invisible and inaudible) for a short period prior to its arrival at the target location. Our main finding was that the facilitation due to simultaneous visual and auditory input is very different for the two conditions. When the target is continuously visible and audible (Condition 1), the bimodal performance is twice as good as the unimodal performances, thus suggesting a very effective integration mechanism. On the other hand, if the object is hidden for a short period (Condition 2) and the task therefore requires the extrapolation of motion speed over a temporal and spatial period, the facilitation due to both sensory inputs is almost absent, and the bimodal performance is limited by the visual performance.

The integration of auditory and visual motion signals at threshold.

To interpret our environment, we integrate information from all our senses. For moving objects, auditory and visual motion signals are correlated and provide information about the speed and the direction of the moving object. We investigated at what level the auditory and the visual modalities interact and whether the human brain integrates only motion signals that are ecologically valid. We found that the sensitivity for identifying motion was improved when motion signals were provided in both modalities. This improvement in sensitivity can be explained by probability summation. That is, auditory and visual stimuli are combined at a decision level, after the stimuli have been processed independently in the auditory and the visual pathways. Furthermore, this integration is direction blind and is not restricted to ecologically valid motion signals.

Cross-modal integration of auditory and visual motion signals.

Real-world moving objects are usually defined by correlated information in multiple sensory modalities such as vision and hearing. The aim of our study was to assess whether simultaneous auditory supra-threshold motion introduces a bias or affects the sensitivity in a visual motion detection task. We demonstrate a bias in the perceived direction of visual motion that is consistent with the direction of the auditory motion (audio-visual motion capture). This bias effect is robust and occurs even if the auditory and visual motion signals come from different locations or move at different speeds. We also show that visual motion detection thresholds are higher for consistent auditory motion than for inconsistent motion, provided the stimuli move at the same speed and are co-localised.

Comparison of visual and ROI-based brain tumour grading using 18F-FDG PET: ROC analyses.

Several studies have suggested that the use of simple visual interpretation criteria for the investigation of brain tumours by positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) might be similarly or even more accurate than quantitative or semi-quantitative approaches. We investigated this hypothesis by comparing the accuracy of FDG-PET brain tumour grading using a proposed six-step visual grading scale (VGS; applied by three independent observers unaware of the clinical history and the results of histopathology) and three different region of interest (ROI) ratios (maximal tumour uptake compared with contralateral tissue [Tu/Tis], grey matter [Tu/GM] and white matter [Tu/WM]). The patient population comprised 47 patients suffering from 17 benign (7 gliomas of grade II, 10 non-gliomatous tumours) and 30 malignant (23 gliomas of grade III-IV, 7 non-gliomatous tumours) tumours. The VGS results were highly correlated with the different ROI ratios (R=0.91 for Tu/GM, R=0.82 for Tu/WM, and R=0.79 for Tu/Tis), and high inter-observer agreement was achieved (kappa=0.63, 0.76 and 0.81 for the three observers). The mean ROI ratios and VGS readings of gliomatous and non-gliomatous lesions were not significantly different. For all measures, high-grade lesions showed significantly higher FDG uptake than low-grade lesions (P<0.005 to P<0.0001, depending on the measure used). Nominal logistic regressions and receiver operating characteristic (ROC) analyses were used to calculate cut-off values to differentiate low- from high-grade lesions. The predicted (by ROC) diagnostic sensitivity/specificity of the different tests (cut-off ratios shown in parentheses) were: Tu/GM: 0.87/0.85 (0.7), Tu/WM: 0.93/0.80 (1.3). Tu/Tis: 0.80/0.80 (0.8) and VGS: 0.84/0.95 (uptake < GM, but >> WM). The VGS yielded the highest Az (+/-SE) value (i.e. area under the ROC curve as a measure of predicted accuracy), 0.97+/-0.03, which showed a strong tendency towards being significantly greater than the Az of Tu/Tis (0.88+/-0.06; P=0.06). Tu/GM (0.92+/-0.04) and Tu/WM (0.91+/-0.05) reached intermediate Az values (not significantly different from any other value). We conclude that the VGS represents a measure at least as accurate as the Tu/GM and Tu/WM ratios. The Tu/Tis ratio is less valid owing to the high dependence on the location of the lesion. Depending on the investigator's experience and the structure of the lesions, the easily used VGS might be the most favourable grading criterion.

History and regulatory issues of generic drugs.

In the November 1987 edition of the Journal of the Society of Clinical Pharmacology and Therapeutics, Dr Richard Weinshilboum of the Department of Pharmacology at the Mayo Clinic made the following observation: "The past half century has been a golden age for pharmacologic therapy. Fifty years ago there were no antibiotics: there were no antihypertensives; there were no antineoplastics; there were no antipsychotics; there were no antidepressants; and the list could go on and on. With the exception of a few effective drugs, the pharmacopeia of that time was filled with placebos. Our generation has witnessed the transformation of medicine. A transformation due in part to the development of drugs capable of controlling or curing diseases that have plagued mankind throughout human history." There is plenty of room for both the innovator and generic manufacturer in this market, but both sides need protection. The regulations adopted by the FDA for providing a safe and effective route to drug approvals will foster both sides while maintaining its primary purpose, assurance to the public that the products they consume have been adequately studied and appropriately applied.

Vowel-onset detection by vowel-strength measurement, cochlear-nucleus simulation, and multilayer perceptrons.

An algorithm for detection of vowel onsets in fluent speech was presented by Hermes [j. Acoust. Soc. Am. 87, 866-873 (1990)]. Performance tests showed that detection was good for fluent speech, although the parameter settings had to be modified for application to well-articulated speech. One of the purposes of the algorithm was application to speech by deaf persons, for which it failed completely. In order to improve the algorithm and to make it more generally applicable, two alternative detection strategies have been explored in the present study. These strategies were (a) simulation of transient-chopper responses in the cochlear nucleus and (B) training of multilayer perceptrons. Two large databases of read speech have been used for performance comparison of the original algorithm and the new strategies. The strategy based on simulating cochlear-nucleus responses is found both to result in a higher false-alarm rate than the original algorithm and to be rather level dependent. On the other hand, the performance of a multilayer-perceptron network, trained on mel-scaled spectra, is comparable to the performance of the Hermes algorithm. In more general terms, the results suggest that temporal information on intensity and (rough) spectral envelope are important for human vowel-onset detection behavior. In formation on harmonicity can be used as a secondary source of information to avoid detection of mainly unvoiced, nonvowel onsets.

Recognition of plosive syllables in noise: comparison of an auditory model with human performance.

Some of the effects of noise on the perception of plosive-vowel syllables have been investigated. It was found that noise added to the syllables for the duration of the speech had a more deleterious effect on perception than noise of the same intensity played continuously. Physiological experiments have shown that the response thresholds of cochlear nerve fibers to tones are raised by continuous background noise but not by short bursts of noise. It is suggested that this may be responsible for the speech perception results. In order to investigate this, an auditory model was developed which incorporated response threshold shifts. This was interfaced to a hidden Markov model recognizer and tested with the same sounds that were employed in the human perception experiments. The recognition scores were greater with the threshold shifts than without them.

Localization of phosphoserine residues in the alpha subunit of rabbit skeletal muscle phosphorylase kinase.

The alpha subunit of skeletal muscle phosphorylase kinase, as isolated, carries phosphate at the serine residues 1018, 1020 and 1023. Employing the S-ethyl-cysteine method, these residues are found to be phosphorylated partially, i.e. differently phosphorylated species exist in muscle. Serine 1018 is a site which can be phosphorylated by the cyclic-AMP-dependent protein kinase. The serine residues 972, 985 and 1007 are phosphorylated by phosphorylase kinase itself when its activity is stimulated by micromolar concentrations of Ca2+. These phosphorylation sites are not identical to those found to be phosphorylated already in the enzyme as prepared from freshly excised muscle. A 'multiphosphorylation loop' uniquely present in this but not in the homologous beta subunit contains all the phosphoserine residues so far identified in the alpha subunit.

The formation of polytene chromosomes during macronuclear development of the hypotrichous ciliate Stylonychia mytilus.

The formation of polytene chromosomes during macronuclear development of the ciliate Stylonychia mytilus was examined in spread electron microscopical preparations. The chromatin organization of early macronuclear anlagen closely resembles the organization of micronuclear chromatin. In the course of polytenization 300 A chromatin fibers become organized in loop-like structures laterally attached to a thinner axial fiber. It is suggested that this reorganization of chromatin during polytenization is a necessary event for the subsequent chromatin elimination.

Chromatin elimination in the hypotrichous ciliate Stylonychia mytilus.

Chromatin elimination in the hypotrichous ciliate Stylonychia mytilus was studied by means of electron microscopy using a microspreading procedure. In the polytene chromosomes of the macronuclear anlagen three organization patterns are observed: Bands of various size composed of 300 A chromatin fibers, large blocks of 300 A nucleofilaments which probably represent the "heterochromatic" regions of the chromosome and axial 120 A filaments. Those DNA sequences which become eliminated belong to the 300 A fiber type. The eliminated chromatin occurs in the form of rings of variable size corresponding to a DNA content between 18 and 160 Kb while the axial 120 A filaments appear to be preserved.

Chromatin rings as products of chromatin diminution in Cyclops.

Nuclei from the interphase preceding the 6th cleavage (=first diminution) division of Cyclops furcifer were subjected to a micro-spreading technique (Counce and Meyer, 1973) and examined by electron microscopy. In some preparations numerous chromatin rings formed by 250--300 A fibers were discovered in sizes ranging from 0.25 micrometers to more than 6 micrometers. These structures are assumed to represent the primary products of chromatin diminution.

Native and reconstituted chromosome fiber fragments.

The structure of hen erythrocyte chromatin fibers was studied with the electron microscope. Chromatin fiber fragments with a length of about 5,000 A and an average diameter of 320 A are composed of 13 globular subunits (superbeads) which contain different numbers of nucleosomes. Their number average corresponds to 17 nucleosomes. - The interaction of lysine-rich histones with nucleosome chains was investigated by reconstitution experiments and was found to be semi-cooperative.

Characterisation of male meiotic-sterile mutations in drosophila melanogaster. The genetic control of meiotic divisions and gametogenesis.

Male meiotic sterile mutations were selected among X-linked male-steriles by detection of micronuclei in early spermatids. Despite severe defects in the 1st or 2nd meiotic spindles in all mutants, no effect on mitosis was observed. Various features of spindle structure, chromosome segregation, and centriole movements were compared in seven meitoic steriles and in XO males. Chromosome behaviour and centriole movement were always affected concomitantly, and were both shown to be genetically independent of "centre" formation in the meiotic spindles. Precocious and delayed centromere separation was observed in the various mutants in both divisions, and similarly attributed to basic spindle lesions rather than chromosome defects. Attachment of the centriole body to the membrane of the spermatid nucleus was normal only in mutants where second division nuclei were formed. The role of the centriole body was shown to be independent of membrane attachment.--The phenomena observed in this study were discussed mainly with regard to genetic interdependence of morphogenetic processes during male meiosis. A common base for the pleiotropic defects of meiotic steriles and XO males is suggested, and the genetic control of meiosis is re-evaluated in the light of comparison with fertile meiotic mutants.