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Specific symptomatic changes following donepezil treatment of Alzheimer's disease: a multi-centre, primary care, open-label study.

BACKGROUND: Standard measurement scales used in anti-dementia trials may not capture symptomatic changes recognized by clinicians and caregivers. We studied a symptom checklist, completed separately by caregivers and by clinicians, to identify patterns of change associated with donepezil treatment. METHODS: In a multi-centre, 6-month, open-label study of 101 primary care patients, changes in a 19-symptom checklist were assessed in relation to changes in standardized scales of cognition, activities of daily living, behavior, and caregiver burden. RESULTS: Three symptoms were reported in more than 80% of patients by both clinicians and caregivers: problems in remembering, (97%), temporal orientation (89%), and repetitiveness (85%). Five others overlapped on each of the clinician and caregiver 'top ten', including cognitive activation, spatial orientation, leisure, attention, and apathy. Clinicians reported that symptoms did not improve in 38 patients, whereas there was some improvement in 43, and improvement in most symptoms in 20. Caregivers reported that symptoms did not improve in 55 patients, whereas 27 and 19 patients showed some and most symptoms improving respectively. Patients with the greatest symptomatic improvement also improved most on the ADAS-Cog and the other standardized measures, whereas no improvement (or decline) in each standardized measure was observed in people whose symptoms worsened or did not improve. CONCLUSION: A symptom checklist allowed clinically meaningful profiles to be identified, but revealed different estimates of response between clinicians and caregivers. Both agreed that improved executive function was the most common response. A symptom checklist can help translate between standard measures and everyday practice.

Activities of Daily Living↗

Role of the inertial eigenvectors in proprioception near the limits of arm adduction range of motion.

Common everyday activities such as reaching for a cup, combing one's hair, or positioning a tool involve the accurate registration of the limb's orientation relative to the body and the environment. Past work has demonstrated that the ability of humans to perceive the spatial orientation of an occluded arm is tied to the arm's inertial eigenvectors, invariant mechanical parameters corresponding to a limb's axes of rotational symmetry. In a recent study participants pointed to visible targets while the arms' inertial eigenvectors were displaced by asymmetrically weighted splints. The lack of an effect of those splints on pointing error led them to conclude that inertial eigenvectors are not the primary invariants used for proprioception. However, their data suggested an effect of the eigenvectors, but only for conditions in which pointing did not require placing the arm near the limits of shoulder adduction range of motion. In the present study we found a significant effect of displacing the eigenvector for all tested arm angles, regardless of degree of shoulder adduction. Overall, the results supported the hypothesis that proprioception is based on sensitivity to the limb's inertial eigenvectors, with no reduction of the eigenvector effect when adducting the arm so as to reach far across the body midline.

Adolescent↗

The dynamics of spatial behavior: how can robust smoothing techniques help?

A variety of setups and paradigms are used in the neurosciences for automatically tracking the location of an animal in an experiment and for extracting features of interest out of it. Many of these features, however, are critically sensitive to the unavoidable noise and artifacts of tracking. Here, we examine the relevant properties of several smoothing methods and suggest a combination of methods for retrieving locations and velocities and recognizing arrests from time series of coordinates of an animal's center of gravity. We accomplish these by using robust nonparametric methods, such as Running Median (RM) and locally weighted regression methods. The smoothed data may, subsequently, be segmented to obtain discrete behavioral units with proven ethological relevance. New parameters such as the length, duration, maximal speed, and acceleration of these units provide a wealth of measures for, e.g., mouse behavioral phenotyping, studies on spatial orientation in vertebrates and invertebrates, and studies on rodent hippocampal function. This methodology may have implications for many tests of spatial behavior.

Algorithms↗

Contrast discrimination with sinusoidal gratings of different spatial frequency.

The detectability of contrast increments was measured as a function of the contrast of a masking or "pedestal" grating at a number of different spatial frequencies ranging from 2 to 16 cycles per degree of visual angle. The pedestal grating always had the same orientation, spatial frequency, and phase as the signal. The shape of the contrast-increment threshold versus pedestal contrast (TvC) functions depends on the performance level used to define the "threshold," but when both axes are normalized by the contrast corresponding to 75% correct detection at each frequency, the TvC functions at a given performance level are identical. Confidence intervals on the slope of the rising part of the TvC functions are so wide that it is not possible with our data to reject Weber's law.

Contrast Sensitivity↗

Complex podokinetic (PK) response to post-rotational vestibular stimulation.

Recent studies identified an adaptive "Podokinetic" (PK) sensory motor system involved in sensing and controlling spatial orientation during locomotion, by referencing body orientation to the space-stable stance foot. This paper investigates the interaction of vestibular and PK systems by asking blindfolded subjects to 'step-in-place' (i.e. without turning) after exposing them to a unidirectional post-rotational vestibular stimulus. Six of the nine subjects consistently began by vigorously propelling themselves round in the direction of preceding turntable rotation, but notably without any sensation of turning. In all these subjects the speed of this PK-induced rotation progressively declined to zero over about the next 30 sec and then reversed direction with increasing speed for about 50 sec. Thereafter the speed of rotation declined slowly to zero over the next 4 to 5 minutes. Since the PK-generated body rotation presumably feeds back into the vestibular-PK drive, we formulated a closed loop model of the combined system to investigate the complex nature of the behavioral response. The simulated response of this model closely resembled the experimental data, suggesting that there is indeed a functionally closed loop operating between the vestibular and podokinetic systems in natural life.

Adult↗

Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment.

Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease (AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse model of AD. We also assessed brain content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Performance was alike in wild-type and APP23 animals in the radial maze. In contrast, performance in the complex maze was better in wild-type than APP23 animals. Contrary to the wild-type, hippocampal BDNF levels decreased on training in APP23 animals. Hippocampal and frontal cortex NGF levels in APP23 animals correlated with the time to solve the complex maze, but correlated inversely with escape time in wild-type animals. NT-3 levels were alike in wild-type and APP23 animals and were unchanged even after training. Both types of mazes depend on hippocampal integrity to some extent. However, according to the cognitive mapping theory of spatial learning, the complex maze because of the increased complexity of the environment most likely depends more strongly on preserved hippocampal function than the radial maze in the working memory configuration applied here. Greater impairment in complex maze performance than in radial maze performance thus resembles the predominant affliction of the loss of hippocampal function in human AD. NGF and BDNF levels on maze learning are different in wild-type and transgenic animals, indicating that biological markers of AD may be altered on challenge even though equilibrium levels are alike.

Amyloid beta-Protein Precursor↗

[Augmented reality in echocardiography. A new method of computer-assisted training and image processing using virtual and real three-dimensional data sets].

Augmented reality (AR) applications link real with virtual image data, in order to increase their information content. In medicine they are especially useful for education and for supporting the interpretation of three-dimensional (3D) image data. Simulators are used to train risky or expensive procedures. In the AR application EchoCom2 a 3D surface model of the human heart is linked with echocardiographic volume data sets. The 3D echocardiographic data sets are registered with the heart model to synchronize it's temporal and spatial orientation. The heart model together with an animated ultrasound sector represents a reference scenario, which displays the currently selected cutting plane within the echocardiographic volume data set. Modifications of the cutting plane within the echocardiographic data are transferred simultaneously and in real time to the reference scenario. The AR application is used as a simulator to train two-dimensional echocardiographic examinations and as an orientation and navigation aid for the exploration of 3D echocardiographic data sets. Beginners in echocardiography have only a rudimentary conception of the spatial relationship between the actual ultrasound image and the 3D anatomy of the heart. They are unable to translate multiple two-dimensional slices into a coherent 3D mental image of the heart. In EchoCom2 the trainee can interactively explore the 3D heart model and the registered 3D echocardiographic data sets by the animated ultrasound sector, whose position is controlled by an electromagnetic orientation and position system (EPOS). The data from the EPOS are used to calculate the echocardiographic images that are analogue to the position of the animated ultrasound sector. EchoCom2 is also used to support the interpretation of 3D echocardiographic data sets. The analysis of 3D echocardiographic data has to be done during a post processing. Defining the exact position of a cutting plane within the volume is difficult due to the lack of a standardized representation, the independence of the cutting plane of any transducer position and the possibility to calculate an indefinite number of views. The simultaneous representation of the current cutting plane both in the volume data, and in the heart model enables the examiner ad hoc to recognize it's position and the visualized structures.

Computer Simulation↗

A method for orienting cryostat sections for three-dimensional reconstructions.

Tissue for cryostat sectioning is embedded together with reference tissue impaled on the needles of a specially constructed trident. To maintain spatial orientation, reference and experimental tissue are frozen in Tissue-Tek O. C. T. compound in the manner usual for enzyme histochemistry using a simply constructed carrier. The trident is removed by heating its handle, thus leaving holes in the reference tissue which in turn are used as reference points to orient successive sections with respect to each other.

Animals↗

Multisensory stimulation with or without saccades: fMRI evidence for crossmodal effects on sensory-specific cortices that reflect multisensory location-congruence rather than task-relevance.

During covert attention to peripheral visual targets, presenting a concurrent tactile stimulus at the same location as a visual target can boost neural responses to it, even in sensory-specific occipital areas. Here, we examined any such crossmodal spatial-congruence effects in the context of overt spatial orienting, when saccadic eye-movements were directed to each peripheral target or central fixation maintained. In addition, we tested whether crossmodal spatial-congruence effects depend on the task-relevance of visual or tactile stimuli. On each trial, subjects received spatially congruent (same location) or incongruent (opposite hemifields) visuo-tactile stimulation. In different blocks, they made saccades either to the location of each visual stimulus, or to the location of each tactile stimulus; or else passively received the multisensory stimulation. Activity in visual extrastriate areas and in somatosensory parietal operculum was modulated by spatial congruence of the multisensory stimulation, with stronger activations when concurrent visual and tactile stimuli were both delivered at the same contralateral location. Critically, lateral occipital cortex and parietal operculum showed such crossmodal spatial effects irrespective of which modality was task relevant; and also of whether the stimuli were used to guide eye-movements or were just passively received. These results reveal crossmodal spatial-congruence effects upon visual and somatosensory sensory-specific areas that are relatively 'automatic', determined by the spatial relation of multisensory input rather than by its task-relevance.

Adolescent↗

A study of behavioral and sensorial bases of radial maze learning in mice.

In order to analyze the various sensorial and behavioral modes implied in learning on a radial maze, three isogenic mice groups (BALB/C, C57BL/6, and CB6F1) were subjected to four different learning procedures, each ending with a probe test. These four procedures examined the use of radial strategies and allowed to dissociate the use of olfactory and spatial cues. Results showed that all mice preferred to use a radial strategy. When the confinement procedure rendered the use of a radial strategy impossible, BALB/C mice were incapable of establishing spatial orientation but were able to learn the task by using olfactory cues. C57BL/6 mice, on the other hand, seemed to use spatial cues exclusively, while the CB6F1 hybrids showed a high degree of plasticity, using either type of information. These strain-specific differences point out the heterogeneity of the processes called into play during radial maze learning and show that unless olfactory cues are carefully controlled they can account for choice accuracy in some mice.

Animals↗

Comparison of the role of somatosensory stimuli in maze learning in a blind subterranean rodent and a sighted surface-dwelling rodent.

We compared the role of tactile perception in maze learning in the blind mole rat and in the laboratory rat. Both species were tested in each of two mazes that were identical in complexity but differed in tunnel width and height: the first was only slightly wider than the animal's body width (narrow maze) while the second was about twice the animal's body width (wide maze). We found that the performances of rats tested in the narrow maze were significantly lower than those tested in the wide maze, as measured by time and number of errors to reach the end of the maze (food reward). The mole rats, in contrast, performed significantly better in the narrow maze than in the wide maze. Further, in contrast to the rats, the mole rats' locomotion in the wide maze was much less continuous than in the narrow maze, reflected in longer and more frequent stops at maze junctions, where they pressed the side of their body tightly against the tunnel walls. Two main conclusions are derived from this experiment. First, subterranean mammals, such as the blind mole rat, appear to rely more on tactile stimuli while exploring and learning a complex maze than do sighted surface-dwelling rodents, such as rat. The extensive use of this somatosensory channel may compensate for the mole rats' visual deficiency, and thus substantially contribute to their excellent spatial orientation ability, previously demonstrated in field and laboratory conditions. Second, poor performance of surface-dwelling rodents, such as the rats, in spatial-maze learning tasks might not be a consequence of impaired cognitive learning ability, but rather due to testing the animal in a physical situation that does not provide the necessary somatosensory stimuli found in their natural habitat.

Animals↗

Water structure around enkephalin near a GeO2 surface: a molecular dynamics study.

A molecular model was created consisting of leucine enkephalin (a pentapeptide protein) near a germanium dioxide (GeO2) surface surrounded by water molecules. A molecular dynamic (MD) simulation of the system was conducted, and forces exerted by the water on both the surface and the protein were calculated. Orientational and spatial distribution functions of the water were calculated and were examined to determine if structured water existed and how it contributed to the intermolecular forces. Results from the study demonstrated that there is a strong spatial and orientational structuring of water near the GeO2 surface and that it is dependent on the proximity of the protein to the surface. Only minimal structuring occurred near the protein. A linear correlation was observed between the force of water on the protein and the angular distribution of water molecules in the region with the highest spatial density. When the protein is oriented with its polar side toward the GeO2 surface, the water structure near the protein disrupts the typical structure of the water near the surface, causing a force that pushes the protein away from the surface. When the protein is oriented with its non-polar side toward the surface, there is only minimal disruption of the typical water structure, and the resulting net forces between surface and protein are attractive.

Adsorption↗

Adult rat's offspring of alcoholic mothers are impaired on spatial learning and object recognition in the Can test.

The aim of this study was to examine spatial and object recognition reference and working memory in adult offspring of Wistar rats exposed to ethanol in prenatal and/or preweaning period. For this purpose, four different conditions of the Can test were performed sequentially: spatial/object discrimination task, spatial orientation task, simple object recognition task and complex object recognition task. The results of present study shows: (1) the significant impairment in spatial learning and object recognition in animals exposed to alcohol during prenatal and/or preweaning period, (2) that cognitive dysfunction become increasingly evident with switching from simple to more sophisticated task, (3) that the most vulnerable period is the early neonatal period which corresponds to the third trimester gestational development in humans and (4) that during the developmental period, abrupt introduction or withdrawal of ethanol, rather than its continuous consumption, can produce higher cognitive deficit later on. In conclusion, moderate ethanol exposure during brain development produce long lasting impairment of spatial and recognition reference and working memory in adult rat's offspring and these effects depend on the developmental period in which they were exposed to ethanol.

Age Factors↗

Effects of particulate matter released by a fish farm (Eilat, Red Sea) on survival and growth of Stylophora pistillata coral nubbins.

This field study aims to determine whether increased levels of organically enriched particulate matter released by net pen fish farms (Eilat, Red Sea) would affect the growth of nubbins taken from the branching coral Stylophora pistillata. We followed the survival and growth of 1322 nubbins pruned from five colonies that were transplanted at a depth of 6 m in the vicinity of the fish cages and in a reference site, in front of the Interuniversity Institute (IUI). Nubbins were attached on U-shaped PVC plates in three orientations (up, vertical and down positions). After 50 days, survival was high in both localities and no difference was recorded between the spatial orientations. At the fish farm, however, burial of the nubbin's lateral growths and partial coverage of nubbins by settled particulate matter resulted in significant reduction of the lateral growth rates of nubbins settled in the up position as compared to the reference site. On the other hand, faster growth rates were recorded in the vertical set of nubbins at the fish farm when compared with the IUI site. These results strengthen the conclusion that physical effects, rather than nutrient enrichment, may constitute the main cause of stress for minute coral fragments (resembling coral recruits) growing near the vicinity of a fish farm.

Animals↗

Quantitative assay for morphogenesis indicates the role of extracellular matrix components and G proteins.

A quantitative assay for morphogenesis is described that involves counting the organizing centers (swirling patterns) formed by many cultured fibroblasts. Organizing centers, which are found in vivo, represent one of the smallest units of morphogenesis. We show that macroscopically visible organizing centers form by the merger of smaller organizing centers. Parallel orientation of cells on plastic substrata requires cell-cell contact, but organizing centers can develop without cell-cell contact on collagen gels. On collagen gels, the orientation of collagen fibers determines the orientation of cells with respect to one another. Although organizing centers resemble fingerprints, we have shown that a stochastic process determines the spatial orientation of organizing centers. Treatment of transformed cell lines with agents that increase cAMP levels or alter the activity of guanine nucleotide binding proteins resulted in the generation of organizing centers. Cholesterol precursors involved in protein isoprenylation were found to be potent reverse-transformation agents that could alter the two-dimensional morphogenesis of cells. The simple assay described should permit the analysis of morphogenesis at the molecular and cellular levels.

Animals↗

Doppler US. Part II. Clinical applications.

Duplex and color Doppler ultrasound (US) are noninvasive techniques capable of providing much information about the condition of blood vessels and flow within them throughout the body. Doppler US provides more than noninvasive angiography. Besides assessment of blood vessel patency and direction of flow, analysis of the flow velocity waveform allows quantitation of arterial stenoses and evaluation of both physiologic and pathologic changes in impedance. In certain situations, Doppler US can aid in tissue characterization and estimation of absolute flow volume. Color Doppler flow imaging may both expedite and clarify the duplex Doppler examination. In addition, color Doppler imaging can demonstrate flow orientation and improve the identification of turbulence and soft plaque. Color and duplex Doppler US are complementary, with color Doppler techniques providing spatial orientation and pulse Doppler techniques providing the time-velocity spectrum for quantitation.

Humans↗

Envelope size tuning for stereo-depth perception of small and large disparities.

Stereopsis is the sense of depth derived from binocular disparities that are formed between targets that are matched between the two retinal images. Binocular matches for sustained stereopsis are based on similarity of orientation, spatial frequency and contrast of the two retinal images whereas matches for transient stereopsis depend on these parameters to a very limited extent. In this investigation we have tested the possibility that transient stereopsis forms matches between objects of similar overall size. The tuning of sustained and transient stereopsis to contrast-envelope size was investigated by presenting narrow-band Gabor targets of unequal size to the two eyes. Bandwidth for envelope-size tuning was estimated from the range of dichoptic size-differences over which stereo performance remained above chance level. An equal bandwidth of 2 octaves was found for the sustained and transient stereo systems when stimulated with parallel orientation Gabors that subtended a small disparity. Sustained-stereo performance with orthogonal carriers was reduced with large envelope sizes. Bandwidth of the transient stereo system increased to 3 octaves when tested with a larger disparity stimulus and it was independent of carrier orientation. Reducing the contrast of the larger-size Gabor improved transient-stereo performance from near chance (48-58%) to 85-95%. Thus the bandwidth for envelope-size tuning is much broader than indicated with equal physical contrast stimuli. The observed tuning to envelope size, while broad, is tighter than that observed for carrier spatial-frequency [Vis. Res. 38 (1998) 3057], carrier orientation [Vis. Res. 39 (1999) 2717] and contrast polarity [Vis. Res. 39 (1999) 4010] of the stimulus. Thus it would appear that envelope size and, to a greater extent, temporal synchrony of the dichoptic stimuli [Perception 24 (1995) 33] are the primary means for selecting matched binocular inputs for transient stereopsis.

Contrast Sensitivity↗

Orienting attention in time.

Temporal information is essential for effective perception and action in the dynamic environment in which we exist. However, our ability to use information about time intervals flexibly to direct attention to an expected point in time has until recently been unexplored. Here we report a series of behavioural, neuroimaging and electrophysiological experiments that investigate and define the ability to orient attention in the temporal domain. These studies reveal that we are able to orient attention selectively to different time intervals, enhancing behavioural performance. These effects are mediated by a left-hemisphere dominant frontal-parietal system, which partially overlaps with the networks involved in spatial orienting. The optimisation of behaviour by temporal orienting appears to be achieved via motor-related mechanisms, in contrast to the typical perceptual enhancements produced by spatial attention. From a more general perspective, these findings illustrate the flexibility of attentional functions in the human brain.

Adaptation, Psychological↗