[Treatment of serous macular retinal detachment with antihistamines]. / Behandlung einer serösen makulären Netzhautablösung mit Antihistaminika.

The etiology of retinal detachment in central serous retinopathy (CSR) is unknown; however, three facts are generally accepted: (1) the serous exudate which raises the layers of the receptors/pigment epithelium is formed due to hyperpermeability in the choriocapillaries, (2) patients frequently suffer from headaches and (3) stress promotes the incidence of CSR. A high blood plasma histamine concentration can cause the abovementioned symptoms which suggests that histamine might provoke CSR. Within 1 week after administration of the antihistamine loratadin a considerable reduction in the retinal exudate and restoration of vision were observed. This supports the hypothesis that histamine could be involved in the process of retinal detachment. Further investigations and large scale clinical trials should clarify if this hypothesis can be proved or disproved and whether antihistamines can be used for age-related macular degeneration (AMD).

[Vision with bifocal and multifocal intraocular lenses]. / Sehen mit bi- und multifokalen Intraokularlinsen.

Bifocal or multifocal intraocular lenses (IOLs) can be used to replace natural lenses during cataract surgery. These lenses are recommended by cataract surgeons as the replacement lenses of choice when patients wish to avoid wearing spectacles. There are, however, drawbacks to these lenses: one drawback is that the contrast in the images of bifocal and multifocal lenses is reduced as documented in the ophthalmology literature. It is claimed that acuity is similar in multifocal compared to monofocal lenses, however, we show that any loss in contrast inevitably reduces visual acuity. The other drawback is that the sharp in-focus image is always seen superimposed on one or more blurred out of focus images of the same object. In the ophthalmology literature it is assumed that the brain can suppress the undesired blurred image and only perceive the sharp image. We argue that there are no known mechanisms that would make this possible. This means that vision with bifocal or multifocal implanted lenses cannot be as good as vision with monofocal implants supplemented by spectacles, and this should be explained to patients before undergoing surgery for lens replacement. The results also hold for bifocal and multifocal contact lenses.

Complex functions of the brain.

Over the course of the last 50 years it has been possible to solve a number of basic problems in neurobiology. Interest is now turning more and more to problems concerning so-called "higher" brain functions, including cognition. Examples from the visual system in primates are presented. First relatively elementary problems are illustrated, such as how long it takes to perceive an object or to respond to a stimulus or combinations of stimuli. Top-down modification of perception by expectation is demonstrated in an illusion of misdirected gaze. Interdisciplinary questions straddling the sciences and the humanities are also approached, such as which part of the brain mediates conscious perception. Finally, the problem of causality and freedom of will is addressed, taking into account the knowledge accumulated in the neurosciences during the last 5 decades.

The role of background movement in goldfish vision.

In experiments described in the literature objects presented to restrained goldfish failed to induce eye movements like fixation and/or tracking. We show here that eye movements can be induced only if the background (visual surround) is not stationary relative to the fish but moving. We investigated the influence of background motion on eye movements in the range of angular velocities of 5-20 degrees s(-1). The response to presentation of an object is a transient shift in mean horizontal eye position which lasts for some 10 s. If an object is presented in front of the fish the eyes move in a direction such that it is seen more or less symmetrically by both eyes. If it is presented at +/-70 degrees from the fish's long axis the eye on the side of the object moves in the direction that the object falls more centrally on its retina. During these object induced eye responses the typical optokinetic nystagmus of amplitude of some 5 degrees with alternating fast and slow phases is maintained, and the eye velocity during the slow phase is not modified by presentation of the object. Presenting an object in front of stationary or moving backgrounds leads to transient suppression of respiration which shows habituation to repeated object presentations.

Metabolic stress reversibly activates the Drosophila light-sensitive channels TRP and TRPL in vivo.

Drosophila transient receptor potential (TRP) is a prototypical member of a novel family of channel proteins underlying phosphoinositide-mediated Ca(2+) entry. Although the initial stages of this signaling cascade are well known, downstream events leading to the opening of the TRP channels are still obscure. In the present study we applied patch-clamp whole-cell recordings and measurements of Ca(2+) concentration by ion-selective microelectrodes in eyes of normal and mutant Drosophila to isolate the TRP and TRP-like (TRPL)-dependent currents. We report that anoxia rapidly and reversibly depolarizes the photoreceptors and induces Ca(2+) influx into these cells in the dark. We further show that openings of the light-sensitive channels, which mediate these effects, can be obtained by mitochondrial uncouplers or by depletion of ATP in photoreceptor cells, whereas the effects of illumination and all forms of metabolic stress were additive. Effects similar to those found in wild-type flies were also found in mutants with strong defects in rhodopsin, Gq-protein, or phospholipase C, thus indicating that the metabolic stress operates at a late stage of the phototransduction cascade. Genetic elimination of both TRP and TRPL channels prevented the effects of anoxia, mitochondrial uncouplers, and depletion of ATP, thus demonstrating that the TRP and TRPL channels are specific targets of metabolic stress. These results shed new light on the properties of the TRP and TRPL channels by showing that a constitutive ATP-dependent process is required to keep these channels closed in the dark, a requirement that would make them sensitive to metabolic stress.

Visual attention and metacontrast modify latency to perception in opposite directions.

In human observers, cue-induced visual attention ('bottom-up' transient focal attention) shortens the latency of perception. Metacontrast reduces the intensity of perception and can even obliterate it. We show that a close relationship exists between both, but that their effects are reversed: cue-induced visual attention not only shortens latency but also intensifies perception, and metacontrast not only lowers intensity of perception but also prolongs latency. A common neurophysiological mechanism for both is possible. Indirect evidence suggests that this could be a subthreshold modulation of neuronal thresholds by de- and hyperpolarization.

[Neural mechanisms of anesthesia]. / Neuronale Mechanismen der Narkose.

Positron emission tomography studies on volunteers showed that, at concentrations inducing the loss of consciousness, propofol, halothane and isoflurane reduce glucose metabolism of neocortical neurones by 20-50%. To find out whether these effects are caused by direct anaesthetic actions on cortical structures, experiments were carried out on isolated neocortical brain slices. In these investigations an excellent correlation was observed between anaesthetic concentrations causing a half-maximal depression of action potential firing in neocortical brain slices and anaesthetic blood concentrations monitored during awaking from anaesthesia in humans. Furthermore, it could be shown that, at concentrations approximately one half the MAC-value, isoflurane decreases the frequency of auditory evoked 30-40 Hz oscillations in the neocortex by 50%. Similar quantitative effects were observed on spontaneously occurring high frequency rhythms in neocortical brain slices. However, not all aspects of cerebral anaesthetic actions can be explained by direct effects on cortical neurones. The EEG synchronisation and the amplitude reduction of mid latency auditory evoked potentials are probably related to the inhibition of thalamic neurones. Halothane, isoflurane, enflurane and propofol reduced action potential firing of cortical neurones by enhancing GABAA receptor-mediated synaptic inhibition. This molecular mechanism seems also to be involved in depressing painful stimuli-induced motor responses. Nevertheless, there must be a difference between relevant anaesthetic mechanisms on the cerebral and spinal level. This follows from the observation that the relation between the concentration causing the loss of consciousness and the concentration that depresses movements considerably varies among different anaesthetic agents.

Afterimages: a tool for defining the neural correlate of visual consciousness.

Our visual system not only mediates information about the visual environment but is capable of generating pictures of nonexistent worlds: afterimages, illusions, phosphenes, etc. We are "aware" of these pictures just as we are aware of the images of natural, physical objects. This raises the question: is the neural correlate of consciousness (NCC) of such images the same as that of images of physical objects? Images of natural objects have some properties in common with afterimages (e.g., stability of verticality) but there are also obvious differences (e.g., images maintain size constancy, whereas afterimages follow Emmert's Law: when seen while screens at different distances are observed, an afterimage looks larger, the greater the distance of the screen). The differences can be explained by differences in the retinal extent of images and afterimages, which favors the view that both have the same NCC. It seems reasonable to assume that before neural activity can produce awareness, all the computations necessary for a veridical representation of, e.g., an object, must be completed within the neural substrate and that information characteristic of a particular object must be available within the NCC. Given these assumptions, it can be shown that no retinotopic (in a strict sense) cortical areas can serve as the NCC, although some type of topographic representation is necessary. It seems also to be unlikely that neurons classified as cardinal cells alone can serve as NCC.

Visual attention modifies spectral sensitivity of nystagmic eye movements.

If we look out of the window of a travelling train our eyes move rapidly back and forth (saccadic movement). With no attention to individual objects, gaze velocity is low but nystagmic frequency is high (stare nystagmus). If we are interested in individual objects, the angular velocity of gaze is high and the nystagmic frequency low (look nystagmus) (Ter Braak, J.W.G. (1936). Untersuchungen ueber optokinetischen Nystagmus. Archives Néerlandaises de Physiologie de L'homme et des Animaux, 21, 309-376). We show that the spectral sensitivities of the two types of nystagmus differ and that the short-wavelength-sensitive cones significantly contribute only to look nystagmus.

Cortical visual processing is temporally dispersed by luminance in human subjects.

Increasing the intensity of a stimulus such as luminance results in faster processing of the signal and therefore decreases simple motor reaction time (RT). We studied the latencies of visual evoked potentials (VEPs, N80, P100, N130) and RTs in eight subjects to flashing spots of light while varying the luminance of the spots from 1 to 1000 cd/m2. The data show that processing time as a function of intensity is modified not only at the retina but also at later processing sites. This indicates a temporal dispersion of the visual signal over the whole processing stream from visual input all the way to motor output.

The Fröhlich effect: a consequence of the interaction of visual focal attention and metacontrast.

Usually we assume that the central nervous system preserves temporal sequences. Here we show that moving objects--in the context of behaviour often dangerous ones--are seen with a shorter latency than stationary (flashed) objects. In addition moving objects are deblurred. Two mechanisms contribute to this functional specialisation: cue-induced visual focal attention and metacontrast. Under unnatural conditions these mechanisms lead to an optical illusion first described by Fröhlich [Fröhlich, F. W. (1923). Uber die Messung der Empfindungszeit. Zeitschrift für Sinnesphysiologie, 54, 58-78].

Effects of volatile anaesthetics on the membrane potential and ion channels of cultured neocortical astrocytes.

Volatile anaesthetics cause changes in the membrane resting potential of central neurons. This effect probably arises from actions on neuronal ion channels, but may also involve alterations in the ion composition of the extracellular space. Since glial cells play a key role in regulating the extracellular ion composition in the brains of mammals, we analyzed the effects of halothane, isoflurane and enflurane on the membrane conductances and ion channels of cultured cortical astrocytes. Astrocytes were dissociated from the neocortex of 0-2-day old rats and grown in culture for 3-4 weeks. Anaesthetic-induced changes in the membrane potential were recorded in the whole cell current-clamp configuration of the patch-clamp technique. We further studied the effects of halothane and enflurane on single ion channels in excised membrane patches. At concentrations corresponding to 1-2 MAC (1 MAC induces general anaesthesia in 50% of the patients and rats), membrane potentials recorded in the presence of enflurane, isoflurane and halothane did not differ significantly from the control values. At higher concentrations, effects of enflurane and halothane, but not of isoflurane, were statistically significant. Single-channel recordings revealed that halothane and enflurane activated a high conductance anion channel, which possibly mediated the effects observed during whole cell recordings. In less than 10% of the membrane patches, volatile anaesthetics either increased or decreased the mean open time of K+-selective ion channels without altering single-channel conductances. In summary, it seems unlikely that the actions of volatile anaesthetics described here are involved in the state of general anaesthesia. Statistically significant effects occurred at concentrations ten times higher than those required to cause half-maximal depression of action potential firing of neocortical neurons in cultured brain slices. However, it cannot be excluded that the changes observed in the membrane conductance of cortical astrocytes disturb the physiological function of these cells, thereby influencing the membrane resting potential of neurons.

Course control and tracking: orientation through image stabilization.

Course control and tracking are based on visual detection of the position and movement of objects. A disadvantage of biological movement detectors is that they cannot provide a signal proportional to the speed at which the image of an object moves over the retina. Other image parameters, such as brightness, contrast, and texture, strongly affect the magnitude of the detectors' output signals. To function well, the optomotor control circuit must solve these problems. One possible solution, realized in Diptera, is the principle of "gain control by feedback oscillations" described in this chapter. The optomotor system serves for course control by stabilizing the image of the visual panorama on the eye, and for tracking a moving object by stabilizing the object's image on the eye. When an object moves in front of a structured background, it is impossible for the images of both object and background to be stabilized simultaneously. Arthropods and vertebrates usually employ the same strategy to cope with this problem: saccadic tracking. In Diptera, the neural substrate for saccadic tracking is partially understood.

Effects of volatile anaesthetics on spontaneous action potential firing of cerebellar Purkinje cells in vitro do not follow the Meyer-Overton rule.

We have investigated in rat brain slices the effects of the volatile anaesthetics enflurane, isoflurane and halothane on spontaneous discharge patterns and mean firing rates of cerebellar Purkinje cells. In the absence of these anaesthetics, Purkinje cells fired bursts of action potentials separated by quiescent periods lasting less than 2 s. Mean discharge rates were 10.8 (SEM 0.4) Hz at 23 +/- 1 degrees C and 25.6 (1.2) Hz at 35 +/- 1 degrees C. The agents exhibited qualitatively different effects when applied at concentrations corresponding to 1-3 MAC. Enflurane markedly lengthened burst and inter-burst durations. Isoflurane acted in a similar manner, but effects were less pronounced. In contrast with isoflurane and enflurane, halothane shortened burst durations. At concentrations corresponding to 1-1.5 MAC, halothane, isoflurane and enflurane significantly depressed action potential firing by 15-30% (P < 0.05). Enflurane 1.2 mmol litre-1 (2.0 MAC), isoflurane 0.9 mmol litre-1 (2.8 MAC) and halothane 0.9 mmol litre-1 (3.8 MAC) depressed spontaneous spike rates by 50%. The changes in discharge patterns and the concentration-dependent decrease in the firing rates were similar at 23 +/- 1 degrees C and 35 +/- 1 degrees C. In summary, we observed that neither the anaesthetic-induced alterations in spontaneous discharge patterns nor the EC50 values of the concentration-dependent depression of the mean firing rates were in accordance with the Meyer-Overton rule. However, at clinically relevant concentrations, depression of average spike rates did not differ significantly between the anaesthetics and thus followed the rule. Our results suggest that anaesthetic actions, which are in accordance with the rule, are frequently masked by several side effects.

Visually elicited head rotation in pigeons (Columba livia).

Horizontal rotational head movements were video-taped from pigeons standing freely in a rotating cylinder. The cylinder carried vertically striped patterns approximating a sinusoidally modulated horizontal intensity distribution. We altered systematically various stimulus parameters: spatial wavelength and contrast of the pattern, angular velocity of the pattern motion and mode of motion onset. We found: (1) both gradual acceleration of the patterned cylinder as well as immediate onset of pattern motion elicit the sequence of smooth following and saccadic resetting movement typical of the rotational "stare" head nystagmus; (2) in experiments with rapid onset of pattern motion, velocity of the smooth following response gradually increases to its steady-state level over a period of about 10 sec; (3) the saccadic head rotations are not stereotyped: larger and shorter saccades follow in an irregular sequence, saccadic velocity and average size varies with stimulus conditions; (4) in the range of 0.9-95 deg/sec, the velocity of the following phase increases in parallel with stimulus speed; (5) in the range of spatial wavelengths of the striped patterns from 6 to 45 deg, at a given drum velocity, patterns of short wavelengths elicit optokinetic head rotations with higher gain (head velocity/drum velocity) than patterns of long wavelengths; (6) response velocity increases with pattern contrast (Michaelson contrast 5, 32 and 75%), following approximately a logarithmic relation; (7) our results on rotational optokinetic head movements support the notion that the neural mechanism underlying motion detection operates like a correlation mechanism.

Cortical oscillations and the origin of express saccades.

The latencies of visually guided saccadic eye movement can form bimodal distributions. The 'express saccades' associated with the first mode of the distributions are thought to be generated via an anatomical pathway different from that for the second mode, which comprises regular saccades. The following previously published observations are the basis for a new alternative model of these effects: (i) visual stimuli can cause oscillations to appear in the electroencephalogram; (ii) visual stimuli can cause a negative shift in the electroencephalogram that lasts for several hundreds of milliseconds; and (iii) negativity in the electroencephalogram can be associated with reduced thresholds of cortical neurons to stimuli. In the new model both express and regular saccades are generated by the same anatomical structures. The differences in saccadic latency are produced by an oscillatory reduction of a threshold in the saccade-generating pathway that is transiently produced under certain stimulus paradigms. The model has implications regarding the functional significance of spontaneous and stimulus-induced oscillations in the central nervous system.

Genetic dissection of light-induced Ca2+ influx into Drosophila photoreceptors.

Invertebrate photoreceptors use the inositol-lipid signaling cascade for phototransduction. A useful approach to dissect this pathway and its regulation has been provided by the isolation of Drosophila visual mutants. We measured extracellular changes of Ca2+ [delta Ca2+]o in Drosophila retina using Ca(2+)-selective microelectrodes in both the transient receptor potential (trp) mutant, in which the calcium permeability of the light-sensitive channels is greatly diminished and in the inactivation-but-no-afterpotential C (inaC) mutant which lacks photoreceptor-specific protein kinase C (PKC). Illumination induced a decrease in extracellular [Ca2+] with kinetics and magnitude that changed with light intensity. Compared to wild-type, the light-induced decrease in [Ca2+]o (the Ca2+ signal) was diminished in trp but significantly enhanced in inaC. The enhanced Ca2+ signal was diminished in the double mutant inaC;trp indicating that the effect of the trp mutation overrides the enhancement observed in the absence of eye-PKC. We suggest that the decrease in [Ca2+]o reflects light-induced Ca2+ influx into the photoreceptors and that the trp mutation blocks a large fraction of this Ca2+ influx, while the absence of eye specific PKC leads to enhancement of light-induced Ca2+ influx. This suggestion was supported by Ca2+ measurements in isolated ommatidia loaded with the fluorescent Ca2+ indicator, Ca Green-5N, which indicated an approximately threefold larger light-induced increase in cellular Ca2+ in inaC relative to WT. Our observations are consistent with the hypothesis that TRP is a light activated Ca2+ channel and that the increased Ca2+ influx observed in the absence of PKC is mediated mainly via the TRP channel.

Motion sensitivity in the nucleus of the basal optic root of the pigeon.

1. Single-unit responses to large-field movement (angular velocity, w = 0.25-42 degrees/s) of sine-wave gratings of different spatial wavelength (lambda = 5.2-41 degrees) and contrast have been recorded in the nucleus of the basal optic root (nBOR) of the accessory optic system (AOS) of the pigeon. 2. The steady-state response to moving sine-wave gratings increases with increasing contrast to reach a saturation level at 25%. 3. Generally the steady-state responses of the cells passed through a maximum when stimulated at various velocities. In 12 of the 15 cells tested with six different velocities and four different spatial wavelengths, the location of the response maximum on the velocity scale depended on the spatial wavelength (lambda) used. That is, in these cells the response depends on the temporal frequency (tf = w/lambda) of the stimulus and not on its velocity alone. This is in agreement with the prediction of the theory of motion detection according to the basic version of the correlation scheme. 4. The temporal frequency for maximal response of individual cells shifts to higher values when the contrast of the sine-wave gratings is reduced to 5%. 5. The steady-state response of 16 of the recorded directional selective cells (53) is modulated with the temporal frequency of the stimulus, regardless of the phase of the grating at the beginning of its movement. 6. In phasic-tonically responding cells, the phasic response peak decays to the steady-state level with a time constant that becomes shorter as the temporal frequency of the stimulus increases. 7. The basic version of the correlation scheme includes only the time constant of one low-pass filter. Therefore the phasic response is expected to decay to the steady-state level with one and the same time constant, and the position of the maximal response on the temporal frequency scale should not be influenced by a change of pattern contrast. According to the model, phase-dependent modulations of the steady-state response should occur only when the spatial wavelength of the stimulus pattern is large compared with the sampling base of the underlying detector. Consequently the results given in points 4-6 cannot be described by a basic version of the correlation scheme.