Neurodevelopmental retardation, as assessed clinically and with magnetoencephalography and electroencephalography, associated with perinatal dioxin exposure.

UNLABELLED: In 1980s Western Europe, human perinatal exposure to background levels of dioxins was rather high. We therefore evaluated the neurodevelopment of our cohort during the prepubertal period and in adolescence. At prepubertal age (7-12 years) 41 children were tested. Both neuromotor functioning and psychological testing were performed (Dutch version of the Wechsler Intelligence Scale for Children (WISC-R) and the Dutch version of the Child Behavior Checklist for ages 4-18 years (CBCL 4-18) and the Teacher Report Form (TRF)). Neurophysiological tests were performed using magnetoencephalography and electroencephalography. In adolescence (14-18 years) the behavior of 33 children was studied again (CBCL and TRF). And the levels of dioxins and dioxin-like PCBs (dl-PCBs) were measured in serum. RESULTS: At prepubertal age no association was found between perinatal dioxin exposure and verbal, performal and total IQ or with the Touwen's test for neuromotor development. There were behavioral problems associated with both prenatal and postnatal dioxin exposure. In adolescence there were problems associated with the current dioxin levels and dioxin-like-PCBs. Neurophysiological tests revealed clear negative dysfunction. An increase in latency time after a motion stimulus (N2b) of 13 ms (= a delay of 10%) is associated with the higher prenatal dioxin exposure. A similar delay was measured in testing cognitive ability by analyzing the odd ball measurements, N200 and P300, together with an amplitude decrease of 12 %. The delay is indicative of a defective myelinisation and the decrease in amplitude of a loss of neurons. CONCLUSION: We found effects on behavior in association with the perinatal dioxin exposure and in adolescence in association with the current dioxin levels. Neurophysiological testing is instrumental in the detection of effects of perinatal background levels of chemicals on brain development in normal, healthy children. The clinical, neurological and psychological tests commonly used are not sensitive enough to detect important effects.

The prenatal development of the human orbit.

During the 1970s, as part of his work for a doctor's thesis in which he described the development of the human orbit in great detail, the first author established the largest anatomical collection of embryonic and fetal orbits ever. Unfortunately, he died before the thesis could be finished. The thousands of sections have now been scanned at high resolution and made publicly available on the Internet at www.visible-orbit.org; 3-D reconstruction software is being developed. The Discussion and part of the 'Methods' section of this thesis are published in translation in this article. The conclusions of the first author at the time read as follows: (1) initially, the developing orbit is vaguely indicated by condensations in the mesenchymal connective tissue area; (2) in this connective tissue area, chondral, osseous and muscular structures develop and grow until, in the fully developed stage, the orbital content is surrounded by bony surfaces with a thin layer of connective tissue as periosteum, and by a muscle fragment; (3) the embryonic and early fetal phase, during which one can only speak of a 'regio orbitalis,' is followed by a period in which we can speak of a primordial orbit; (4) the phase of the primordial orbit extends until after birth; (5) the surface area of all orbital walls increases more or less linearly; (6) the 'musculus orbitalis Mülleri' occupies a special place in the orbital wall; (7) the so-called 'regio craniolateralis' is the primordium, which, in the fully developed stage, is occupied by the thick intersection of the frontolateral and the horizontal part of the frontal bone; (8) in the frontal plane, the shape of the primordial orbit, as well as that of the fully developed orbit, is more or less round; (9) the prenatal development of an eye socket is a complex event, characterized by changes in composition, shape and size of the orbital wall; and (10) the orbit can only be denoted by the term "eye socket" when it is fully developed. At the end of the thesis, he also presented the following postulates: (1) in the prenatal orbit, the development of the so-called 'periorbita' is at the forefront; (2) the mutual rotation of the orbital axes and the frontalization of the eyes from approx. 180 degrees in the early prenatal stages to approx. 50 degrees in adulthood do not seem to be caused by mechanical influences of the surrounding tissue; (3) the pterygopalatine fossa and the 'cavum cerebri' are not part of the orbit at any developmental stage; (4) in the prenatal skull, the inferior nasal concha, which forms part of the maxilla in the fully developed skull, is part of the 'capsula nasalis'; and (5) in order to achieve normal development of the eye socket in microphthalmus and anophthalmus, the normal orbital content should be restored.

Temporal and spatial congruence of components of motion-onset evoked responses investigated by whole-head magneto-electroencephalography.

Motion-onset related components in averaged whole head co-recorded MEG and EEG responses of 24 adults to a low-contrast checkerboard pattern were studied. The aims were to identify these components, to characterize quantitatively their maps and to localize the underlying sources by equivalent-current-dipole (ECD) analyses with a spherical head model.After a weak P1, a large start-elicited negativity arises, comprising the novel N2a (occipital positive and parieto-central negative, peak-latency 141 ms) and the N2 like N2b (bilateral parieto-temporal, 175 ms) component. It is followed by a large positive stop-related component, P2 (156 ms after motion-offset). The corresponding MEG components N2am and N2bm showed bilateral dipole fields with considerable overlap. P1m has a single dipole field around the midline. N2a(m) and N2b(m) can be modelled with two bilateral ECDs with significant different locations. The study shows that accurate mapping and ECD analyses can distinguish two neighbouring areas of the visual cortex, 21+/-4 (SE) mm separated, which activities are reflected in both spatio-temporally closely related N2(m) components. N2a(m) and N2b(m) originate in the extrastriate cortex, possibly close to or in V3/V3A and MT/V5 respectively. Motion-evoked activity in (near) V3/V3A is novel on the basis of EEG data.

A gradual spread of attention during mental curve tracing.

The visual system has to segregate objects that are relevant to behavior from other objects and the background, if they are embedded in a visual scene. This segregation process can be time consuming, especially if the relevant object is spatially extended and overlaps with other image components, but the cause of the delays is presently not well understood. In the present study, we used a curve-tracing task to investigate processing delays during the grouping of contour segments into elongated curves. Our results indicate that contour segments that need to be grouped together are labeled with visual attention. Attention gradually spreads from contour segments that were labeled previously to other contours that are colinear and connected to them. The contour-grouping task is completed as soon as attention is directed to the entire curve. We conclude that processing delays during contour grouping are caused by a time-consuming spread of visual attention.

Ocular toxicity study of trypan blue injected into the vitreous cavity of rabbit eyes.

BACKGROUND: To evaluate the ocular toxicity of trypan blue (TB) injected into the vitreous cavity of rabbit eyes. TB is a dye that could be useful for staining epiretinal membranes during vitrectomy surgery. METHODS: Ten New Zealand White (NZW) rabbits underwent gas-compression vitrectomy. Rabbits were divided into three groups to receive injections of 0.1 ml basic salt solution, 0.1 ml of a 0.06% TB solution or 0.1 ml of a 0.2% TB solution. Ocular toxicity was assessed by slit-lamp biomicroscopy, ophthalmoscopy, electroretinography and histology. RESULTS: Transient posterior capsule opacification was noted in all animals. No significant reductions in a-wave or b-wave amplitudes were found in any of the animals. Light and electron microscopic examination of the inferior retina in the 0.2% TB-treated eyes showed damaged photoreceptors and marked disorganization. Immunohistochemical staining for rhodopsin was strongly reduced in those sections and staining for proliferation with Ki-67 was positive. No histological abnormalities were found in the upper retina of the 0.2% TB-treated eyes or in any part of the retina of the 0.06% TB-treated or control eyes. No histological abnormalities were found in any of the anterior chamber angle specimens. CONCLUSIONS: Although no signs of toxicity were found after the prolonged presence of TB at a concentration of 0.06% in the vitreous cavity of rabbit eyes, marked damage occurred in the lower retina of 0.2% TB-treated eyes. The short-term presence of TB at a concentration of 0.06% in the vitreous cavity is harmless to the rabbit eye but a higher concentration of TB could be unsafe.

The representation of erroneously perceived stimuli in the primary visual cortex.

In order to attain a correct interpretation of an ambiguous visual stimulus, the brain may have to elaborate on the sensory evidence. Are the neurons that carry the sensory evidence also involved in generating an interpretation? To address this question, we studied the activity of neurons in the primary visual cortex of macaque monkeys involved in a task in which they have to trace a curve mentally, without moving their eyes. On a percentage of trials, the monkeys made errors and traced the wrong curve. Here, we show that these errors are predicted by activity in area V1. Thus, neurons in the primary visual cortex do not only represent sensory events, but also the way in which they are interpreted by the monkey.

The spatial profile of visual attention in mental curve tracing.

In a curve-tracing task, subjects have to judge whether items are located on a single, continuous curve. Spatially separate segments of such a curve are related to each other through grouping criteria, like collinearity and connectedness. These grouping cues need to be exploited during curve tracing, but it is still an open issue how grouping of contour segments is achieved by the visual system. Many contemporary theories of visual perception assume that grouping operations are carried out pre-attentively, with unlimited capacity. The present study examines this assumption by investigating the involvement of attention in curve tracing. The results show that attention is directed to contour segments that need to be grouped together. The distribution of attention is guided by grouping criteria, such as connectedness. Apparently, attention is required to group spatially separate contour segments into a coherent representation of a curve.

The dynamic characteristics of the feedback signal from horizontal cells to cones in the goldfish retina.

1. The dynamic properties of the microcircuitry formed by cones and horizontal cells in the isolated goldfish retina were studied. Cones project to horizontal cells and horizontal cells feed back to cones via a relatively slow negative feedback pathway. 2. The time constant of the feedback signal in cones and of the effect this feedback signal had on the responses of second-order neurons was determined using whole-cell patch clamp and intracellular recording techniques. 3. It was found that the feedback signal in cones had a time constant of around 80 ms, whereas the time constant of the effect this feedback signal had on the second-order neurons ranged from 36 to 116 ms. This range of time constants can be accounted for by the non-linearity of the Ca(2+) current in the cones. In depolarized cones, the feedback-mediated response in second-order neurons had a similar time constant to that of the direct light response of the cone, whereas in hyperpolarized cones, the time constant of the feedback-mediated response in second-order neurons was considerably larger. 4. Further, it was shown that there was no delay in the feedback pathway. This is in contrast to what has been deduced from the response properties of second-order neurons. In one type of horizontal cell, the responses to red light were delayed relative to the responses to green light. This delay in the second-order neurons can be accounted for by the interaction of the direct light response of the medium-wavelength-sensitive cones (M-cones) with the feedback response of the M-cones received from the horizontal cells.

A neural correlate of working memory in the monkey primary visual cortex.

The brain frequently needs to store information for short periods. In vision, this means that the perceptual correlate of a stimulus has to be maintained temporally once the stimulus has been removed from the visual scene. However, it is not known how the visual system transfers sensory information into a memory component. Here, we identify a neural correlate of working memory in the monkey primary visual cortex (V1). We propose that this component may link sensory activity with memory activity.

Preliminary report: prescription of prism-glasses by the Measurement and Correction Method of H.-J. Haase or by conventional orthoptic examination: a multicenter, randomized, double-blind, cross-over study.

In a multicenter, randomized, double-blind, cross-over study in the Netherlands, the effectiveness of (prism-)glasses prescribed by the Measurement and Correction Method of H.-J. Haase (MKH) was compared to that of glasses prescribed by conventional orthoptic examination. Nine pairs of MKH-optometrists and orthoptists recruited patients who primarily presented with asthenopia, and each prescribed the patient (prism-)glasses. A questionnaire for asthenopia was developed that rated headache and tired eyes as 0-7 days per week and none-light-medium-severe, respectively. Light sensitivity, problems with focusing, near-work problems and burning eyes were each rated as: never-occasionally-often-always. A patient was eligible if he scored 'medium', 'often' or '5 days a week' twice; or 'medium' (etc.) once and 'light' (etc.) twice. Controls, in contrast to the patients, typically answered 'none' or 'never' to half of the complaints, but 37% of them would have passed the admission criteria. Among other criteria were: 18 to 40 years of age, horizontal angle < 4 degrees, vertical < 1.7 degrees, acuity > or = 0.8, stereopsis threshold disparity < 120". Seventy-two patients fulfilled all criteria and returned sufficient questionnaires. They wore the first glasses for six weeks, were without glasses for two weeks, and then wore the second glasses for six weeks. At the start, halfway and at the end of each 6-week period, questionnaires were filled out; 97% were returned. Only 19 of the orthoptists' glasses contained prisms (14 horizontal, 5 vertical; horizontal average of all glasses 0.49 PD, vertical 0.05 PD). Five of the orthoptists' glasses were plano. All MKH glasses contained prisms, 53 of 72 both horizontal and vertical, 18 only horizontal and one only vertical (horizontal average of all glasses 2.83 PD, vertical 0.79 PD). The starting levels of complaints were high and both glasses improved complaints dramatically. The starting levels were lower, but not significantly, in the second 6-week period and improvement was less outspoken. Because of these differences, the two periods had to be evaluated separately. The primary outcome of the study was defined as the difference between the effect of the MKH glasses and that of the orthoptists' glasses in the first and second 6-week periods. For problems with focusing, in the first 6-week period, and for tired eyes, in the second 6-week period, the difference exceeded the difference that had been defined as clinically significant (one day per week less headache or half the distance light-medium or half the distance occasionally-often), but it did not reach statistical significance. The statistical power was approximately 0.7 for demonstrating this clinically significant difference. Statistical significance was not reached in multivariate repeated measure ANOVA either. Forty-four patients preferred to keep the MKH glasses, 25 the orthoptists' glasses, including one plano. It is striking that 25% of the patients did not prefer the glasses that, according to the questionnaire, improved their complaints the most. A year after the study, the questionnaire was sent again to all patients: The levels of complaints after a year were similar to those at the end of the second 6-week period, whether they had preferred the MKH or the orthoptists' glasses, and were similar to the levels in controls. The most conspicuous finding was that both glasses improved the complaints dramatically. Apart from the prisms, other reasons could be: spherical and cylindrical correction, improved wearing comfort of the frame, placebo effect, Hawthorne effect and regression to the mean.

Two distinct modes of sensory processing observed in monkey primary visual cortex (V1).

Even salient sensory stimuli are sometimes not detected. What goes wrong in the brain in that case? Here we show that a late (> 100-ms) component of the neural activity in the primary visual cortex of the monkey is selectively suppressed when stimuli are not seen. As there is evidence that this activity depends on feedback from extrastriate areas, these findings suggest a specific role for recurrent processing when stimuli are reaching a perceptual level. Further results show that this perceptual level is situated between purely sensory and decision or motor stages of processing.

Event-related desynchronization during anticipatory attention for an upcoming stimulus: a comparative EEG/MEG study.

OBJECTIVES: Our neurophysiological model of anticipatory behaviour (e.g. Acta Psychol 101 (1999) 213; Bastiaansen et al., 1999a) predicts an activation of (primary) sensory cortex during anticipatory attention for an upcoming stimulus. In this paper we attempt to demonstrate this by means of event-related desynchronization (ERD). METHODS: Five subjects performed a time estimation task, and were informed about the quality of their time estimation by either visual or auditory stimuli providing Knowledge of Results (KR). EEG and MEG were recorded in separate sessions, and ERD was computed in the 8-10 and 10-12 Hz frequency bands for both datasets. RESULTS: Both in the EEG and the MEG we found an occipitally maximal ERD preceding the visual KR for all subjects. Preceding the auditory KR, no ERD was present in the EEG, whereas in the MEG we found an ERD over the temporal cortex in two of the 5 subjects. These subjects were also found to have higher levels of absolute power over temporal recording sites in the MEG than the other subjects, which we consider to be an indication of the presence of a 'tau' rhythm (e.g. Neurosci Lett 222 (1997) 111). CONCLUSIONS: It is concluded that the results are in line with the predictions of our neurophysiological model.

The open- and closed-loop gain-characteristics of the cone/horizontal cell synapse in goldfish retina.

Under constant light-adapted conditions, vision seems to be rather linear. However, the processes underlying the synaptic transmission between cones and second-order neurons (bipolar cells and horizontal cells) are highly nonlinear. In this paper, the gain-characteristics of the transmission from cones to horizontal cells and from horizontal cells to cones are determined with and without negative feedback from horizontal cells to cones. It is shown that 1) the gain-characteristic from cones to horizontal cells is strongly nonlinear without feedback from horizontal cells, 2) the gain-characteristic between cones and horizontal cells becomes linear when feedback is active, and 3) horizontal cells feed back to cones via a linear mechanism. In a quantitative analysis, it will be shown that negative feedback linearizes the synaptic transmission between cones and horizontal cells. The physiological consequences are discussed.

Self-organized dynamics in plastic neural networks: bistability and coherence.

In this paper, we study the combined dynamics of the neural activity and the synaptic efficiency changes in a fully connected network of biologically realistic neurons with simple synaptic plasticity dynamics including both potentiation and depression. Using a mean-field of technique, we analyzed the equilibrium states of neural networks with dynamic synaptic connections and found a class of bistable networks. For this class of networks, one of the stable equilibrium states shows strong connectivity and coherent responses to external input. In the other stable equilibrium, the network is loosely connected and responds non coherently to external input. Transitions between the two states can be achieved by positively or negatively correlated external inputs. Such networks can therefore switch between their phases according to the statistical properties of the external input. Non-coherent input can only "rcad" the state of the network, while a correlated one can change its state. We speculate that this property, specific for plastic neural networks, can give a clue to understand fully unsupervised learning models.

Predictive value of neonatal neurological tests for developmental outcome of preterm infants.

BACKGROUND: There is a need to identify, as early as possible, infants who are at risk for long-term neurological morbidity. METHODS: To predict neurodevelopment outcome of preterm infants <30 weeks' gestation in a population of 100 infants, we used several neonatal and neurobehavioral tests, including cranial ultrasonography, the Prechtl neurological test, quality of spontaneous general movements, and quality of sleep-wake organization. RESULTS: The Prechtl test at corrected term age and findings on cranial sonograms both had high specificity, but the Prechtl test had better overall positive predictive power for normal neurological and developmental outcomes at 2 years' corrected age. Developmental changes in sleep and the amount of indeterminate sleep did not correlate with outcome. Scoring general movement quality did not predict outcome and did not augment the positive predictive power of the Prechtl test. CONCLUSIONS: The Prechtl test at corrected term age (independent of the other tests) is the best positive predictor of normal neurological outcome and Bayley test results at 2 years' corrected age.

The implementation of visual routines.

Many visual tasks can be decomposed into a sequence of simpler subtasks. Ullman suggested that such subtasks are carried out by elemental operations that are implemented by specialized processes in the visual brain [Ullman, S. (1984). Visual routines. Cognition (18), 97-159]. According to this hypothesis, there are a limited number of elemental operations that, since they can be applied sequentially, may nevertheless give rise to a large number of visual routines. Examples of such elemental operations are visual search, texture segregation and contour grouping. Here we attempt to delineate how such elemental operations are implemented in the visual brain. When an image appears, feedforward processing rapidly leads to an activity pattern that is distributed across many visual areas. Thereafter, elemental operations come into play, and these are implemented by the modulation of firing rates. Firing rate modulations effectuate grouping of neural responses into coherent object representations. Moreover, they permit transfer of information from one operator to the next, which allows flexibility in the sequencing of operations. We discuss how the elemental operations provide a tool to relate cortical physiology to psychophysics, and suggest a reclassification of pre-attentive and attentive processes.

The role of primary visual cortex (V1) in visual awareness.

In the search for the neural correlate of visual awareness, much controversy exists about the role of primary visual cortex. Here, the neurophysiological data from V1 recordings in awake monkeys are examined in light of two general classes of models of visual awareness. In the first model type, visual awareness is seen as being mediated either by a particular set of areas or pathways, or alternatively by a specific set of neurons. In these models, the role of V1 seems rather limited, as the mere activity of V1 cells seems insufficient to mediate awareness. In the second model type, awareness is hypothesized to be mediated by a global mechanism, i.e. a specific kind of activity not linked to a particular area or cell type. Two separate versions of global models are discussed, synchronous oscillations and spike rate modulations. It is shown that V1 synchrony does not reflect perception but rather the horizontal connections between neurons, indicating that V1 synchrony cannot be a direct neural correlate of conscious percepts. However, the rate of spike discharges of V1 neurons is strongly modulated by perceptual context, and these modulations correlate very well with aspects of perceptual organization, visual awareness, and attention. If these modulations serve as a neural correlate of visual awareness, then V1 contributes to that neural correlate. Whether V1 plays a role in the neural correlate of visual awareness thus strongly depends on the way visual awareness is hypothesized to be implemented in the brain.

The development of hemispheric asymmetry in human motion VEPs.

In six healthy adults we examined the sources underlying P1 and N2 of the motion VEP. For this purpose was acquired, in addition to the VEP, MRI images and patterns of regional cerebral blood flow with SPECT for three of the subjects. With the same motion stimulus we also examined the spatial distribution of N2 in children. In both adults and children left and right half-field responses were compared. It was found that N2 is generated by extrastriate activity and that motion stimuli are not equivalently processed in the two cerebral hemispheres. In adults, N2 dominates in one hemisphere irrespective of the visual half-field used for stimulation whereas children show an ipsilateral maximum for N2 upon half-field presentation.

Modulations of primary visual cortex activity representing attentive and conscious scene perception.

In the visual cortex, information is transferred from one area to the next by means of feedforward connections. These connections shape the receptive field properties of neurons in subsequent visual areas. Horizontal and feedback connections modulate this neuronal activity, resulting in the phenomenon of contextual modulation. In area V1, where receptive field properties reflect only low level processing, contextual modulation can be observed that represents fully evaluated perceptual saliency of the features within the receptive field. Here, we discuss to what extent these modulations are related to high level visual processes like perceptual organization, attention and visual awareness. Contextual modulation appears to reflects a process very distinct from receptive field based processing. This process seems to integrate information from distant areas in visual cortex to neurophysiologically 'highlight' those neurons that represent image elements or features of objects that stand out perceptually. Moreover, similar modulations are observed in relation to whether objects are attended to or not. Finally, these modulations are only present when subjects are aware of the visual input.