Residual visual processing following real or virtual lesions to primary visual pathways

Lesions to the primary geniculo-striate visual pathway cause blindness in the contralesional visual field. Nevertheless, previous studies have suggested that patients with visual field defects may still be able to implicitly process the affective valence of unseen emotional stimuli (affective blindsight) through alternative visual pathways bypassing the striate cortex. These alternative pathways may also allow exploitation of multisensory (audio-visual) integration mechanisms, such that auditory stimulation can enhance visual detection of stimuli which would otherwise be undetected when presented alone (crossmodal blindsight). The present dissertation investigated implicit emotional processing and multisensory integration when conscious visual processing is prevented by real or virtual lesions to the geniculo-striate pathway, in order to further clarify both the nature of these residual processes and the functional aspects of the underlying neural pathways. The present experimental evidence demonstrates that alternative subcortical visual pathways allow implicit processing of the emotional content of facial expressions in the absence of cortical processing. However, this residual ability is limited to fearful expressions. This finding suggests the existence of a subcortical system specialised in detecting danger signals based on coarse visual cues, therefore allowing the early recruitment of flight-or-fight behavioural responses even before conscious and detailed recognition of potential threats can take place. Moreover, the present dissertation extends the knowledge about crossmodal blindsight phenomena by showing that, unlike with visual detection, sound cannot crossmodally enhance visual orientation discrimination in the absence of functional striate cortex. This finding demonstrates, on the one hand, that the striate cortex plays a causative role in crossmodally enhancing visual orientation sensitivity and, on the other hand, that subcortical visual pathways bypassing the striate cortex, despite affording audio-visual integration processes leading to the improvement of simple visual abilities such as detection, cannot mediate multisensory enhancement of more complex visual functions, such as orientation discrimination.

The importance of visual and olfactory stimuli during flower visits in Apis mellifera

Flowers attract honeybees using colour and scent signals. Bimodality (having both scent and colour) in flowers leads to increased visitation rates, but how the signals influence each other in a foraging situation is still quite controversial. We studied four basic questions: When faced with conflicting scent and colour information, will bees choose by scent and ignore the “wrong” colour, or vice versa? To get to the bottom of this question, we trained bees on scent-colour combination AX (rewarded) versus BY (unrewarded) and tested them on AY (previously rewarded colour and unrewarded scent) versus BX (previously rewarded scent and unrewarded colour). It turned out that the result depends on stimulus quality: if the colours are very similar (unsaturated blue and blue-green), bees choose by scent. If they are very different (saturated blue and yellow), bees choose by colour. We used the same scents, lavender and rosemary, in both cases. Our second question was: Are individual bees hardwired to use colour and ignore scent (or vice versa), or can this behaviour be modified, depending on which cue is more readily available in the current foraging context? To study this question, we picked colour-preferring bees and gave them extra training on scent-only stimuli. Afterwards, we tested if their preference had changed, and if they still remembered the scent stimulus they had originally used as their main cue. We came to the conclusion that a colour preference can be reversed through scent-only training. We also gave scent-preferring bees extra training on colour-only stimuli, and tested for a change in their preference. The number of animals tested was too small for statistical tests (n = 4), but a common tendency suggested that colour-only training leads to a preference for colour. A preference to forage by a certain sensory modality therefore appears to be not fixed but flexible, and adapted to the bee’s surroundings. Our third question was: Do bees learn bimodal stimuli as the sum of their parts (elemental learning), or as a new stimulus which is different from the sum of the components’ parts (configural learning)? We trained bees on bimodal stimuli, then tested them on the colour components only, and the scent components only. We performed this experiment with a similar colour set (unsaturated blue and blue-green, as above), and a very different colour set (saturated blue and yellow), but used lavender and rosemary for scent stimuli in both cases. Our experiment yielded unexpected results: with the different colours, the results were best explained by elemental learning, but with the similar colour set, bees exhibited configural learning. Still, their memory of the bimodal compound was excellent. Finally, we looked at reverse-learning. We reverse-trained bees with bimodal stimuli to find out whether bimodality leads to better reverse-learning compared to monomodal stimuli. We trained bees on AX (rewarded) versus BY (unrewarded), then on AX (unrewarded) versus BY (rewarded), and finally on AX (rewarded) and BY (unrewarded) again. We performed this experiment with both colour sets, always using the same two scents (lavender and rosemary). It turned out that bimodality does not help bees “see the pattern” and anticipate the switch. Generally, bees trained on the different colour set performed better than bees trained on the similar colour set, indicating that stimulus salience influences reverse-learning.

BPAG1 isoform-b: Complex distribution pattern in striated and heart muscle and association with plectin and α-actinin

BPAG1-b is the major muscle-specific isoform encoded by the dystonin gene, which expresses various protein isoforms belonging to the plakin protein family with complex, tissue-specific expression profiles. Recent observations in mice with either engineered or spontaneous mutations in the dystonin gene indicate that BPAG1-b serves as a cytolinker important for the establishment and maintenance of the cytoarchitecture and integrity of striated muscle. Here, we studied in detail its distribution in skeletal and cardiac muscles and assessed potential binding partners. BPAG1-b was detectable in vitro and in vivo as a high molecular mass protein in striated and heart muscle cells, co-localizing with the sarcomeric Z-disc protein alpha-actinin-2 and partially with the cytolinker plectin as well as with the intermediate filament protein desmin. Ultrastructurally, like alpha-actinin-2, BPAG1-b was predominantly localized at the Z-discs, adjacent to desmin-containing structures. BPAG1-b was able to form complexes with both plectin and alpha-actinin-2, and its NH(2)-terminus, which contains an actin-binding domain, directly interacted with that of plectin and alpha-actinin. Moreover, the protein level of BPAG1-b was reduced in muscle tissues from plectin-null mutant mice versus wild-type mice. These studies provide new insights into the role of BPAG1-b in the cytoskeletal organization of striated muscle.

Distribution pattern of 68Ga-DOTATATE in disease-free patients

68Ga-DOTA-DPhe1,Tyr3-octreotate (68Ga-DOTATATE) is a somatostatin analogue that shows high affinity for somatostatin receptor subtype 2 (sst2) and has been used for imaging neuroendocrine tumours. However, normal uptake patterns and potential pitfalls have not been described with this high-sensitivity radiotracer. The aim of this study was therefore to outline the normal distribution pattern of 68Ga-DOTATATE in disease-free patients, to provide standardized uptake values (SUVs) of various organs and to compare our results with the current knowledge on sst2 receptor expression in vitro.

Rapid adaptation of visual search in simulated hemianopia

Patients with homonymous hemianopia have altered visual search patterns, but it is unclear how rapidly this develops and whether it reflects a strategic adaptation to altered perception or plastic changes to tissue damage. To study the temporal dynamics of adaptation alone, we used a gaze-contingent display to simulate left or right hemianopia in 10 healthy individuals as they performed 25 visual search trials. Visual search was slower and less accurate in hemianopic than in full-field viewing. With full-field viewing, there were improvements in search speed, fixation density, and number of fixations over the first 9 trials, then stable performance. With hemianopic viewing, there was a rapid shift of fixation into the blind field over the first 5-7 trials, followed by continuing gradual improvements in completion time, number of fixations, and fixation density over all 25 trials. We conclude that in the first minutes after onset of hemianopia, there is a biphasic pattern of adaptation to altered perception: an early rapid qualitative change that shifts visual search into the blind side, followed by more gradual gains in the efficiency of using this new strategy, a pattern that has parallels in other studies of motor learning.

Incidence, aetiology and pattern of mandibular fractures in central Switzerland

The two major causative factors for mandibular fractures, as stated in the literature, are either interpersonal violence or motor vehicle accidents. The purpose of this study was to describe epidemiological trends of mandibular fractures in Switzerland. A special emphasis was directed towards the potential impact of socio-economic standards on the mechanism and pattern of mandible fractures.

Misleading Population Estimates: Biases and Consistency of Visual Surveys and Matrix Modelling in the Endangered Bearded Vulture

Conservation strategies for long-lived vertebrates require accurate estimates of parameters relative to the populations' size, numbers of non-breeding individuals (the “cryptic” fraction of the population) and the age structure. Frequently, visual survey techniques are used to make these estimates but the accuracy of these approaches is questionable, mainly because of the existence of numerous potential biases. Here we compare data on population trends and age structure in a bearded vulture (Gypaetus barbatus) population from visual surveys performed at supplementary feeding stations with data derived from population matrix-modelling approximations. Our results suggest that visual surveys overestimate the number of immature (<2 years old) birds, whereas subadults (3–5 y.o.) and adults (>6 y.o.) were underestimated in comparison with the predictions of a population model using a stable-age distribution. In addition, we found that visual surveys did not provide conclusive information on true variations in the size of the focal population. Our results suggest that although long-term studies (i.e. population matrix modelling based on capture-recapture procedures) are a more time-consuming method, they provide more reliable and robust estimates of population parameters needed in designing and applying conservation strategies. The findings shown here are likely transferable to the management and conservation of other long-lived vertebrate populations that share similar life-history traits and ecological requirements.

A shared 336 kb haplotype associated with the belt pattern in three divergent cattle breeds

We recently mapped the belt mutation in Brown Swiss cattle to a 922 kb interval on BTA3. In this study, we analysed two additional cattle breeds with the belted phenotype: Galloway and Dutch Belted (Lakenvelder). By genotyping microsatellites in solid-coloured and belted Galloways, we confirmed that the belt mutation in Galloways is strongly associated with the same chromosomal locus as in Brown Swiss cattle. Subsequently, we analysed 36 SNPs in the belt interval in three breeds. We identified a single belt-associated haplotype for each of the analysed breeds. The three breed-specific belt haplotypes share alleles in four blocks. Three of these blocks comprise only one single or two consecutive markers, while the largest shared haplotype block encompasses nine consecutive SNPs in a 336 kb interval. The large shared haplotype across divergent breeds suggests a common mutation for the belt phenotype in all three breeds. We identified a potential candidate gene within this interval coding for the developmental transcription factor HES6. We re-sequenced the complete HES6 coding sequence in belted and solid-coloured cattle but did not find belt-associated polymorphisms. In conclusion, our data provide strong evidence in favour of a common founder for the belt phenotype in different cattle breeds and have resulted in an improved fine-mapping of the causative mutation.

Orientation-selective functional magnetic resonance imaging adaptation in primary visual cortex revisited

The processing of orientations is at the core of our visual experience. Orientation selectivity in human visual cortex has been inferred from psychophysical experiments and more recently demonstrated with functional magnetic resonance imaging (fMRI). One method to identify orientation-selective responses is fMRI adaptation, in which two stimuli—either with the same or with different orientations—are presented successively. A region containing orientation-selective neurons should demonstrate an adapted response to the “same orientation” condition in contrast to the “different orientation” condition. So far, human primary visual cortex (V1) showed orientation-selective fMRI adaptation only in experimental designs using prolonged pre-adaptation periods (∼40 s) in combination with top-up stimuli that are thought to maintain the adapted level. This finding has led to the notion that orientation-selective short-term adaptation in V1 (but not V2 or V3) cannot be demonstrated using fMRI. The present study aimed at re-evaluating this question by testing three differently timed adaptation designs. With the use of a more sensitive analysis technique, we show robust orientation-selective fMRI adaptation in V1 evoked by a short-term adaptation design.

Transient rhythmic network activity in the somatosensory cortex evoked by distributed input in vitro

The initiation and maintenance of physiological and pathophysiological oscillatory activity depends on the synaptic interactions within neuronal networks. We studied the mechanisms underlying evoked transient network oscillation in acute slices of the adolescent rat somatosensory cortex and modeled its underpinning mechanisms. Oscillations were evoked by brief spatially distributed noisy extracellular stimulation, delivered via bipolar electrodes. Evoked transient network oscillation was detected with multi-neuron patch-clamp recordings under different pharmacological conditions. The observed oscillations are in the frequency range of 2-5 Hz and consist of 4-12 mV large, 40-150 ms wide compound synaptic events with rare overlying action potentials. This evoked transient network oscillation is only weakly expressed in the somatosensory cortex and requires increased [K+]o of 6.25 mM and decreased [Ca2+]o of 1.5 mM and [Mg2+]o of 0.5 mM. A peak in the cross-correlation among membrane potential in layers II/III, IV and V neurons reflects the underlying network-driven basis of the evoked transient network oscillation. The initiation of the evoked transient network oscillation is accompanied by an increased [K+]o and can be prevented by the K+ channel blocker quinidine. In addition, a shift of the chloride reversal potential takes place during stimulation, resulting in a depolarizing type A GABA (GABAA) receptor response. Blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionate (AMPA), N-methyl-D-aspartate (NMDA), or GABA(A) receptors as well as gap junctions prevents evoked transient network oscillation while a reduction of AMPA or GABA(A) receptor desensitization increases its duration and amplitude. The apparent reversal potential of -27 mV of the evoked transient network oscillation, its pharmacological profile, as well as the modeling results suggest a mixed contribution of glutamatergic, excitatory GABAergic, and gap junctional conductances in initiation and maintenance of this oscillatory activity. With these properties, evoked transient network oscillation resembles epileptic afterdischarges more than any other form of physiological or pathophysiological neocortical oscillatory activity.

Comparison of spatial and temporal pattern for fMRI obtained with BOLD and arterial spin labeling

Functional magnetic resonance imaging (fMRI) is presently either performed using blood oxygenation level-dependent (BOLD) contrast or using cerebral blood flow (CBF), measured with arterial spin labeling (ASL) technique. The present fMRI study aimed to provide practical hints to favour one method over the other. It involved three different acquisition methods during visual checkerboard stimulation on nine healthy subjects: 1) CBF contrast obtained from ASL, 2) BOLD contrast extracted from ASL and 3) BOLD contrast from Echo planar imaging. Previous findings were replicated; i) no differences between the three measurements were found in the location of the activated region; ii) differences were found in the temporal characteristics of the signals and iii) BOLD has significantly higher sensitivity than ASL perfusion. ASL fMRI was favoured when the investigation demands for perfusion and task related signal changes. BOLD fMRI is more suitable in conjunction with fast event related design.

Differential regulation of metzincins in experimental chronic renal allograft rejection: potential markers and novel therapeutic targets

Chronic renal allograft rejection is characterized by alterations in the extracellular matrix compartment and in the proliferation of various cell types. These features are controlled, in part by the metzincin superfamily of metallo-endopeptidases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase (ADAM) and meprin. Therefore, we investigated the regulation of metzincins in the established Fisher to Lewis rat kidney transplant model. Studies were performed using frozen homogenates and paraffin sections of rat kidneys at day 0 (healthy controls) and during periods of chronic rejection at day +60 and day +100 following transplantation. The messenger RNA (mRNA) expression was examined by Affymetrix Rat Expression Array 230A GeneChip and by real-time Taqman polymerase chain reaction analyses. Protein expression was studied by zymography, Western blot analyses, and immunohistology. mRNA levels of MMPs (MMP-2/-11/-12/-14), of their inhibitors (tissue inhibitors of metalloproteinase (TIMP)-1/-2), ADAM-17 and transforming growth factor (TGF)-beta1 significantly increased during chronic renal allograft rejection. MMP-2 activity and immunohistological staining were augmented accordingly. The most important mRNA elevation was observed in the case of MMP-12. As expected, Western blot analyses also demonstrated increased production of MMP-12, MMP-14, and TIMP-2 (in the latter two cases as individual proteins and as complexes). In contrast, mRNA levels of MMP-9/-24 and meprin alpha/beta had decreased. Accordingly, MMP-9 protein levels and meprin alpha/beta synthesis and activity were downregulated significantly. Members of metzincin families (MMP, ADAM, and meprin) and of TIMPs are differentially regulated in chronic renal allograft rejection. Thus, an altered pattern of metzincins may represent novel diagnostic markers and possibly may provide novel targets for future therapeutic interventions.

The effects of dexmedetomidine/remifentanil and midazolam/remifentanil on auditory-evoked potentials and electroencephalogram at light-to-moderate sedation levels in healthy subjects

Avoidance of excessively deep sedation levels is problematic in intensive care patients. Electrophysiologic monitoring may offer an approach to solving this problem. Since electroencephalogram (EEG) responses to different sedation regimens vary, we assessed electrophysiologic responses to two sedative drug regimens in 10 healthy volunteers. Dexmedetomidine/remifentanil (dex/remi group) and midazolam/remifentanil (mida/remi group) were infused 7 days apart. Each combination of medications was given at stepwise intervals to reach Ramsay scores (RS) 2, 3, and 4. Resting EEG, bispectral index (BIS), and the N100 amplitudes of long-latency auditory-evoked potentials (ERP) were recorded at each level of sedation. During dex/remi, resting EEG was characterized by a recurrent high-power low-frequency pattern which became more pronounced at deeper levels of sedation. BIS Index decreased uniformly in only the dex/remi group (from 94 +/- 3 at baseline to 58 +/- 14 at RS 4) compared to the mida/remi group (from 94 +/- 2 to 76 +/- 10; P = 0.029 between groups). The ERP amplitudes decreased from 5.3 +/- 1.3 at baseline to 0.4 +/- 1.1 at RS 4 (P = 0.003) in only the mida/remi group. We conclude that ERPs in volunteers sedated with dex/remi, in contrast to mida/remi, indicate a cortical response to acoustic stimuli, even when sedation reaches deeper levels. Consequently, ERP can monitor sedation with midazolam but not with dexmedetomidine. The reverse is true for BIS.

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

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

Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration

OBJECTIVE: Mesenchymal stem cells (MSCs) have a broad differentiation potential. We aimed to determine if MSCs are present in fetal membranes and placental tissue and to assess their potential to differentiate into neurogenic and mesodermal lineages. STUDY DESIGN: MSCs isolated from first and third trimester chorion and amnion and first trimester chorionic villi and characterized morphologically and by flourescence-activated cell sorting analysis. Their ability to mature under different culture conditions into various cells of mesodermal and neuroectodermal cell lines was assessed by immuno- and cytochemical staining. RESULTS: Independent of gestational age, cells isolated from fetal membranes and placenta showed typical MSC phenotype (positive for CD166, CD105, CD90, CD73, CD49e, CD44, CD29, CD13, MHC I; negative for CD14, CD34, CD45, MHC II) and were able to differentiate into mesodermal cells expressing cell markers/cytologic staining consistent with mature chondroblasts, osteoblasts, adipocytes, or myocytes and into neuronal cells presenting markers of various stages of maturation. The differentiation pattern was mainly dependent on cell type. CONCLUSION: Mesenchymal cells from chorion, amnion, and villous stroma can be differentiated into neurogenic, chondrogenic, osteogenic, adipogenic, and myogenic lineage. Placental tissue obtained during prenatal chorionic villous sampling or at delivery might be an ideal source for autologous stem cell graft for peripartum neuroregeneration and other clinical issues.