Detection of information flow between cortical laminae activities and auditory evoked potentials in rats by means of Granger causality.

We seek to understand the relation between invasive high-resolution data and non-invasive measurement in an animal model in an auditory sensory adaptation experimental setting. In a previous study, we estimated the mutual information between the phase of auditory evoked responses (AER) with the phase of local field potentials (LFP) of auditory cortices at different frequency ranges. The results showed a consistently high level of information sharing between the AER activities as well as the responses from the granular layer, which was known as the main thalamo-recipient layer. However, mutual information was fundamentally an undirected measure of information flow. In this study we investigated how well we could characterize direction of information flow, by using Granger causality (GC), between different cortical laminae and functional projections on to the AER activities. We obtained that based on the GC coefficients, we are able to extract the connectivity between different cortical laminae to some extend and also a strong connection between the AER and granular layer. In our future study, we would like to construct a reliable picture of network connectivity, both functionally and anatomically, between different layers at more specified frequencies and much finer temporal resolutions.

Motion reduction and multidimensional denoising in Voltage-sensitive Dye imaging.

Optical Imaging using Voltage-sensitive Dyes is characterized by low fractional changes in fluorescent light intensity upon the application of a stimulus, which leads to slight value differences between pixels on an in-general noisy image sequence. The application of an anisotropic diffusion filtering scheme, in order to contribute to the denoising of the optical images, is proposed as one option to improve its quality and for a better understanding of the physiological processes they represent. We apply an image registration approach to compensate for motion artifacts, such that we do not need to mount a fixed cranial chamber onto the skull. In this work, electrical stimulation to the tibial nerve in a rat model was used to register evoke potentials, imaging the somatosensory cortex of the animal, which was previously stained with the RH1691 dye.

Assessment of long-term habituation correlates in event-related potentials using a von Mises model.

In our preliminary work we were able to demonstrate habituation by analyzing attention correlates in single-trial sequences of auditory event-related potentials (ERPs). Despite different quantitative studies of instantaneous phase of ERPs in long-term habituation, there have been no former studies in generative process underlying the distribution of instantaneous phase information in the context of long-term habituation and its relation to attentional binding. For this means we used a von Mises model, representing the phase information over a set of single trial responses. Additionally we use a quantitative neurofunctional model to predict the dynamics of the instantaneous phase in single-trial ERP data during the long-term habituation. Measured habituation data is used to cross-validate the model's prediction. We conclude that the described method allows for an assessment of dynamic changes in the course of long-term habituation. The results also reinforce our neurofunctional multiscale model of long-term habituation and show the applicability of the described method for the experimental/clinical neurodiagnostic assessment of attentional binding.

Detection of change points in phase data: a Bayesian analysis of habituation processes.

Given a time series of data points, as obtained in biosignal monitoring, the change point problem poses the question of identifying times of sudden variations in the parameters of the underlying data distribution. We propose a method for extracting a discrete set of change points from directional data. Our method is based on a combination of the Bayesian change point model (CPM) and the Viterbi algorithm. We apply our method to the instantaneous phase information of single-trial auditory event-related potentials (ERPs) in a long term habituation paradigm. We have seen in previous studies that the phase information enters a phase-locked mode with respect to the repetition of a stimulus in the state of focused attention. With adaptation to an insignificant stimulus, attention tends to trail away (long-term habituation), characterized by changes in the phase signature, becoming more diffuse across trials. We demonstrate that the proposed method is suitable for detecting the effects of long-term habituation on phase information in our experimental setting.

Modeling prediction of a generalized habituation deficit in decompensated tinnitus sufferers.

The pathologic auditory sensation in decompensated tinnitus patients is accompanied by the inability to habituate even temporary to this sound. This disability might originate from simultaneous activation of brain areas for the appraisal of the stimulus valence as, e.g., the limbic system. This coactivation of limbic areas is likely to modulate the degree and persistence of selective attention assigned to the tinnitus stream, which in turn could also explain interindividual differences in tinnitus loudness perception. Preliminary studies demonstrate that the amount of allocated attention and the habituation deficit can be mapped to changes in auditory late evoked responses (ALRs). Utilizing a numerical model for the simulation of ALRs we were able to predict a general habituation behavior in two patient groups with different degrees of tinnitus severity. Evaluating the instantaneous phase of simulated and measured ALRs by its von Mises concentration parameter, we verify a habituation deficit relative to the degree of decompensation and thus provide additional support for our neurofunctional model of limbic influences on neural processing of sensory information.

Support of a patient-specific therapeutical acoustic stimulation in tinnitus by numerical modeling.

The pathogenesis of tinnitus involves multiple hierarchical levels of auditory processing and appraisal of sensory saliency. Early tinnitus onset is most likely attributed to homeostatic plasticity in the periphery, while the chronification and decompensation are tightly linked to brain areas for the allocation of attentional resources, such as e.g., the thalamocortical feedback loops and the limbic system. Increased spontaneous firing after sensory deafferentation might be sufficient to generate a phantom perception, yet the question why not every peripheral hearing loss automatically elicits a tinnitus sensation is still to be addressed. Utilizing quantitative modeling of multiple hierarchical levels in the auditory pathway, we demonstrate the effects of lateral inhibition on increased spontaneous firing and the resulting elevation of firing regularity and synchronization of neural activity. The presented therapeutical approach is based on the idea of disrupting the heightened regularity of the neural population response in the tinnitus frequency range. This neural activity regularity depends on lateral dispersion of common noise and thus is susceptible for edge effects and might be influenced by a change in neural activity in bordering frequency ranges by fitted acoustical stimulation. We propose the use of patient specifically adapted tailor-made notched acoustic stimulation, utilizing modeling results for the optimal adjustment of the stimulation frequencies to archive a therapeutical edge-effect.

Biocybernetics of attention in the tinnitus decompensation: An integrative multiscale modeling approach.

Tinnitus is one of the most common symptoms affecting people all over the world. In the absence of an established cure many individuals are not only faced with the need to adjust to the sensation of the tinnitus noise, but also with psychological comorbidities. In recent years, different studies have been directed to elucidate the psychophysiological mechanisms that are involved in the tinnitus decompensation. From these, special emphasis has been placed on studies related to attention and habituation, which accordingly play a crucial role in current tinnitus therapy approaches. In spite of such progress, the relationship between selective attention and the tinnitus decompensation with respect to large-scale neural correlates is still not well understood. In order to address this issue, we propose an integrative multiscale modeling approach for studying neural correlates of auditory selective attention in the tinnitus decompensation. Computational simulations based on our model confirmed electroencephalographic human data of both auditory selective attention and the tinnitus decompensation. It is concluded that the proposed methodology represents a promising approach to give insight into the neurodynamics of auditory selective attention in the tinnitus decompensation.

Evidence for a dual source of relaxin in the pregnant rat: immunolocalization in the corpora lutea and endometrium.

Uterine tissue was collected from intact pregnant rats on days 4, 10-15, 18, and 22 of pregnancy and day 2 postpartum and from rats on day 22 of pregnancy after ovariectomy (day 9) and progesterone-estrogen treatment. Placental, cervical, mammary, and pituitary tissues were collected from intact pregnant rats on day 22. Ovarian tissue was collected from intact pregnant rats on days 15, 20, and 22. These tissues were evaluated for relaxin immunostaining at the light microscope level using an antiserum to purified rat relaxin and the avidin biotin immunostaining technique. Since the corpus luteum is the major source of relaxin in the rat, this tissue was used as a positive control. Relaxin immunostaining in the corpus luteum was observed in a discrete region of the cytoplasm. This pattern of staining corresponded with the discrete clustering of relaxin-containing secretory granules found in the rat luteal cells. Relaxin was not observed in the day 22 placenta, cervix, mammary gland, pituitary gland, or day 4-13 pregnant uterus. Relaxin immunostaining was detected in endometrial epithelial cells on days 14-22 of pregnancy and day 2 postpartum. Relaxin immunostaining was more evident at implantation sites than between implantation sites. Antimesometrial epithelial cells at implantation sites contained relaxin immunostaining. The mesometrial surface, which consists of the placenta and decidualized endometrium, did not contain relaxin immunostaining. Relaxin immunostaining was also present in the endometrial epithelial cells of the day 22 pregnant rats that had been ovariectomized on day 9 and given subsequent replacement therapy with ovarian steroids. The presence of relaxin immunostaining in the ovariectomized rat indicates the endometrium is not sequestering relaxin secreted from the corpus luteum. These data provide evidence that the pregnant rat endometrium is a source of relaxin in addition to the corpus luteum. The appearance of relaxin in endometrial epithelial cells after implantation and its prominence at implantation sites may indicate that locally secreted conceptus factors stimulate endometrial relaxin synthesis.

Monoclonal antibodies specific for rat relaxin. VI. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts histological changes associated with cervical softening at parturition in rats.

Relaxin, which is secreted by the corpora lutea throughout the second half of rat pregnancy, promotes the growth and softening of the cervix. The mechanisms at both the cellular and molecular levels by which relaxin brings about these effects remain to be determined. The present study examined the influence of endogenous relaxin on the histological changes associated with cervical softening. A monoclonal antibody for rat relaxin, designated MCA1, was injected iv daily on days 12-22 of gestation. Cervices were removed on day 22, fixed in 10% buffered formalin, embedded in paraffin, and processed for histological staining. Tissue sections (5 microns thick) were stained with Gomori's trichrome stain (collagen), Orcein stain (elastin), or periodic acid-Schiff (polysaccharide). Qualitative and quantitative analyses identified several histological parameters in MCA1-treated rats that differed markedly from those in control rats. Cervices obtained from MCA1-treated rats contained collagen fiber bundles with greater compactness; elastin fibers with greater density, length and interdigitation; arteries with smaller cross-sectional areas; and luminal involutions with smaller areas than controls. The cervices of MCA1-treated rats appeared to contain fewer vacuolated epithelial cells, which secrete polysaccharide-rich material, than did cervices obtained from controls. It seems plausible that most, if not all, of these relaxin-induced modifications of the histological characteristics of the cervix facilitate birth.

Monoclonal antibodies specific for rat relaxin. V. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts development of the mammary apparatus and, hence, lactational performance in rats.

There were two related objectives to this study. The first was to determine the influence of relaxin on development of the mammary apparatus (nipples and glands) during the second half of pregnancy. The second was to determine whether the relaxin-dependent development of the mammary apparatus was required for normal postpartum lactational performance. Both objectives were accomplished by neutralizing endogenous relaxin throughout the second half of pregnancy with a monoclonal antibody specific for rat relaxin (MCA1). MCA1 was administered iv to rats daily from days 12-22 of pregnancy. On day 22 the morphology of the mammary apparatus of MCA1-treated rats differed from that of controls; nipples were dramatically smaller, collagen fibers had significantly greater mean density and consistency, and elastin fibers had greater mean density, length, and interdigitation. In addition, the mean number of alveoli surrounding lactiferous ducts was significantly smaller in MCA1-treated rats than in controls. There were no differences between MCA1-treated rats and controls in the mean thickness of connective tissue surrounding ducts, the height or density of luminal cells lining lactiferous ducts, or the sizes of either adipocytes or arteries. To examine lactational performance, MCA1-treated and control rats were cesarean sectioned between 2100-2400 h on day 22 of pregnancy and given foster pups born of untreated intact donors. Although both MCA1-treated rats and control rats exhibited a high incidence of maternal behavior after cesarean delivery, mean pup weight and incidence of live pups declined markedly during days 1-5 of fosterage in MCA1-treated rats compared to controls. Furthermore, unlike controls, there was no observable postpartum nipple development in MCA1-treated rats by day 5 of fosterage. Mammary glands obtained from MCA1-treated rats on day 5 of fosterage had markedly lower mean weight than controls. This study demonstrates that passive immunization of endogenous relaxin throughout the second half of pregnancy disrupts development of the nipples and mammary glands in the rat. Moreover, it establishes that relaxin's effects on the development of the mammary apparatus during pregnancy are essential for growth and survival of the young during lactation.