Brain-derived neurotrophic factor protects against multiple forms of brain injury in bacterial meningitis

BACKGROUND Brain-derived neurotrophic factor (BDNF) blocks activation of caspase-3, reduces translocation of apoptosis-inducing factor (AIF), attenuates excitotoxicity of glutamate, and increases antioxidant enzyme activities. The mechanisms of neuroprotection suggest that BDNF may be beneficial in bacterial meningitis. METHODS To assess a potentially beneficial effect of adjuvant treatment with BDNF in bacterial meningitis, 11-day-old infant rats with experimental meningitis due to Streptococcus pneumoniae or group B streptococci (GBS) were randomly assigned to receive intracisternal injections with either BDNF (3 mg/kg) or equal volumes (10 mu L) of saline. Twenty-two hours after infection, brains were analyzed, by histomorphometrical examination, for the extent of cortical and hippocampal neuronal injury. RESULTS Compared with treatment with saline, treatment with BDNF significantly reduced the extent of 3 distinct forms of brain cell injury in this disease model: cortical necrosis in meningitis due to GBS (median, 0.0% [range, 0.0%-33.7%] vs. 21.3% [range, 0.0%-55.3%]; P<.03), caspase-3-dependent cell death in meningitis due to S. pneumoniae (median score, 0.33 [range, 0.0-1.0] vs. 1.10 [0.10-1.56]; P<.05), and caspase-3-independent hippocampal cell death in meningitis due to GBS (median score, 0 [range, 0-2] vs. 0.88 [range, 0-3.25]; P<.02). The last form of injury was associated with nuclear translocation of AIF. CONCLUSION BDNF efficiently reduces multiple forms of neuronal injury in bacterial meningitis and may hold promise as adjunctive therapy for this disease.

Clinical relevance of brain volume measures in multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA [Structural Image Evaluation using Normalization of Atrophy]). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.

Capture of activity-induced ultrastructural changes at synapses by high-pressure freezing of brain tissue.

Electron microscopy (EM) allows for the simultaneous visualization of all tissue components at high resolution. However, the extent to which conventional aldehyde fixation and ethanol dehydration of the tissue alter the fine structure of cells and organelles, thereby preventing detection of subtle structural changes induced by an experiment, has remained an issue. Attempts have been made to rapidly freeze tissue to preserve native ultrastructure. Shock-freezing of living tissue under high pressure (high-pressure freezing, HPF) followed by cryosubstitution of the tissue water avoids aldehyde fixation and dehydration in ethanol; the tissue water is immobilized in ∼50 ms, and a close-to-native fine structure of cells, organelles and molecules is preserved. Here we describe a protocol for HPF that is useful to monitor ultrastructural changes associated with functional changes at synapses in the brain but can be applied to many other tissues as well. The procedure requires a high-pressure freezer and takes a minimum of 7 d but can be paused at several points.

First valence, then arousal: the temporal dynamics of brain electric activity evoked by emotional stimuli

The temporal dynamics of the neural activity that implements the dimensions valence and arousal during processing of emotional stimuli were studied in two multi-channel ERP experiments that used visually presented emotional words (experiment 1) and emotional pictures (experiment 2) as stimulus material. Thirty-two healthy subjects participated (mean age 26.8 +/- 6.4 years, 24 women). The stimuli in both experiments were selected on the basis of verbal reports in such a way that we were able to map the temporal dynamics of one dimension while controlling for the other one. Words (pictures) were centrally presented for 450 (600) ms with interstimulus intervals of 1,550 (1,400) ms. ERP microstate analysis of the entire epochs of stimulus presentations parsed the data into sequential steps of information processing. The results revealed that in several microstates of both experiments, processing of pleasant and unpleasant valence (experiment 1, microstate #3: 118-162 ms, #6: 218-238 ms, #7: 238-266 ms, #8: 266-294 ms; experiment 2, microstate #5: 142-178 ms, #6: 178-226 ms, #7: 226-246 ms, #9: 262-302 ms, #10: 302-330 ms) as well as of low and high arousal (experiment 1, microstate #8: 266-294 ms, #9: 294-346 ms; experiment 2, microstate #10: 302-330 ms, #15: 562-600 ms) involved different neural assemblies. The results revealed also that in both experiments, information about valence was extracted before information about arousal. The last microstate of valence extraction was identical with the first microstate of arousal extraction.

Coherence and phase locking in the scalp EEG and between LORETA model sources, and microstates as putative mechanisms of brain temporo-spatial functional organization

Brain electric mechanisms of temporary, functional binding between brain regions are studied using computation of scalp EEG coherence and phase locking, sensitive to time differences of few milliseconds. However, such results if computed from scalp data are ambiguous since electric sources are spatially oriented. Non-ambiguous results can be obtained using calculated time series of strength of intracerebral model sources. This is illustrated applying LORETA modeling to EEG during resting and meditation. During meditation, time series of LORETA model sources revealed a tendency to decreased left-right intracerebral coherence in the delta band, and to increased anterior-posterior intracerebral coherence in the theta band. An alternate conceptualization of functional binding is based on the observation that brain electric activity is discontinuous, i.e., that it occurs in chunks of up to about 100 ms duration that are detectable as quasi-stable scalp field configurations of brain electric activity, called microstates. Their functional significance is illustrated in spontaneous and event-related paradigms, where microstates associated with imagery- versus abstract-type mentation, or while reading positive versus negative emotion words showed clearly different regions of cortical activation in LORETA tomography. These data support the concept that complete brain functions of higher order such as a momentary thought might be incorporated in temporal chunks of processing in the range of tens to about 100 ms as quasi-stable brain states; during these time windows, subprocesses would be accepted as members of the ongoing chunk of processing.

Validation of network communicability metrics for the analysis of brain structural networks.

Computational network analysis provides new methods to analyze the brain's structural organization based on diffusion imaging tractography data. Networks are characterized by global and local metrics that have recently given promising insights into diagnosis and the further understanding of psychiatric and neurologic disorders. Most of these metrics are based on the idea that information in a network flows along the shortest paths. In contrast to this notion, communicability is a broader measure of connectivity which assumes that information could flow along all possible paths between two nodes. In our work, the features of network metrics related to communicability were explored for the first time in the healthy structural brain network. In addition, the sensitivity of such metrics was analysed using simulated lesions to specific nodes and network connections. Results showed advantages of communicability over conventional metrics in detecting densely connected nodes as well as subsets of nodes vulnerable to lesions. In addition, communicability centrality was shown to be widely affected by the lesions and the changes were negatively correlated with the distance from lesion site. In summary, our analysis suggests that communicability metrics that may provide an insight into the integrative properties of the structural brain network and that these metrics may be useful for the analysis of brain networks in the presence of lesions. Nevertheless, the interpretation of communicability is not straightforward; hence these metrics should be used as a supplement to the more standard connectivity network metrics.

The structural substrate of brain function: analysis of brain structural networks based on diffusion-weighted imaging

The brain is a complex neural network with a hierarchical organization and the mapping of its elements and connections is an important step towards the understanding of its function. Recent developments in diffusion-weighted imaging have provided the opportunity to reconstruct the whole-brain structural network in-vivo at a large scale level and to study the brain structural substrate in a framework that is close to the current understanding of brain function. However, methods to construct the connectome are still under development and they should be carefully evaluated. To this end, the first two studies included in my thesis aimed at improving the analytical tools specific to the methodology of brain structural networks. The first of these papers assessed the repeatability of the most common global and local network metrics used in literature to characterize the connectome, while in the second paper the validity of further metrics based on the concept of communicability was evaluated. Communicability is a broader measure of connectivity which accounts also for parallel and indirect connections. These additional paths may be important for reorganizational mechanisms in the presence of lesions as well as to enhance integration in the network. These studies showed good to excellent repeatability of global network metrics when the same methodological pipeline was applied, but more variability was detected when considering local network metrics or when using different thresholding strategies. In addition, communicability metrics have been found to add some insight into the integration properties of the network by detecting subsets of nodes that were highly interconnected or vulnerable to lesions. The other two studies used methods based on diffusion-weighted imaging to obtain knowledge concerning the relationship between functional and structural connectivity and about the etiology of schizophrenia. The third study integrated functional oscillations measured using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) as well as diffusion-weighted imaging data. The multimodal approach that was applied revealed a positive relationship between individual fluctuations of the EEG alpha-frequency and diffusion properties of specific connections of two resting-state networks. Finally, in the fourth study diffusion-weighted imaging was used to probe for a relationship between the underlying white matter tissue structure and season of birth in schizophrenia patients. The results are in line with the neurodevelopmental hypothesis of early pathological mechanisms as the origin of schizophrenia. The different analytical approaches selected in these studies also provide arguments for discussion of the current limitations in the analysis of brain structural networks. To sum up, the first studies presented in this thesis illustrated the potential of brain structural network analysis to provide useful information on features of brain functional segregation and integration using reliable network metrics. In the other two studies alternative approaches were presented. The common discussion of the four studies enabled us to highlight the benefits and possibilities for the analysis of the connectome as well as some current limitations.

Differential recruitment of brain networks during visuospatial and color processing: Evidence from ERP microstates

Recent functional magnetic resonance imaging (fMRI) studies consistently revealed contributions of fronto-parietal and related networks to the execution of a visuospatial judgment task, the so-called "Clock Task". However, due to the low temporal resolution of fMRI, the exact cortical dynamics and timing of processing during task performance could not be resolved until now. In order to clarify the detailed cortical activity and temporal dynamics, 14 healthy subjects performed an established version of the "Clock Task", which comprises a visuospatial task (angle discrimination) and a control task (color discrimination) with the same stimulus material, in an electroencephalography (EEG) experiment. Based on the time-resolved analysis of network activations (microstate analysis), differences in timing between the angle compared to the color discrimination task were found after sensory processing in a time window starting around 200ms. Significant differences between the two tasks were observed in an analysis window from 192ms to 776ms. We divided this window in two parts: an early phase - from 192ms to ∼440ms, and a late phase - from ∼440ms to 776ms. For both tasks, the order of network activations and the types of networks were the same, but, in each phase, activations for the two conditions were dominated by differing network states with divergent temporal dynamics. Our results provide an important basis for the assessment of deviations in processing dynamics during visuospatial tasks in clinical populations.

Development and Evaluation of a New Tablet Computer Application for the Therapy of Brain-Injured Patients with Aphasia

Introduction Language is the most important mean of communication and plays a central role in our everyday life. Brain damage (e.g. stroke) can lead to acquired disorders of lan- guage affecting the four linguistic modalities (i.e. reading, writing, speech production and comprehension) in different combinations and levels of severity. Every year, more than 5000 people (Aphasie Suisse) are affected by aphasia in Switzerland alone. Since aphasia is highly individual, the level of difficulty and the content of tasks have to be adapted continuously by the speech therapists. Computer-based assignments allow patients to train independently at home and thus increasing the frequency of ther- apy. Recent developments in tablet computers have opened new opportunities to use these devices for rehabilitation purposes. Especially older people, who have no prior experience with computers, can benefit from the new technologies. Methods The aim of this project was to develop an application that enables patients to train language related tasks autonomously and, on the other hand, allows speech therapists to assign exercises to the patients and to track their results online. Seven categories with various types of assignments were implemented. The application has two parts which are separated by a user management system into a patient interface and a therapist interface. Both interfaces were evaluated using the SUS (Subject Usability Scale). The patient interface was tested by 15 healthy controls and 5 patients. For the patients, we also collected tracking data for further analysis. The therapist interface was evaluated by 5 speech therapists. Results The SUS score are xpatients = 98 and xhealthy = 92.7 (median = 95, SD = 7, 95% CI [88.8, 96.6]) in case of the patient interface and xtherapists = 68 in case of the therapist interface. Conclusion Both, the patients and the healthy subjects, attested high SUS scores to the patient interface. These scores are considered as "best imaginable". The therapist interface got a lower SUS score compared to the patient interface, but is still considered as "good" and "usable". The user tracking system and the interviews revealed that there is room for improvements and inspired new ideas for future versions.

Visibility of lipid resonances in HR-MAS spectra of brain biopsies subject to spinning rate variation.

Lipid resonances from mobile lipids can be observed by (1)H NMR spectroscopy in multiple tissues and have also been associated with malignancy. In order to use lipid resonances as a marker for disease, a reference standard from a healthy tissue has to be established taking the influence of variable factors like the spinning rate into account. The purpose of our study was to investigate the effect of spinning rate variation on the HR-MAS pattern of lipid resonances in non-neoplastic brain biopsies from different regions and visualize polar and non-polar lipids by fluorescence microscopy using Nile Red staining. (1)H HR-MAS NMR spectroscopy demonstrated higher lipid peak intensities in normal sheep brain pure white matter biopsies compared to mixed white and gray matter biopsies and pure gray matter biopsies. High spinning rates increased the visibility particularly of the methyl resonances at 1.3 and the methylene resonance at 0.89ppm in white matter biopsies stronger compared to thalamus and brainstem biopsies, and gray matter biopsies. The absence of lipid droplets and presence of a large number of myelin sheaths observed in white matter by Nile Red fluorescence microscopy suggest that the observed lipid resonances originate from the macromolecular pool of lipid protons of the myelin sheath's plasma membranes. When using lipid contents as a marker for disease, the variable behavior of lipid resonances in different neuroanatomical regions of the brain and at variable spinning rates should be considered. The findings may open up interesting possibilities for investigating lipids in myelin sheaths.

The effect of brain size evolution on feeding propensity, digestive efficiency, and juvenile growth

One key hypothesis in the study of brain size evolution is the expensive tissue hypothesis; the idea that increased investment into the brain should be compensated by decreased investment into other costly organs, for instance the gut. Although the hypothesis is supported by both comparative and experimental evidence, little is known about the potential changes in energetic requirements or digestive traits following such evolutionary shifts in brain and gut size. Organisms may meet the greater metabolic requirements of larger brains despite smaller guts via increased food intake or better digestion. But increased investment in the brain may also hamper somatic growth. To test these hypotheses we here used guppy (Poecilia reticulata) brain size selection lines with a pronounced negative association between brain and gut size and investigated feeding propensity, digestive efficiency (DE), and juvenile growth rate. We did not find any difference in feeding propensity or DE between large- and small-brained individuals. Instead, we found that large-brained females had slower growth during the first 10 weeks after birth. Our study provides experimental support that investment into larger brains at the expense of gut tissue carries costs that are not necessarily compensated by a more efficient digestive system.

Magnetic resonance imaging and computer tomography of brain lesions in water buffaloes and cattle stunned with handguns or captive bolts

Owing to the demand for genuine mozzarella, some 330 water buffaloes are being slaughtered every year in Switzerland albeit a stunning procedure meeting animal welfare and occupational safety requirements remains to be established. To provide a basis for improvements, we sized anatomical specifics in water buffaloes and cattle and we assessed brain lesions after stunning with captive bolts or handguns by diagnostic imaging. In water buffaloes and cattle, the median distance from the frontal skin surface to the inner bone table was 74.0 mm (56.0–100.0 mm) vs 36.6 mm (29.3–44.3 mm) and from skin to the thalamus 144.8 mm (117.1–172.0 mm) vs 102.0 (101.0–121.0 mm), respectively. Consequently, customary captive bolt stunners may be inadequate. Free bullets are potentially suitable for stunning buffaloes but involve occupational safety hazards. The results of the present study shall be used to develop a device allowing effective and safe stunning of water buffaloes.