Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients.

BACKGROUND: Developing novel therapeutic agents to treat amyotrophic lateral sclerosis (ALS) has been difficult due to multifactorial pathophysiologic processes at work. Intrathecal drug administration shows promise due to close proximity of cerebrospinal fluid (CSF) to affected tissues. Development of effective intrathecal pharmaceuticals will rely on accurate models of how drugs are dispersed in the CSF. Therefore, a method to quantify these dynamics and a characterization of differences across disease states is needed. METHODS: Complete intrathecal 3D CSF geometry and CSF flow velocities at six axial locations in the spinal canal were collected by T2-weighted and phase-contrast MRI, respectively. Scans were completed for eight people with ALS and ten healthy controls. Manual segmentation of the spinal subarachnoid space was performed and coupled with an interpolated model of CSF flow within the spinal canal. Geometric and hydrodynamic parameters were then generated at 1 mm slice intervals along the entire spine. Temporal analysis of the waveform spectral content and feature points was also completed. RESULTS: Comparison of ALS and control groups revealed a reduction in CSF flow magnitude and increased flow propagation velocities in the ALS cohort. Other differences in spectral harmonic content and geometric comparisons may support an overall decrease in intrathecal compliance in the ALS group. Notably, there was a high degree of variability between cases, with one ALS patient displaying nearly zero CSF flow along the entire spinal canal. CONCLUSION: While our sample size limits statistical confidence about the differences observed in this study, it was possible to measure and quantify inter-individual and cohort variability in a non-invasive manner. Our study also shows the potential for MRI based measurements of CSF geometry and flow to provide information about the hydrodynamic environment of the spinal subarachnoid space. These dynamics may be studied further to understand the behavior of CSF solute transport in healthy and diseased states

Interaction of locomotion and intraspinal lumbosacral organ in birds

Die Fähigkeit von Vögeln sich wendig und präzise in jedem bewohnbaren Lebensraum fortzubewegen, fasziniert Forscher seit über einem Jahrhundert. Es wird vermutet, dass die Beweglichkeit der Vögel durch ein mechanosensorisches Organ ermöglicht wird, welches direkt in die untere Wirbelsäule, im sog. Lumbosakralbereich, integriert ist. Diese Spezialisierung der Vögel im Lumbosakralbereich ist dabei einzigartig unter den Wirbeltieren. Obwohl die morphologischen Spezialisierungen bereits vor mehr als einem Jahrhundert entdeckt wurden, sind ihre funktionellen Merkmale nach wie vor unbekannt. Die unmittelbare Nähe dieses mechanosensorischen Organs zum Ischiasnerv und den damit ver- bundenen motorischen Schaltkreisen könnte erklären, wie Vögel die Grenzen der Nervenleitgeschwindigkeit umgehen, die neuronalen Schaltkreise verkürzen und so die Agilität und Tiefensensibilität (Propriozeption) auch bei hohen Geschwindigkeiten ermöglichen. Die lumbosakrale Region bzw. das "lumbosakrale Organ" (LSO) besteht aus einem sehr dichten Glykogenkörper, der zwischen den Ruckenmarkshälften eingekeilt ist und von einem Geflecht aus zahnförmigen Bändern gestützt wird. Aus den lateralen Seiten des Ruckenmarks ragen akzessorische Lappen in einen mit Flüssigkeit gefüllten, erweiterten Ruckenmarkskanal mit halbkreisförmigen, querverlaufenden Rillen auf der Dorsalseite. Diese akzessorischen Lappen könnten möglicherweise eine mechanosensorischer Funktion aufweisen. Die topographische Analyse der Anatomie dieser Lappen lässt auf zwei Anregungsmechanismen schließen, welche sich nicht zwangsläufig gegenseitig ausschließen. Zum einen könnte die enge Verbindung der akzessorischen Lappen mit dem das Rückenmark stützenden Ligamentum denticulare, einen dehnungsbasierten Mechanismus darstellen. Zum anderen deutet die Ausrichtung der Lappen hin zu den öffnungen der querliegenden Rillen, welche den Bogengängen eines Säugetierinnenohrs ähneln, auf einen Mechanismus hin, welcher über die Bewegung der Flüssigkeit induziert wird. In dieser Arbeit wurden existierende Hypothesen zur Funktionsweise des LSO und dessen Wahrnehmung von Strömungen, Druck oder Dehnung durch die Anwendung moderner Techniken erweitert. Im Gegensatz zu früheren Theorien wurden hier die Interaktion der lumbosakralen Spezialisierungen berücksichtigt. Die morphometrische 3D-Analyse von Daten, die per digitaler Dissektion erzeugt wurden, ermöglichen es den Flussigkeitsraum um das neurale Weichgewebe zu analysieren. Zusätzlich zeigt die klassische Dissektion zeigt feine Details des hängemattenartigen Netzwerks der dentikulären Bänder, die in unserer 3D-Karte nicht sichtbar sind. Durch die Kombination der Ergebnisse der digitalen und der klassischen Dissektion können wir die Verschiebung- und Verformungskapazität des Weichgewebes im vergrößerten und mit Flüssigkeit gefüllten lumbosakralen Wirbelsäulenkanal abschätzen. Die Ermittlung der morphologischen und biomechanischen Eigenschaften erlaubt uns die Hypothese eines sensorischen Mechanismus aufzustellen, der auf der Oszillation des lumbosakralen Weichgewebes durch externe Beschleunigung beruht und dessen Bewegung einem flussigkeitsgefullten Feder-Masse-Dämpfer-System ähnelt. Möglicherweise könnten Auslenkungen des neuralen Weichgewebes durch äußere physikalische Kräfte, über die mechanosensiblen, akzessorischen Lappen erfasst werden. Auf diese Weise könnte der LSO Beschleunigungskräfte unabhängig von dem im Kopf lokalisierten vestibulären Apparat wahrnehmen. Eventuell wird das viskoelastische Rückenmark durch den dichten Glykogenkörper belastet und dadurch verformt. Allerdings wurde bisher in keiner Studie untersucht, ob die Weichteile im Lumbosakralkanal von Vögeln beweglich sind. Die Identifizierung der Weichteilbewegungen in vivo innerhalb der stark pneumatisierten Knochen des fusionierten Synsakrums, die ebenfalls mit mehrschichtigem Weichgewebe bedeckt sind, ist mit den derzeit verfügbaren Techniken nur sehr schwierig zu analysieren. Aus diesem Grund haben wir eine Kombination aus digitaler in situ Dissektion und biophysikalischer Simulation zur Analyse herangezogen. Durch 3D-Scanns von Kadaver-LSO-Proben in verschiedenen Orientierungen konnten wir zeigen, dass die LSO-Weichgewebe im statischen Zustand eine geringe Positionsverschiebung aufweisen. Durch eine Abwandlung des traditionellen diceCT (Iod-kontrastverstärkende Computertomographie)-Protokolls konnten wir außerdem weitere Details der Topologie der Ligamenta denticularis sichtbar machen, welche sich auf die Mobilität des Weichgewebes auswirken könnten. Inspiriert von der LSO-Morphometrie entwickelten wir so ein konfigurierbares, biophysikalisches LSO-Modell, um die Auswirkungen einzelner Strukturen zu untersuchen. Die biophysikalische Simulation bestätigte unsere Annahme, dass das Netzwerk der dentikulären Bänder, sowie das Ausmaß der Beschleunigung, die Beweglichkeit der Weichteile beeinflussen. Durch Veränderung der Parameter des LSO-Modells konnten wir zeigen, dass fluiddynamische Effekte des lumbosakralen Wirbelkanals ebenfalls einen Einfluss auf die Zeit-und Frequenzantwort der Weichteile haben. Unsere Hypothese, dass das LSO einem Feder-Dämpfer-System ähnelt, wird durch das Glykogenkörper-Modell gestützt, welches als mechanischer Verstärker für Ruckenmarksschwingungen fungiert.Avian ability to agile and precise locomotion in every livable habitat has fascinated researchers for over a century. One explanation for birds' agility is a mechanosensory organ directly integrated into the lower spine in the lumbosacral region. The proximity of the potential mechanosensory organ to the sciatic nerve and its associated motor circuits could explain how birds circumvent the limits of nerve conduction velocity associated with proprioception by shortening neural circuits, thereby contributing to the agility of avian locomotion. Avian lumbosacral region's specializations are unique among vertebrates. The lumbosacral region, recently referred to as the lumbosacral organ (LSO), consists of a high-density glycogen body wedged between the spinal cord hemispheres, supported by a pronounced network of denticulate ligaments. From the lateral sides of the spinal cord, accessory lobes with potential mechanosensory function protrude into a fluid-filled expanded spinal canal with transverse semicircular grooves on the dorsal side. Although the LSO specializations were discovered more than a century ago, their functional features remain unknown. The topographic anatomy of the accessory lobes suggests two excitation mechanisms that are not necessarily mutually exclusive. Firstly, the intimal connection of the accessory lobes to the denticulate ligament network supporting the spinal cord offers a strain-based mechanism of accessory lobe excitation. Secondly, the accessory lobes' alignment with the opening of transverse grooves, which resemble the semicircular canals of the mammalian inner ear, indicates that the excitation mechanism could be associated with a fluid flow. In this thesis, by applying modern techniques to earlier hypotheses about the LSO’s perception of fluid flow, pressure, and strain - we developed a new mechanosensing hypothesis, which in contrast to previous theories, considers the interaction of the lumbosacral specializations. 3D morphometric analysis of data produced by digital dissection allows us to evaluate the fluid space around the neural soft tissue. Additionally, classical dissection shows fine details of the hammock-like network of denticulate ligaments not visible in our 3D map. We estimate potential soft tissue displacement and deformation capacity inside the enlarged and fluid-filled lumbosacral spinal canal by combining the digital and classical dissection results. Establishing morphological and biomechanical properties allows us to hypothesize a sensing mechanism based on lumbosacral soft tissue oscillation caused by external acceleration, with a motion similar to a fluid-filled spring-mass-damper system. Potentially the mechanosensitive accessory lobes encode signals about the internal state of the neural soft tissue, entrained by external physical forces. Hence, the LSO may sense acceleration forces independently from the vestibular apparatus localized in the head. A relatively dense glycogen body potentially loads the viscoelastic spinal cord, causing it to deform. However, no study has tested whether the soft tissues inside the lumbosacral canal of birds are movable. The state-of-the-art techniques show limits in identifying soft tissue movements in vivo inside highly pneumatized bones of a fused synsacrum covered with multilayered soft tissue. Therefore, we combined in situ digital dissection and biophysical simulation. 3D scanning of cadaver LSO samples in different orientations enabled us to reveal that the LSO soft tissues exhibit minor position displacement in a static state. Our modification of the traditional diceCT protocol allowed us to visualize previously undocumented details on the denticulate ligament topology, which potentially affects soft tissue mobility. Inspired by LSO morphometrics, we developed a reconfigurable biophysical LSO model to study the impact of individual lumbosacral anatomical structures. The biophysical simulation confirmed our assumption that the denticulate ligament network and the magnitude of acceleration affect soft tissue mobility. By altering the LSO model parameters, we also revealed the fluid dynamics effects of the lumbosacral spinal canal morphology on the soft tissues' time and frequency response. Our hypothesis that the LSO resembles a spring-damper system is supported by the glycogen body model acting as a mechanical amplifier for spinal cord oscillations

Impact of Extremely Low-Frequency Magnetic and Electric Stimuli on Vestibular-Driven Outcomes

The vestibular system is extremely sensitive to electric fields (E-fields). Indeed, vestibular hair cells are graded potential cells and this property makes them very susceptible to small membrane potential modulations. Studies show that extremely low-frequency magnetic fields (ELF-MF) induced E-fields impact postural control in which the vestibular system plays an important role. However, the knowledge of whether this is indeed a vestibular specific effect is still pending. Considering its crucial role and the specific neurophysiological characteristics of its hair cells, the vestibular system emerges as an ELF-MF likely target The three studies presented in this thesis aimed to further address whether ELF-MF modulate vestibular-driven outcomes. Studies 1 and 2 aimed to investigate postural responses while more specifically targeting the vestibular system. However, we did not find any modulation in either study. Nonetheless, based on both studies, study 3 aimed to determine whether the orientation and frequency of our stimulations were more likely to target the otoliths. Therefore, the third study looked at the subjective visual vertical. Here, we found a potential ELF-MF utricular modulation. This thesis is the first steppingstone in a new field of research. Further investigations regarding the interaction between the ELF-MF and the vestibular system will have to look at more reflexives vestibular outcomes. Nonetheless, this thesis provides valuable information that will need to be taken into consideration when writing future international guidelines and standards related to ELF-MF

Non-invasive Multimodal Monitoring in Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability, often resulting in increased intracranial pressure (ICP) and cerebral ischemia. Current ICP measurement methods involve invasive, non-therapeutic procedures. This research aims to develop a non-invasive, continuous optical system for monitoring ICP and cerebral oxygenation. Using backscattered brain optical signals, it leverages cerebral pulsatile photoplethysmograms (PPGs) and non-pulsatile near-infrared spectroscopy (NIRS) signals to assess ICP and oxygenation. The innovation lies in using cerebral NIRS-PPGs to measure ICP, based on the hypothesis that changes in ICP affect cerebral PPG signal morphology. These changes in morphological features, with the support of advanced algorithms including Machine Learning (ML) models, could be utilised in translating the changes in the pulsatile signals in absolute measurements of ICP. The research firstly implemented Monte Carlo simulations to fully understand the effect of multi-source detector separations on brain light tissue interaction. Secondly, a novel reflectance, custom-made TBI multiwavelength and multisource-detector optical sensor and instrumentation, including advanced signal processing algorithms, was designed to acquire, pre-process, and analyse raw PPG signals (AC + DC) from the brain. Thirdly, a novel head phantom and an in vitro brain haemodynamic system were developed for evaluating the sensor. The phantom was the ideal tool for simulating different clinical scenarios that cannot be implemented in real in vivo studies. Fourthly, this research carried out three in vitro studies to investigate the sensor's capability to non-invasively monitor intracranial pressure and oxygenation. The first study evaluated the quality of the optical signals acquired from the developed probe at different source-detector (S-D) separations and multiple wavelengths. It was concluded that the optimal S-D separation to reach the cerebral tissue, and acquire good quality PPG signals, was within 3 cm and 4 cm. The second study assessed the central hypothesis of this research by recording PPG signals from the phantom’s brain at different intracranial pressure levels and implementing ML models utilising pertinent features from the PPG. Results from the second study showed a correlation coefficient of 0.86, mean absolute error of 3.7 mmHg, and limits of agreement of ±4 mmHg, which suggest that NIRS-PPG signals could estimate ICP non invasively. Finally, a third study demonstrated the sensor’s response to in vitro changes in blood oxygenation levels, with less than 33.8% error in half the measurements compared to the reference. This final implementation of spatially resolved spectroscopy algorithms actualize the proposed non-invasive multimodal monitoring sensor for traumatic brain injury. The novel technological developments and the new knowledge acquired from this research paves the way for the development of a transformative non-invasive optical sensor technology for the continuous monitoring of ICP and cerebral oxygenation in TBI patients and beyond

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)

Space Biology and Medicine

Volume IV is devoted to examining the medical and associated organizational measures used to maintain the health of space crews and to support their performance before, during, and after space flight. These measures, collectively known as the medical flight support system, are important contributors to the safety and success of space flight. The contributions of space hardware and the spacecraft environment to flight safety and mission success are covered in previous volumes of the Space Biology and Medicine series. In Volume IV, we address means of improving the reliability of people who are required to function in the unfamiliar environment of space flight as well as the importance of those who support the crew. Please note that the extensive collaboration between Russian and American teams for this volume of work resulted in a timeframe of publication longer than originally anticipated. Therefore, new research or insights may have emerged since the authors composed their chapters and references. This volume includes a list of authors' names and addresses should readers seek specifics on new information. At least three groups of factors act to perturb human physiological homeostasis during space flight. All have significant influence on health, psychological, and emotional status, tolerance, and work capacity. The first and most important of these factors is weightlessness, the most specific and radical change in the ambient environment; it causes a variety of functional and structural changes in human physiology. The second group of factors precludes the constraints associated with living in the sealed, confined environment of spacecraft. Although these factors are not unique to space flight, the limitations they entail in terms of an uncomfortable environment can diminish the well-being and performance of crewmembers in space. The third group of factors includes the occupational and social factors associated with the difficult, critical nature of the crewmembers' work: the risks involved in space flight, changes in circadian rhythms, and intragroup interactions. The physical and emotional stress and fatigue that develop under these conditions also can disturb human health and performance. In addition to these factors, the risk also exists that crewmembers will develop various illnesses during flight. The risk of illness is no less during space flight than on Earth, and may actually be greater for some classes of diseases

Life Sciences Program Tasks and Bibliography

This document includes information on all peer reviewed projects funded by the Office of Life and Microgravity Sciences and Applications, Life Sciences Division during fiscal year 1995. Additionally, this inaugural edition of the Task Book includes information for FY 1994 programs. This document will be published annually and made available to scientists in the space life sciences field both as a hard copy and as an interactive Internet web pag