Influence of age on the relation between body position and noninvasively acquired intracranial pulse waves.

The capacitive measurement of the head's dielectric properties has been recently proposed as a noninvasive method for deriving surrogates of craniospinal compliance (CC), a parameter used in the evaluation of space-occupying neurological disorders. With the higher prevalence of such disorders in the older compared to the younger population, data on the head's dielectric properties of older healthy individuals would be of particularly high value before assessing pathologic changes. However, so far only measurements on young volunteers (< 30 years) were reported. In the present study, we have investigated the capacitively obtained electric signal known as W in older healthy individuals. Thirteen healthy subjects aged > 60 years were included in the study. W was acquired in the resting state (supine horizontal position), and during head-up and head-down tilting. AMP, the peak-to-valley amplitude of W related to cardiac action, was extracted from W. AMP was higher in this older cohort compared to the previously investigated younger one (0°: 5965 ± 1677 arbitrary units (au)). During head-up tilting, AMP decreased (+ 60°: 4446 ± 1620 au, P < 0.001), whereas it increased during head-down tilting (- 30°: 7600 ± 2123 au, P < 0.001), as also observed in the younger cohort. Our observation that AMP, a metric potentially reflective of CC, is higher in the older compared to the younger cohort aligns with the expected decrease of CC with age. Furthermore, the robustness of AMP is reinforced by the consistent relative changes observed during tilt testing in both cohorts.

Assessment of liver function by gadoxetic acid avidity in MRI in a model of rapid liver regeneration in rats.

BACKGROUND: This animal study investigates the hypothesis of an immature liver growth following ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) by measuring liver volume and function using gadoxetic acid avidity in magnetic resonance imaging (MRI) in models of ALPPS, major liver resection (LR) and portal vein ligation (PVL). METHODS: Wistar rats were randomly allocated to ALPPS, LR or PVL. In contrast-enhanced MRI scans with gadoxetic acid (Primovist®), liver volume and function of the right median lobe (=future liver remnant, FLR) and the deportalized lobes (DPL) were assessed until post-operative day (POD) 5. Liver functionFLR/DPL was defined as the inverse value of time from injection of gadoxetic acid to the blood pool-corrected maximum signal intensityFLR/DPL multiplied by the volumeFLR/DPL. RESULTS: In ALPPS (n = 6), LR (n = 6) and PVL (n = 6), volumeFLR and functionFLR increased proportionally, except on POD 1. Thereafter, functionFLR exceeded volumeFLR increase in LR and ALPPS, but not in PVL. Total liver function was significantly reduced after LR until POD 3, but never undercuts 60% of its pre-operative value following ALPPS and PVL. DISCUSSION: This study shows for the first time that functional increase is proportional to volume increase in ALPPS using gadoxetic acid avidity in MRI.

Current Understanding of the Anatomy, Physiology, and Magnetic Resonance Imaging of Neurofluids: Update From the 2022 "ISMRM Imaging Neurofluids Study group" Workshop in Rome.

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery. Evidence level: 1 Technical Efficacy: Stage 3.

Incorporating Unresolved Stresses in Blood Damage Modeling: Energy Dissipation More Accurate Than Reynolds Stress Formulation.

OBJECTIVE: Reynolds Averaged Navier Stokes (RANS) models are often used as the basis for modeling blood damage in turbulent flows. To predict blood damage by turbulence stresses that are not resolved in RANS, a stress formulation that represents the corresponding scales is required. Here, we compare two commonly employed stress formulations: a scalar stress representation that uses Reynolds stresses as a surrogate for unresolved fluid stresses, and an effective stress formulation based on energy dissipation. METHODS: We conducted unsteady RANS simulations of the CentriMag blood pump with three different closure models and a Large Eddy Simulation (LES) for reference. We implemented both stress representations in all models and compared the resulting total stress distributions in Eulerian and Lagrangian frameworks. RESULTS: The Reynolds-stress-based approach overestimated the contribution of unresolved stresses in RANS, with differences between closure models of up to several orders of magnitude. With the dissipation-based approach, the total stresses predicted with RANS deviated by about 50% from the LES reference, which was more accurate than only considering resolved stresses. CONCLUSION: The Reynolds-stress-based formulation proved unreliable for estimating scalar stresses in our RANS simulations, while the dissipation-based approach provided an accuracy improvement over simply neglecting unresolved stresses. SIGNIFICANCE: Our results suggest that dissipation-based inclusion of unresolved stresses should be the preferred choice for blood damage modeling in RANS.

Terabyte-scale supervised 3D training and benchmarking dataset of the mouse kidney.

The performance of machine learning algorithms, when used for segmenting 3D biomedical images, does not reach the level expected based on results achieved with 2D photos. This may be explained by the comparative lack of high-volume, high-quality training datasets, which require state-of-the-art imaging facilities, domain experts for annotation and large computational and personal resources. The HR-Kidney dataset presented in this work bridges this gap by providing 1.7 TB of artefact-corrected synchrotron radiation-based X-ray phase-contrast microtomography images of whole mouse kidneys and validated segmentations of 33 729 glomeruli, which corresponds to a one to two orders of magnitude increase over currently available biomedical datasets. The image sets also contain the underlying raw data, threshold- and morphology-based semi-automatic segmentations of renal vasculature and uriniferous tubules, as well as true 3D manual annotations. We therewith provide a broad basis for the scientific community to build upon and expand in the fields of image processing, data augmentation and machine learning, in particular unsupervised and semi-supervised learning investigations, as well as transfer learning and generative adversarial networks.

Radiological feature heterogeneity supports etiological diversity among patient groups in Meniere's disease.

We aimed to determine the prevalence of radiological temporal bone features that in previous studies showed only a weak or an inconsistent association with the clinical diagnosis of Meniere's disease (MD), in two groups of MD patients (n = 71) with previously established distinct endolymphatic sac pathologies; i.e. the group MD-dg (ES degeneration) and the group MD-hp (ES hypoplasia). Delayed gadolinium-enhanced MRI and high-resolution CT data were used to determine and compare between and within (affected vs. non-affected side) groups geometric temporal bone features (lengths, widths, contours), air cell tract volume, height of the jugular bulb, sigmoid sinus width, and MRI signal intensity alterations of the ES. Temporal bone features with significant intergroup differences were the retrolabyrinthine bone thickness (1.04 ± 0.69 mm, MD-hp; 3.1 ± 1.9 mm, MD-dg; p < 0.0001); posterior contour tortuosity (mean arch-to-chord ratio 1.019 ± 0.013, MD-hp; 1.096 ± 0.038, MD-dg; p < 0.0001); and the pneumatized volume (1.37 [0.86] cm3, MD-hp; 5.25 [3.45] cm3, MD-dg; p = 0.03). Features with differences between the affected and non-affected sides within the MD-dg group were the sigmoid sinus width (6.5 ± 1.7 mm, affected; 7.6 ± 2.1 mm, non-affected; p = 0.04) and the MRI signal intensity of the endolymphatic sac (median signal intensity, affected vs. unaffected side, 0.59 [IQR 0.31-0.89]). Radiological temporal bone features known to be only weakly or inconsistently associated with the clinical diagnosis MD, are highly prevalent in either of two MD patient groups. These results support the existence of diverse-developmental and degenerative-disease etiologies manifesting with distinct radiological temporal bone abnormalities.

Assessment of extracranial carotid artery disease using digital twins - A pilot study.

To improve risk stratification in extracranial internal carotid artery disease (CAD), patients who would benefit maximally from revascularization must be identified. In cardiology, the fractional flow reserve (FFR) has become a reference standard for evaluating the functional severity of coronary artery stenosis, and noninvasive surrogates thereof relying on computational fluid dynamics (CFD) have been developed. Here, we present a CFD-based workflow using digital twins of patients' carotid bifurcations derived from computed tomography angiography for the noninvasive functional assessment of CAD. We reconstructed patient-specific digital twins of 37 carotid bifurcations. We implemented a CFD model using common carotid artery peak systolic velocity (PSV) acquired with Doppler ultrasound (DUS) as inlet boundary condition and a two-element Windkessel model as oulet boundary condition. The agreement between CFD and DUS on the PSV in the internal carotid artery (ICA) was then compared. The relative error for the agreement between DUS and CFD was 9% ± 20% and the intraclass correlation coefficient was 0.88. Furthermore, hyperemic simulations in a physiological range were feasible and unmasked markedly different pressure drops along two ICA stenoses with similar degree of narrowing under comparable ICA blood flow. Hereby, we lay the foundation for prospective studies on noninvasive CFD-based derivation of metrics similar to the FFR for the assessment of CAD.

Queckenstedt's test repurposed for the quantitative assessment of the cerebrospinal fluid pulsatility curve.

PURPOSE: Before the era of spinal imaging, presence of a spinal canal block was tested through gross changes in cerebrospinal fluid pressure (CSFP) provoked by manual compression of the jugular veins (referred to as Queckenstedt's test; QT). Beyond these provoked gross changes, cardiac-driven CSFP peak-to-valley amplitudes (CSFPp) can be recorded during CSFP registration. This is the first study to assess whether the QT can be repurposed to derive descriptors of the CSF pulsatility curve, focusing on feasibility and repeatability. METHOD: Lumbar puncture was performed in lateral recumbent position in fourteen elderly patients (59.7±9.3 years, 6F) (NCT02170155) without stenosis of the spinal canal. CSFP was recorded during resting state and QT. A surrogate for the relative pulse pressure coefficient was computed from repeated QTs (i.e., RPPC-Q). RESULTS: Resting state mean CSFP was 12.3 mmHg (IQR 3.2) and CSFPp was 1.0 mmHg (0.5). Mean CSFP rise during QT was 12.5 mmHg (7.3). CSFPp showed an average 3-fold increase at peak QT compared to the resting state. Median RPPC-Q was 0.18 (0.04). There was no systematic error in the computed metrics between the first and second QT. CONCLUSION: This technical note describes a method to reliably derive, beyond gross CSFP increments, metrics related to cardiac-driven amplitudes during QT (i.e., RPPC-Q). A study comparing these metrics as obtained by established procedures (i.e., infusion testing) and by QT is warranted.

Evolution of hypoxia and hypoxia-inducible factor asparaginyl hydroxylase regulation in chronic kidney disease.

BACKGROUND: The roles of hypoxia and hypoxia inducible factor (HIF) during chronic kidney disease (CKD) are much debated. Interventional studies with HIF-α activation in rodents have yielded contradictory results. The HIF pathway is regulated by prolyl and asparaginyl hydroxylases. While prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect asparaginyl hydroxylase factor inhibiting HIF (FIH). METHODS: We used a model of progressive proteinuric CKD and a model of obstructive nephropathy with unilateral fibrosis. In these models we assessed hypoxia with pimonidazole and vascularization with three-dimensional micro-computed tomography imaging. We analysed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies of various severity degrees to assess FIH expression. Finally, we modulated FIH activity in vitro and in vivo using a pharmacologic approach to assess its relevance in CKD. RESULTS: In our model of proteinuric CKD, we show that early CKD stages are not characterized by hypoxia or HIF activation. At late CKD stages, some areas of hypoxia are observed, but these are not colocalizing with fibrosis. In mice and in humans, we observed a downregulation of the HIF pathway, together with an increased FIH expression in CKD, according to its severity. Modulating FIH in vitro affects cellular metabolism, as described previously. In vivo, pharmacologic FIH inhibition increases the glomerular filtration rate of control and CKD animals and is associated with decreased development of fibrosis. CONCLUSIONS: The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seems promising in proteinuric kidney disease.

Cerebrospinal Fluid Pressure Dynamics as a Bedside Test in Traumatic Spinal Cord Injury to Assess Surgical Spinal Cord Decompression: Safety, Feasibility, and Proof-of-Concept.

BACKGROUND: Sufficient and timely spinal cord decompression is a critical surgical objective for neurological recovery in spinal cord injury (SCI). Residual cord compression may be associated with disturbed cerebrospinal fluid pressure (CSFP) dynamics. OBJECTIVES: This study aims to assess whether intrathecal CSFP dynamics in SCI following surgical decompression are feasible and safe, and to explore the diagnostic utility. METHODS: Prospective cohort study. Bedside lumbar CSFP dynamics and cervical MRI were obtained following surgical decompression in N = 9 with mostly cervical acute-subacute SCI and N = 2 patients with non-traumatic SCI. CSFP measurements included mean CSFP, cardiac-driven CSFP peak-to-valley amplitudes (CSFPp), Valsalva maneuver, and Queckenstedt's test (firm pressure on jugular veins, QT). From QT, proxies for cerebrospinal fluid pulsatility curve were calculated (ie, relative pulse pressure coefficient; RPPC-Q). CSFP metrics were compared to spine-healthy patients. computer tomography (CT)-myelography was done in 3/8 simultaneous to CSFP measurements. RESULTS: Mean age was 45 ± 9 years (range 17-67; 3F), SCI was complete (AIS A, N = 5) or incomplete (AIS B-D, N = 6). No adverse events related to CSFP assessments. CSFP rise during QT was induced in all patients [range 9.6-26.6 mmHg]. However, CSFPp was reduced in 3/11 (0.1-0.3 mmHg), and in 3/11 RPPC-Q was abnormal (0.01-0.05). Valsalva response was reduced in 8/11 (2.6-23.4 mmHg). CSFP dynamics corresponded to CT-myelography. CONCLUSIONS: Comprehensive bedside lumbar CSFP dynamics in SCI following decompression are safe, feasible, and can reveal distinct patterns of residual spinal cord compression. Longitudinal studies are required to define critical thresholds of impaired CSFP dynamics that may impact neurological recovery and requiring surgical revisions.

The effect of body position change on noninvasively acquired intracranial pulse waves.

Objective. Craniospinal compliance (CC) is an important metric for the characterization of space-occupying neurological pathologies. CC is obtained using invasive procedures that carry risks for the patients. Therefore, noninvasive methods for acquiring surrogates of CC have been proposed, most recently based on changes in the head's dielectric properties during the cardiac cycle. Here, we have tested whether changes in body position, which are known to influence CC, are reflected in a capacitively acquired signal (hereinafter referred to as W) originating from dynamic changes of the head's dielectric properties.Approach. eighteen young healthy volunteers were included in the study. After 10 min in supine position, subjects were tilted head-up (HUT), back to 0° (horizontal, control), and then head-down (HDT). Metrics related to cardiovascular action were extracted from W, including AMP, the peak-to-valley amplitude of the cardiac modulation of W. Computational electromagnetic simulations were performed to probe the association between intracranial volume change and W.Main results. AMP decreased during HUT (0°: 2869 ± 597 arbitrary units (au); +75°: 2307 ± 490 au,P= 0.002) and increased during HDT (-30°: 4403 ± 1428 au,P< 0.0001). The same behavior was predicted by the electromagnetic model.Significance. tilting affects the distribution of CC between cranial and spinal compartments. Cardiovascular action induces compliance-dependent oscillatory changes in the intracranial fluid composition, which causes corresponding variations in the head's dielectric properties. These manifest as increasing AMP with decreasing intracranial compliance, which suggests that W may contain information related to CC, and that it might be possible to derive CC surrogates therefrom.

Are standing osmotic gradients the main driver of cerebrospinal fluid production? A computational analysis.

BACKGROUND: The mechanisms of cerebrospinal fluid (CSF) production by the ventricular choroid plexus (ChP) have not been fully deciphered. One prominent hypothesized mechanism is trans-epithelial water transport mediated by accumulation of solutes at the luminal ChP membrane that produces local osmotic gradients. However, this standing osmotic gradient hypothesis has not been systematically tested. METHODS: To assess the plausibility of the standing gradient mechanism serving as the main driver of CSF production by the ChP, we developed a three-dimensional (3D) and a one-dimensional (1D) computational model to quantitatively describe the associated processes in the rat ChP inter-microvillar spaces and in CSF pools between macroscopic ChP folds (1D only). The computationally expensive 3D model was used to examine the applicability of the 1D model for hypothesis testing. The 1D model was employed to predict the rate of CSF produced by the standing gradient mechanism for 200,000 parameter permutations. Model parameter values for each permutation were chosen by random sampling from distributions derived from published experimental data. RESULTS: Both models predict that the CSF production rate by the standing osmotic gradient mechanism is below 10% of experimentally measured values that reflect the contribution of all actual production mechanisms. The 1D model indicates that increasing the size of CSF pools between ChP folds, where diffusion dominates solute transport, would increase the contribution of the standing gradient mechanism to CSF production. CONCLUSIONS: The models suggest that the effect of standing osmotic gradients is too small to contribute substantially to CSF production. ChP motion and movement of CSF in the ventricles, which are not accounted for in the models, would further reduce this effect, making it unlikely that standing osmotic gradients are the main drivers of CSF production.

Large-scale morphometry of the subarachnoid space of the optic nerve.

BACKGROUND: The meninges, formed by dura, arachnoid and pia mater, cover the central nervous system and provide important barrier functions. Located between arachnoid and pia mater, the cerebrospinal fluid (CSF)-filled subarachnoid space (SAS) features a variety of trabeculae, septae and pillars. Like the arachnoid and the pia mater, these structures are covered with leptomeningeal or meningothelial cells (MECs) that form a barrier between CSF and the parenchyma of the optic nerve (ON). MECs contribute to the CSF proteome through extensive protein secretion. In vitro, they were shown to phagocytose potentially toxic proteins, such as α-synuclein and amyloid beta, as well as apoptotic cell bodies. They therefore may contribute to CSF homeostasis in the SAS as a functional exchange surface. Determining the total area of the SAS covered by these cells that are in direct contact with CSF is thus important for estimating their potential contribution to CSF homeostasis. METHODS: Using synchrotron radiation-based micro-computed tomography (SRµCT), two 0.75 mm-thick sections of a human optic nerve were acquired at a resolution of 0.325 µm/pixel, producing images of multiple terabytes capturing the geometrical details of the CSF space. Special-purpose supercomputing techniques were employed to obtain a pixel-accurate morphometric description of the trabeculae and estimate internal volume and surface area of the ON SAS. RESULTS: In the bulbar segment, the ON SAS microstructure is shown to amplify the MECs surface area up to 4.85-fold compared to an "empty" ON SAS, while just occupying 35% of the volume. In the intraorbital segment, the microstructure occupies 35% of the volume and amplifies the ON SAS area 3.24-fold. CONCLUSIONS: We provided for the first time an estimation of the interface area between CSF and MECs. This area is of importance for estimating a potential contribution of MECs on CSF homeostasis.

Characterising spinal cerebrospinal fluid flow in the pig with phase-contrast magnetic resonance imaging.

BACKGROUND: Detecting changes in pulsatile cerebrospinal fluid (CSF) flow may assist clinical management decisions, but spinal CSF flow is relatively understudied. Traumatic spinal cord injuries (SCI) often cause spinal cord swelling and subarachnoid space (SAS) obstruction, potentially causing pulsatile CSF flow changes. Pigs are emerging as a favoured large animal SCI model; therefore, the aim of this study was to characterise CSF flow along the healthy pig spine. METHODS: Phase-contrast magnetic resonance images (PC-MRI), retrospectively cardiac gated, were acquired for fourteen laterally recumbent, anaesthetised and ventilated, female domestic pigs (22-29 kg). Axial images were obtained at C2/C3, T8/T9, T11/T12 and L1/L2. Dorsal and ventral SAS regions of interest (ROI) were manually segmented. CSF flow and velocity were determined throughout a cardiac cycle. Linear mixed-effects models, with post-hoc comparisons, were used to identify differences in peak systolic/diastolic flow, and maximum velocity (cranial/caudal), across spinal levels and dorsal/ventral SAS. Velocity wave speed from C2/C3 to L1/L2 was calculated. RESULTS: PC-MRI data were obtained for 11/14 animals. Pulsatile CSF flow was observed at all spinal levels. Peak systolic flow was greater at C2/C3 (dorsal: - 0.32 ± 0.14 mL/s, ventral: - 0.15 ± 0.13 mL/s) than T8/T9 dorsally (- 0.04 ± 0.03 mL/s; p < 0.001), but not different ventrally (- 0.08 ± 0.08 mL/s; p = 0.275), and no difference between thoracolumbar levels (p > 0.05). Peak diastolic flow was greater at C2/C3 (0.29 ± 0.08 mL/s) compared to T8/T9 (0.03 ± 0.03 mL/s, p < 0.001) dorsally, but not different ventrally (p = 1.000). Cranial and caudal maximum velocity at C2/C3 were greater than thoracolumbar levels dorsally (p < 0.001), and T8/T9 and L1/L2 ventrally (p = 0.022). Diastolic velocity wave speed was 1.41 ± 0.39 m/s dorsally and 1.22 ± 0.21 m/s ventrally, and systolic velocity wave speed was 1.02 ± 0.25 m/s dorsally and 0.91 ± 0.22 m/s ventrally. CONCLUSIONS: In anaesthetised and ventilated domestic pigs, spinal CSF has lower pulsatile flow and slower velocity wave propagation, compared to humans. This study provides baseline CSF flow at spinal levels relevant for future SCI research in this animal model.

Noninvasive Monitoring of Intracranial Pulse Waves.

OBJECTIVE: The clinical management of several neurological disorders benefits from the assessment of intracranial pressure and craniospinal compliance. However, the associated procedures are invasive in nature. Here, we aimed to assess whether naturally occurring periodic changes in the dielectric properties of the head could serve as the basis for deriving surrogates of craniospinal compliance noninvasively. METHODS: We designed a device and electrodes for noninvasive measurement of periodic changes of the dielectric properties of the human head. We characterized the properties of the device-electrode-head system by measurements on healthy volunteers, by computational modeling, and by electromechanical modeling. We then performed hyperventilation testing to assess whether the measured signal is of intracranial origin. RESULTS: Signals obtained with the device on volunteers showed characteristic cardiac and respiratory modulations. Signal oscillations can be attributed primarily to changes in resistive properties of the head during cardiac and respiratory cycles. Reduction of end-tidal CO2, through hyperventilation, resulted in a decrease in the signal amplitude associated with cardiovascular action. CONCLUSION: Given the higher CO2 reactivity of intracranial vessels compared to extracranial ones, the results of hyperventilation testing suggest that the acquired signal is, in part, of intracranial origin. SIGNIFICANCE: If confirmed in larger cohorts, our observations suggest that noninvasive capacitive acquisition of changes in the dielectric properties of the head could be used to derive surrogates of craniospinal compliance.

Theory for a non-invasive diagnostic biomarker for craniospinal diseases.

Monitoring intracranial pressure (ICP) and craniospinal compliance (CC) is frequently required in the treatment of patients suffering from craniospinal diseases. However, current approaches are invasive and cannot provide continuous monitoring of CC. Dynamic exchange of blood and cerebrospinal fluid (CSF) between cranial and spinal compartments due to cardiac action transiently modulates the geometry and dielectric properties of the brain. The resulting impedance changes can be measured and might be usable as a non-invasive CC surrogate. A numerically robust and computationally efficient approach based on the reciprocity theorem was developed to compute dynamic impedance changes resulting from small geometry and material property changes. The approach was successfully verified against semi-analytical benchmarks, before being combined with experimental brain pulsation data to study the information content of the impedance variation. The results indicate that the measurable signal is dominated by the pulsatile displacement of the cortical brain surface, with minor contributions from the ventricular surfaces and from changes in brain perfusion. Different electrode setups result in complementary information. The information content from the investigated three electrode pairs was employed to successfully infer subject-specific brain pulsation and motion features. This suggests that non-invasive CC surrogates based on impedance monitoring could be established.

Cerebrospinal fluid pressure dynamics reveal signs of effective spinal canal narrowing in ambiguous spine conditions.

Spinal canal narrowing with consecutive spinal cord compression is considered a key mechanism in degenerative cervical myelopathy (DCM). DCM is a common spine condition associated with progressive neurological disability, and timely decompressive surgery is recommended. However, the clinical and radiological diagnostic workup is often ambiguous, challenging confident proactive treatment recommendations. Cerebrospinal fluid pressure dynamics (CSFP) are altered by spinal canal narrowing. Therefore, we aim to explore the potential value of bedside CSFP assessments for qualitative and quantitative assessment of spinal canal narrowing in DCM. In this prospective case series, seven patients with DCM underwent bedside lumbar puncture with measurement of CSFP dynamics and routine CSF analysis (NCT02170155). The patients were enrolled when standard diagnostic algorithms did not permit a clear treatment decision. Measurements include baseline CSFP, cardiac-driven CSFP peak-to-trough amplitude (CSFPp), and the Queckenstedt's test (firm pressure on jugular veins) in neutral and reclined head position. From the Queckenstedt's test, proxies for craniospinal elastance (i.e., relative pulse pressure coefficient; RPPC-Q) were calculated analogously to infusion testing. CSFP metrics were deemed suspicious of canal narrowing when numbers were lower than the minimum value from a previously tested elderly spine-healthy cohort (N = 14). Mean age was 56 ± 13 years (range, 38-75; 2F); symptom severity was mostly mild to moderate (mean mJOA, 13.5 ± 2.6; range, 9-17). All the patients showed some extent of cervical stenosis in the MRI of unclear significance (5/7 following decompressive cervical spine surgery with an adjacent level or residual stenosis). Baseline CSFP was normal except for one patient (range, 4.7-17.4 mmHg). Normal values were found for CSFPp (0.4-1.3 mmHg) and the Queckenstedt's test in normal head positioning (9.-25.3 mmHg). During reclination, the Queckenstedt's test significantly decreased in one, and CSFPp in another case (>50% compared to normal position). RPPC-Q (0.07-0.19) aligned with lower values from spine-healthy (0.10-0.44). Routine CSF examinations showed mild total protein elevation (mean, 522 ± 108 mg/ml) without further evidence for the disturbed blood brain barrier. Intrathecal CSFP measurements allow discerning disturbed from normal CSFP dynamics in this population. Prospective longitudinal studies should further evaluate the diagnostic utility of CSFP assessments in DCM.

Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure.

BACKGROUND: Disturbances in the brain fluid balance can lead to life-threatening elevation in the intracranial pressure (ICP), which represents a vast clinical challenge. Nevertheless, the details underlying the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP. METHODS: Experimental rats were employed for in vivo determinations of CSF secretion rates, ICP, blood pressure and ex vivo excised choroid plexus for morphological analysis and quantification of expression and activity of various transport proteins. CSF and blood extractions from rats, pigs, and humans were employed for osmolality determinations and a mathematical model employed to determine a contribution from potential local gradients at the surface of choroid plexus. RESULTS: We demonstrate that CSF secretion can occur independently of conventional osmosis and that local osmotic gradients do not suffice to support CSF secretion. Instead, the CSF secretion across the luminal membrane of choroid plexus relies approximately equally on the Na+/K+/2Cl- cotransporter NKCC1, the Na+/HCO3- cotransporter NBCe2, and the Na+/K+-ATPase, but not on the Na+/H+ exchanger NHE1. We demonstrate that pharmacological modulation of CSF secretion directly affects the ICP. CONCLUSIONS: CSF secretion appears to not rely on conventional osmosis, but rather occur by a concerted effort of different choroidal transporters, possibly via a molecular mode of water transport inherent in the proteins themselves. Therapeutic modulation of the rate of CSF secretion may be employed as a strategy to modulate ICP. These insights identify new promising therapeutic targets against brain pathologies associated with elevated ICP.

Shape Trumps Size: Image-Based Morphological Analysis Reveals That the 3D Shape Discriminates Intracranial Aneurysm Disease Status Better Than Aneurysm Size.

Background: To date, it remains difficult for clinicians to reliably assess the disease status of intracranial aneurysms. As an aneurysm's 3D shape is strongly dependent on the underlying formation processes, it is believed that the presence of certain shape features mirrors the disease status of the aneurysm wall. Currently, clinicians associate irregular shape with wall instability. However, no consensus exists about which shape features reliably predict instability. In this study, we present a benchmark to identify shape features providing the highest predictive power for aneurysm rupture status. Methods: 3D models of aneurysms were extracted from medical imaging data (3D rotational angiographies) using a standardized protocol. For these aneurysm models, we calculated a set of metrics characterizing the 3D shape: Geometry indices (such as undulation, ellipticity and non-sphericity); writhe- and curvature-based metrics; as well as indices based on Zernike moments. Using statistical learning methods, we investigated the association between shape features and aneurysm disease status. This processing was applied to a clinical dataset of 750 aneurysms (261 ruptured, 474 unruptured) registered in the AneuX morphology database. We report here statistical performance metrics [including the area under curve (AUC)] for morphometric models to discriminate between ruptured and unruptured aneurysms. Results: The non-sphericity index NSI (AUC = 0.80), normalized Zernike energies Z N s u r f (AUC = 0.80) and the modified writhe-index W ¯ m e a n L 1 (AUC = 0.78) exhibited the strongest association with rupture status. The combination of predictors further improved the predictive performance (without location: AUC = 0.82, with location AUC = 0.87). The anatomical location was a good predictor for rupture status on its own (AUC = 0.78). Different protocols to isolate the aneurysm dome did not affect the prediction performance. We identified problems regarding generalizability if trained models are applied to datasets with different selection biases. Conclusions: Morphology provided a clear indication of the aneurysm disease status, with parameters measuring shape (especially irregularity) being better predictors than size. Quantitative measurement of shape, alone or in conjunction with information about aneurysm location, has the potential to improve the clinical assessment of intracranial aneurysms.

Insights Into the Low Rate of In-Pump Thrombosis With the HeartMate 3: Does the Artificial Pulse Improve Washout?

While earlier studies reported no relevant effect of the HeartMate 3 (HM3) artificial pulse (AP) on bulk pump washout, its effect on regions with prolonged residence times remains unexplored. Using numerical simulations, we compared pump washout in the HM3 with and without AP with a focus on the clearance of the last 5% of the pump volume. Results were examined in terms of flush-volume (V f , number of times the pump was flushed with new blood) to probe the effect of the AP independent of changing flow rate. Irrespective of the flow condition, the HM3 washout scaled linearly with flush volume up to 70% washout and slowed down for the last 30%. Flush volumes needed to washout 95% of the pump were comparable with and without the AP (1.3-1.4 V f ), while 99% washout required 2.1-2.2 V f with the AP vs. 2.5 V f without the AP. The AP enhanced washout of the bend relief and near-wall regions. It also transiently shifted or eliminated stagnation regions and led to rapid wall shear stress fluctuations below the rotor and in the secondary flow path. Our results suggest potential benefits of the AP for clearance of fluid regions that might elicit in-pump thrombosis and provide possible mechanistic rationale behind clinical data showing very low rate of in-pump thrombosis with the HM3. Further optimization of the AP sequence is warranted to balance washout efficacy while limiting blood damage.