Advancing multiscale structural mapping of the brain through fluorescence imaging and analysis across length scales.

Brain function emerges from hierarchical neuronal structure that spans orders of magnitude in length scale, from the nanometre-scale organization of synaptic proteins to the macroscopic wiring of neuronal circuits. Because the synaptic electrochemical signal transmission that drives brain function ultimately relies on the organization of neuronal circuits, understanding brain function requires an understanding of the principles that determine hierarchical neuronal structure in living or intact organisms. Recent advances in fluorescence imaging now enable quantitative characterization of neuronal structure across length scales, ranging from single-molecule localization using super-resolution imaging to whole-brain imaging using light-sheet microscopy on cleared samples. These tools, together with correlative electron microscopy and magnetic resonance imaging at the nanoscopic and macroscopic scales, respectively, now facilitate our ability to probe brain structure across its full range of length scales with cellular and molecular specificity. As these imaging datasets become increasingly accessible to researchers, novel statistical and computational frameworks will play an increasing role in efforts to relate hierarchical brain structure to its function. In this perspective, we discuss several prominent experimental advances that are ushering in a new era of quantitative fluorescence-based imaging in neuroscience along with novel computational and statistical strategies that are helping to distil our understanding of complex brain structure.

Optimal linearized Poisson-Boltzmann theory applied to the simulation of flexible polyelectrolytes in solution.

Optimal linearized Poisson-Boltzmann (OLPB) theory is applied to the simulation of flexible polyelectrolytes in solution. As previously demonstrated in the contexts of the cell model [H. H. von Grunberg, R. van Roij, and G. Klein, Europhys. Lett. 55, 580 (2001)] and a particle-based model [B. Beresfordsmith, D. Y. C. Chan, and D. J. Mitchell, J. Colloid Interface Sci. 105, 216 (1985)] of charged colloids, OLPB theory is applicable to thermodynamic states at which conventional, Debye-Huckel (DH) linearization of the Poisson-Boltzmann equation is rendered invalid by violation of the condition that the electrostatic coupling energy of a mobile ion be much smaller than its thermal energy throughout space, |nu(alpha)e psi(r)|<

A fluid--structure interaction finite element analysis of pulsatile blood flow through a compliant stenotic artery.

A new model is used to analyze the fully coupled problem of pulsatile blood flow through a compliant, axisymmetric stenotic artery using the finite element method. The model uses large displacement and large strain theory for the solid, and the full Navier-Stokes equations for the fluid. The effect of increasing area reduction on fluid dynamic and structural stresses is presented. Results show that pressure drop, peak wall shear stress, and maximum principal stress in the lesion all increase dramatically as the area reduction in the stenosis is increased from 51 to 89 percent. Further reductions in stenosis cross-sectional area, however, produce relatively little additional change in these parameters due to a concomitant reduction in flow rate caused by the losses in the constriction. Inner wall hoop stretch amplitude just distal to the stenosis also increases with increasing stenosis severity, as downstream pressures are reduced to a physiological minimum. The contraction of the artery distal to the stenosis generates a significant compressive stress on the downstream shoulder of the lesion. Dynamic narrowing of the stenosis is also seen, further augmenting area constriction at times of peak flow. Pressure drop results are found to compare well to an experimentally based theoretical curve, despite the assumption of laminar flow.

Enhancement of in vitro effectiveness for hydrodynamic thrombectomy devices. Simultaneous high-pressure rt-PA application.

RATIONALE AND OBJECTIVES: To determine the efficacy of simultaneous high-pressure recombinant tissue plasminogen activator (rt-PA) application for clot removal and procedure-related peripheral particle embolization for the hydrodynamic thrombectomy devices LF 140 AngioJet (LF 140) and triplelumen Hydrolyser (triple HL) in an in vitro flow model. METHODS: Thrombectomy of clots (n = 47) from 5-day-old human blood (8.9-9.7 g) was performed with the LF 140 and the triple HL, each with and without simultaneous rt-PA (9.97-12.59 g) application in a flow model (flow 1 liter/min) made of silicone tubes (7 mm inner tube diameter). All catheters were used according to the manufacturer's recommendations. RESULTS: The triple HL revealed no statistically significant performance differences with additional rt-PA. For the LF 140, mean thrombectomy time ranged from 23.5 sec (with rt-PA) to 33.5 sec (P = 0.05). The ratio of peripheral embolus weight to thrombus weight was reduced from 2.12% to 0.46% (rt-PA; P = 0.05). None of the tested devices had an isovolumetric performance; the mean ratio of applied saline to aspirated fluid for the devices were different from one, ranging from 0.89 to 0.92 (rt-PA) for the triple HL and from 0.43 to 0.52 (rt-PA) for the LF 140. No significant differences for remaining thrombus within the tubes were found. CONCLUSIONS: Simultaneous rt-PA-enhanced hydrodynamic thrombectomy is feasible in vitro. This combination reduces the time for thrombectomy and procedure-related peripheral particle embolization for the LF 140. No effect could be demonstrated for the triple HL in an in vitro flow model. It remains unclear whether this procedure is effective in vivo. It seems likely that the incidence of fibrinolysis-associated complications may increase in vivo.

In vitro effectiveness study for hydrodynamic thrombectomy devices of the second generation.

RATIONALE AND OBJECTIVES: To determine the efficacy of clot removal and the amount of applied saline and aspirated fluid and to compare procedure-related particle embolization for the hydrodynamic thrombectomy devices the LF 140 Angiojet (LF 140), the double-lumen Hydrolyser (double HL), and the triple-lumen Hydrolyser (triple HL) in an in vitro flow model. METHODS: Thrombectomy of clots (n = 42) from 7-day-old porcine blood (9.8 g) was performed with the LF 140, the double HL, and the triple HL in a flow model (flow 1 L/min) made of silicone tubes (7 mm inner tube diameter). All catheters were used according to the manufacturer's recommendations. RESULTS: Mean time of thrombectomy ranged from 20 seconds (triple HL) to 58 seconds (LF 140, P < 0.05). Only for the triple HL was remaining thrombus found within the tubes (41 mg). None of the tested devices worked isovolumetrically: the mean ratio of applied saline and aspirated fluid for the devices ranged from 0.79 (triple HL) to 0.89 (double HL, P < 0.05). Mean embolus weight and percentage of embolism from original thrombus were 675 mg/6.7% (LF 140, P < 0.05), 38 mg/0.4% (double HL), and 26 mg/0.3% (triple HL). CONCLUSIONS: Thrombectomy time and embolus weight depend on the device chosen. The ratio of applied to aspirated fluid, indicating the capability to work nearly isovolumetrically, is acceptable for all tested devices. In vitro, the triple HL seems to be the most appropriate device for rapid mechanical, hydrodynamic thrombectomy. Because of the high in vitro particle embolization rate, the LF 140 seems to be strictly limited to small-caliber vessels.