Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria.

Sequestration of infected red blood cells (iRBCs) in the microcirculation is a hallmark of cerebral malaria (CM) in post-mortem human brains. It remains controversial how this might be linked to the different disease manifestations, in particular brain swelling leading to brain herniation and death. The main hypotheses focus on iRBC-triggered inflammation and mechanical obstruction of blood flow. Here, we test these hypotheses using murine models of experimental CM (ECM), SPECT-imaging of radiolabeled iRBCs and cerebral perfusion, MR-angiography, q-PCR, and immunohistochemistry. We show that iRBC accumulation and reduced flow precede inflammation. Unexpectedly, we find that iRBCs accumulate not only in the microcirculation but also in large draining veins and sinuses, particularly at the rostral confluence. We identify two parallel venous streams from the superior sagittal sinus that open into the rostral rhinal veins and are partially connected to infected skull bone marrow. The flow in these vessels is reduced early, and the spatial patterns of pathology correspond to venous drainage territories. Our data suggest that venous efflux reductions downstream of the microcirculation are causally linked to ECM pathology, and that the different spatiotemporal patterns of edema development in mice and humans could be related to anatomical differences in venous anatomy.

The oxygenation response to functional stimulation: is there a physiological meaning to the lag between parameters?

To investigate the regulation of the hemodynamic response to functional stimulation, functional near-infrared spectroscopy (fNIRS) has been used, due to its ability to assess the dynamics of oxygenated, deoxygenated and total hemoglobin concentration ([oxy-Hb], [deoxy-Hb] and [tot-Hb]). Concerning the latency of these parameters, recent studies have returned a consistent picture when comparing the oxygenation response in the sensorimotor to the visual system: changes in [oxy-Hb] lead those in [deoxy-Hb] by 1.6+/-0.2 s (mean+/-SD) for the sensorimotor system but not for the visual system (0.1+/-0.3 s). A number of physiological differences between these cortical areas may account for such a discrepancy, however, the methodological properties of transcranial NIRS also have a relevant influence. Here we show that for the motor system the latency between changes in oxy- compared to deoxy-Hb vanishes once efforts are made to reduce the effects of a systemic response accompanying sensorimotor activity. We apply two independent approaches to reduce the systemic response and find a simultaneous change in [oxy-Hb] and [deoxy-Hb] even in response to a motor paradigm. The two approaches are: (i) an experimental paradigm with alternating contralateral and ipsilateral motor performance without interspersed rest periods designed to minimize systemic changes and (ii) a global correction scheme in an experiment, comparing a unilateral motor performance to rest. These data shed some doubt on the alleged fundamental physiological difference between cortical hemodynamic regulation in motor and visual cortex and highlight the relevance to respect contributions of the systemic hemodynamics.