How Migraine Develops: Migraine is a common medical disorder. Unfortunately, how and why migraine headache is initiated is unclear. Karatas et al. (p. 1092 ) now describe a signaling pathway between stressed neurons and meningeal trigeminal afferents, which may explain how migraine headaches can be generated.

Ever since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in salvageable penumbra after reperfusion. These stalls, which are different from permanent cellular plugs of no-reflow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling slowly through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments under reperfused conditions. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. Decreased number and duration of stalls were associated with improvement in penumbral blood flow within 2–24 h after reperfusion along with increased capillary oxygenation, decreased cellular damage and improved functional outcome. Thereby, dynamic microcirculatory stall phenomenon can be a contributing factor to ongoing penumbral injury and is a potential hyperacute mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.

Nature of red blood cell dynamics and light scattering interactions unraveled to accurately probe cerebral blood flow.

Optical coherence tomography (OCT) allows label-free imaging of red blood cell (RBC) flux within capillaries with high spatio-temporal resolution. In this study, we utilized time-series OCT-angiography to demonstrate interruptions in capillary RBC flux in mouse brain in vivo. We noticed ∼7.5% of ∼200 capillaries had at least one stall in awake mice with chronic windows during a 9-min recording. At any instant, ∼0.45% of capillaries were stalled. Average stall duration was ∼15 s but could last over 1 min. Stalls were more frequent and longer lasting in acute window preparations. Further, isoflurane anesthesia in chronic preparations caused an increase in the number of stalls. In repeated imaging, the same segments had a tendency to stall again over a period of one month. In awake animals, functional stimulation decreased the observance of stalling events. Stalling segments were located distally, away from the first couple of arteriolar-side capillary branches and their average RBC and plasma velocities were lower than nonstalling capillaries within the same region. This first systematic analysis of capillary RBC stalls in the brain, enabled by rapid and continuous volumetric imaging of capillaries with OCT-angiography, will lead to future investigations of the potential role of stalling events in cerebral pathologies.

Intravital or multiphoton microscopy and laser-speckle imaging have become popular because they allow live monitoring of several processes during cerebral ischemia. Available rodent models have limitations for these experiments; e.g., filament occlusion of the proximal middle cerebral artery (MCA) is difficult to perform under a microscope, whereas distal occlusion methods may damage the MCA and the peri-arterial cortex. We found that placement of a 10% FeCl₃-soaked filter paper strip (0.3 × 1 mm²) on the duramater over the trunk of the distal MCA through a cranial window for 3 minutes induced intraarterial thrombus without damaging the peri-arterial cortex in the mouse. This caused a rapid regional cerebral blood flow decrease within 10 minutes and total occlusion of the MCA segment under the filter paper in 17 ± 2 minutes, which resulted in a typical cortical infarct of 27 ±4 mm³ at 24 hours and moderate sensorimotor deficits. There was no significant hemispheric swelling or hemorrhage or mortality at 24 hours. Reperfusion was obtained in half of the mice with tissue plasminogen activator, which allowed live monitoring of clot lysis along with restoration of tissue perfusion and MCA flow. In conclusion, this relatively simple and noninvasive stroke model is easy to perform under a microscope, making it suitable for live imaging and thrombolysis studies.

Extracellular vesicles (EVs) originate from membranes of all cell types and can be found in all tissues and biological fluids.^{1 – 4} They are $\sim 30$ to 1000 nm in diameter and play a crucial role in intercellular communication by delivering a variety of cargo, including nucleic acids, proteins, glycans, and lipids to local and distant cells where they influence cellular phenotype.^2,3,5,6 EV-mediated intercellular signaling contributes to the regulation of a wide range of biological functions in target cells including immunological processes (e.g., antigen presentation), communication between components of the neurovascular unit, glial and neuronal function, development and differentiation of stem cells, and tissue regeneration. Additionally, in aberrant conditions, EVs have been associated with the pathophysiology of stroke, Alzheimer’s disease, Parkinson’s disease, cancer, obesity, cardiovascular disease, and rheumatoid arthritis.^{2,5,7 – 11} Therefore, there is a rapidly increasing scientific interest in EVs including their detection and imaging in tissue or biological fluids.