Multi-parametric photoacoustic microscopy (PAM) has emerged as a promising new technique for high-resolution quantification of hemodynamics and oxygen metabolism in the mouse brain. In this work, we have extended the scope of multi-parametric PAM to longitudinal, cortex-wide, awake-brain imaging with the use of a long-lifetime (24 weeks), wide-field (5 × 7 mm 2 ), light-weight (2 g), dual-transparency ( i.e., light and ultrasound) cranial window. Cerebrovascular responses to the window installation were examined in vivo, showing a complete recovery in 18 days. In the 22-week monitoring after the recovery, no dura thickening, skull regrowth, or changes in cerebrovascular structure and function were observed. The promise of this technique was demonstrated by monitoring vascular and metabolic responses of the awake mouse brain to ischemic stroke throughout the acute, subacute, and chronic stages. Side-by-side comparison of the responses in the ipsilateral (injury) and contralateral (control) cortices shows that despite an early recovery of cerebral blood flow and an increase in microvessel density, a long-lasting deficit in cerebral oxygen metabolism was observed throughout the chronic stage in the injured cortex, part of which proceeded to infarction. This longitudinal, functional-metabolic imaging technique opens new opportunities to study the chronic progression and therapeutic responses of neurovascular diseases.
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Hemodynamic and oxygen-metabolic responses of the awake mouse brain to hypercapnia revealed by multi-parametric photoacoustic microscopy
A widely used cerebrovascular stimulus and common pathophysiologic condition, hypercapnia is of great interest in brain research. However, it remains controversial how hypercapnia affects brain hemodynamics and energy metabolism. By using multi-parametric photoacoustic microscopy, the multifaceted responses of the awake mouse brain to different levels of hypercapnia are investigated. Our results show significant and vessel type-dependent increases of the vessel diameter and blood flow in response to the hypercapnic challenges, along with a decrease in oxygen extraction fraction due to elevated venous blood oxygenation. Interestingly, the increased blood flow and decreased oxygen extraction are not commensurate with each other, which leads to reduced cerebral oxygen metabolism. Further, time-lapse imaging over 2-hour chronic hypercapnic challenges reveals that the structural, functional, and metabolic changes induced by severe hypercapnia (10% CO 2 ) are not only more pronounced but more enduring than those induced by mild hypercapnia (5% CO 2 ), indicating that the extent of brain’s compensatory response to chronic hypercapnia is inversely related to the severity of the challenge. Offering quantitative, dynamic, and CO 2 level-dependent insights into the hemodynamic and metabolic responses of the brain to hypercapnia, these findings might provide useful guidance to the application of hypercapnia in brain research.
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- Award ID(s):
- 2023988
- NSF-PAR ID:
- 10317841
- Date Published:
- Journal Name:
- Journal of Cerebral Blood Flow & Metabolism
- Volume:
- 41
- Issue:
- 10
- ISSN:
- 0271-678X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Objective To incorporate chronic vascular adaptations into a mathematical model of the rat hindlimb to simulate flow restoration following total occlusion of the femoral artery.
Methods A vascular wall mechanics model is used to simulate acute and chronic vascular adaptations in the collateral arteries and collateral‐dependent arterioles of the rat hindlimb. On an acute timeframe, the vascular tone of collateral arteries and distal arterioles is determined by responses to pressure, shear stress, and metabolic demand. On a chronic timeframe, sustained dilation of arteries and arterioles induces outward vessel remodeling represented by increased passive vessel diameter (arteriogenesis), and low venous oxygen saturation levels induce the growth of new capillaries represented by increased capillary number (angiogenesis).
Results The model predicts that flow compensation to an occlusion is enhanced primarily by arteriogenesis of the collateral arteries on a chronic time frame. Blood flow autoregulation is predicted to be disrupted and to occur for higher pressure values following femoral arterial occlusion.
Conclusions Structural adaptation of the vasculature allows for increased blood flow to the collateral‐dependent region after occlusion. Although flow is still below pre‐occlusion levels, model predictions indicate that interventions which enhance collateral arteriogenesis would have the greatest potential for restoring flow.
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Abstract Vasoactive stress tests (i.e. hypercapnia, elevated partial pressure of arterial CO2[PaCO2]) are commonly used in functional MRI (fMRI), to induce cerebral blood flow changes and expose hidden perfusion deficits in the brain. Compared with fMRI, near‐infrared spectroscopy (NIRS) is an alternative low‐cost, real‐time, and non‐invasive tool, which can be applied in out‐of‐hospital settings. To develop and optimize vasoactive stress tests for NIRS, several hypercapnia‐induced tasks were tested using concurrent‐NIRS/fMRI on healthy subjects. The results indicated that the cerebral and extracerebral reactivity to elevated PaCO2depended on the rate of the CO2increase. A steep increase resulted in different cerebral and extracerebral reactivities, leading to unpredictable NIRS measurements compared with fMRI. However, a ramped increase, induced by ramped‐CO2inhalation or breath‐holding tasks, induced synchronized cerebral, and extracerebral reactivities, resulting in consistent NIRS and fMRI measurements. These results demonstrate that only tasks that increase PaCO2gradually can produce reliable NIRS results.
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Abstract Objective The development of earlier and less invasive treatments for peripheral arterial disease requires a more complete understanding of vascular responses following a major arterial occlusion. A mechanistic model of the vasculature of the rat hindlimb is developed to predict acute (immediate) changes in vessel diameters and smooth muscle tone following femoral arterial occlusion.
Methods Vascular responses of collateral arteries and distal arterioles to changes in pressure, shear stress, and metabolism are assessed before and after occlusion. The effects of exercise are also simulated and compared with venous flow measurements from WKY rats.
Results The model identifies collateral arteries as the primary contributors to flow compensation following occlusion. Increasing the number of capillaries has minimal effect on blood flow while increasing the number of collateral arteries significantly increases flow, since the primary site of resistance shifts upstream to the collateral arteries following occlusion. Despite significant collateral dilation, calf flow remains below pre‐occlusion levels and the deficit becomes more severe with increased activity.
Conclusions Although unable to compensate fully for an occlusion, the model demonstrates the importance of the shear response in collateral arteries and the metabolic response in the distal microcirculation in acute adaptations to a major arterial occlusion.
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1177/0271678X211010352
