By Nicha Talamona

Historically, researchers have focussed on harmful forms of angiogenesis, but now researchers are exploring the ways in which angiogenesis can be induced through exercise to have a positive effect on the brain and cognition. Neuroimaging (or brain imaging) is the process by which the structures and blood flow around the brain can be ‘mapped’ through a series of images. Neuroimaging can be used in medical settings to assess brain health and in research settings to understand how the brain works. When studying angiogenesis – the growth of new capillaries from existing blood vessels (Cleveland Clinic, 2022) – it is important to understand changes in blood flow. For this reason, neuroimaging techniques that allow us to see the circulation of blood in the brain are most helpful when aiming to understand angiogenesis. There are multiple types of neuroimaging that can achieve this: 

1. Magnetic Resonance Imaging (MRI)

MRI is a commonly used method to look at blood flow and volume in the brain. MRI uses a magnetic field, emitted by the scanner, and radio waves to determine where atoms in your brain are located. This produces an image that can be analyzed for diagnostic or research purposes. Multiple MRIs can be performed over a period of time to understand how the brain has changed – in a research setting, the participant may undergo MRI before and after participating in the experiment to understand the effect on the brain. MRI is useful to researchers and medical professionals because it is minimally invasive and does not require exposure to ionizing radiation like some other imaging methods (Johns Hopkins Medicine, n.d.(a)). 

There are many different types of MRI, for example:  

• Diffusion-weighted imaging: measures the movement of water in tissues 
• T2-weighted imaging: shows fat and water-based tissues 
• Perfusion-weighted imaging: uses a contrast dye to map many things, including cerebral blood flow 
• fMRI: measures blood flow and electrical activity

There are many other types of MRI that are used in various settings, but these four have been commonly applied in angiogenesis research. 

2. Functional Magnetic Resonance Imaging (fMRI)

Here we will explore fMRI in more detail. Functional Magnetic Resonance Imaging, or fMRI, measures small changes in circulation that occur when we engage different areas of our brain using ‘blood-oxygen-level-dependent signals’. As we engage areas of our brain to complete various tasks, our neurons are activated. These ‘brain cells’ require oxygenated blood to function – the more blood flow, the more activity. These scans use color to represent activation level, some colors meaning low amounts of oxygen and others meaning lots of oxygen. These contrasting colors make it easy to visualize activation and circulation changes in the brain.

fMRI may be particularly helpful to understand angiogenesis as it allows researchers to see if oxygen or activation levels have increased in various areas of the brain. For example, if the color changes from yellow to white across scans after a period of physical exercise, we know that blood flow to this area has improved. This would imply that angiogenesis has occurred, as more capillaries would result in more blood flow.                                                                                                                                    

3. Magnetic Resonance Angiography (MRA)

This technique is similar to fMRI because it also uses a magnetic field to produce images. Magnetic Resonance Angiography also utilizes pulses of radio waves, allowing this technique to produce 3D images of blood vessels, rather than the general ‘heat map’ of activity that is produced by fMRI scans. MRA may also involve the injection of a contrast dye to make blood vessels easier to see, but this is not always necessary (John Hopkins Medicine, n.d.(b)) making this a minimally invasive technique. As MRA produces 3D images of blood vessels, it may be a particularly useful technique for visualizing cerebral angiogenesis as this will make the density, length and diameter of blood vessels clearer to researchers. Indeed, in the medical field MRA is used to assess the health of blood vessels by observing the thickness, orientation and shape (American Society of Neuroradiology, n.d.). 

A 2009 study used this neuroimaging technique to visualize the effect of aerobic exercise on blood vessels in the brains of participants aged 60-74. Half of the participants reported high physical activity levels and half reported low levels of physical activity. All participants underwent MRA, which ultimately showed that those who reported high levels of physical activity had more small blood vessels and lower levels of tortuosity (twisting) in their cerebral blood vessels. This indicates that exercise may contribute to healthy aging of the brain (Bullit et al., 2009) and demonstrates that MRA can be a useful tool for measuring this due to its ability to provide detailed 3D images. 

However, there are significant limitations of this technique that are particularly relevant to angiogenesis: firstly, MRA cannot depict small capillaries, which is very important when looking at the emergence of new capillaries from existing blood vessels. Additionally, it cannot measure very slow blood flow, meaning that it will only detect some blood flow, ultimately limiting our view of the vasculature of the brain (American Society of Neuroradiology, n.d.).

4. Transcranial Doppler Ultrasound

Doppler ultrasound is a non-targeted method for measuring angiogenesis, meaning that angiogenesis can be inferred from the results. Doppler ultrasound is a valuable tool for non-invasive assessment of cerebral angiogenesis (Sheps, n.d). Utilizing the Doppler effect – changes in frequency detected according to the velocity of blood (Shah and Irshad, 2023) – this imaging technique allows for the measurement of blood flow velocities within the blood vessels in the brain.

In the context of angiogenesis, Doppler ultrasound detects changes in blood flow patterns which indicate the formation and remodeling of blood vessels. This approach offers advantages such as real-time monitoring, cost-effectiveness, and absence of ionizing radiation compared to other imaging techniques. This technique has been used to study the effect of exercise on the brain. Cho and Roh (2016) found that taekwondo increases cerebral blood flow (CBF) and improves cognitive function in elderly women, demonstrating the utility of Doppler ultrasonography in studies such as these. 

There are many different types of Doppler ultrasound that can be useful in the context of measuring cerebral angiogenesis, for example, color Doppler ultrasound can visualize tortuous (twisted) veins, which would indicate anti-angiogenic effects (Kurdziel et al., 2011). This technique’s non-invasive nature and ability to provide functional information make it a promising technique for studying cerebral angiogenesis in various clinical and research settings.

In summary, there are a variety of interesting ways to observe changes to the brain, namely changes to the vasculature. These neuroimaging methods take many different approaches which can be targeted or non-targeted. Some methods target indicators of angiogenesis like blood volume and growth factors, whilst others can help researchers to visualize the vasculature of the brain directly. The most commonly used methods are certainly MRI methods, such as fMRI or perfusion-weighted imaging, but the other methods have also demonstrated their utility in the literature. 

This blog has outlined a few intriguing studies about angiogenesis in the brain, and has briefly delved into the positive effects of exercise, which can be observed using neuroimaging. Ultimately, exercising is a simple way to boost angiogenesis in the brain – this fuels your brain with the essentials (like oxygen and nutrients) to keep your mind sharp!

Disclaimer: Before starting any exercise program, it is important to consult with a qualified healthcare professional or physician to ensure that it is safe for you to do so, especially if you have any pre-existing medical conditions, injuries, or concerns about your health.

References

American Society of Neuroradiology (n.d.) MR Angiography Retrieved Jan 26, 2024, from https://www.asnr.org/patientinfo/procedures/mrangiography.shtml 

Bullitt, E., Rahman, F.M., Smith, J.K., Kim, E., Zeng, D., Katz, L.M. and Marks, B.L. (2009). The Effect of Exercise on the Cerebral Vasculature of Healthy Aged Subjects as Visualized by MR Angiography. American Journal of Neuroradiology, 30(10), 1857-1863. https://doi.org/10.3174/ajnr.A1695 

Cho, S. Y., and Roh, H. T. (2019). Taekwondo enhances cognitive function as a result of increased neurotrophic growth factors in elderly women. Int. J. Environ. Res. Public Health. 16, 962. doi: 10.3390/ijerph16060962

Cleveland Clinic (2022) Angiogenesis Retrieved Mar 2 2024, from https://my.clevelandclinic.org/health/articles/24206-angiogenesis 

Johns Hopkins Medicine (n.d.)(a) Magnetic Resonance Imaging (MRI) Retrieved Feb 10 2024, from https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/magnetic-resonance-imaging-mri 

Johns Hopkins Medicine (n.d.)(b) Magnetic Resonance Angiography (MRA) Retrieved Jan 26, 2024, from https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/magnetic-resonance-angiography-mra 

Kurdziel, K. A., Lindenberg, L. and Choyke, P. L. Oncologic Angiogenesis Imaging in the clinic – how and why. Imaging Med, 3(4). doi: 10.2217/iim.11.31 

Shah A, Irshad A. (2023) Sonography Doppler Flow Imaging Instrumentation. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.  Available from: https://www.ncbi.nlm.nih.gov/books/NBK580539/ 

Sheps, S. G. (n.d.) Doppler ultrasound: What is it used for?. Mayo Clinic. https://www.mayoclinic.org/doppler-ultrasound/expert-answers/faq-20058452 

Steventon, J.J., Chandler, H.L., Foster, C., Dingsdale, H., Germuska, M., Massey, T., Parker, G., Wise, R. G. and Murphy, K.  (2021) Changes in white matter microstructure and MRI-derived cerebral blood flow after 1-week of exercise training. Sci Rep 11, 22061. https://doi.org/10.1038/s41598-021-01630-7