Are fMRI Telling The Truth? Role Of Astrocytes In Cerebral Blood Flow Regulation

The prominent rise of late of interdisciplinary fields like cognitive psychology, cognitive neuroscience and neuropsychology is due in no small part to the emergence of the functional magnetic resonance imaging (fMRI) two decades ago. By making use of this technology, researchers can penetrate the skull and visualize areas of the brain which are ‘activated' at particular points in time. This technology allows researchers to correlate different areas of brain activation with particular tasks.

For instance, performing an fMRI scan of the brain of a person asked to spot colorful sparks on a screen (a task which heavily involves visual stimulation) will depict a marked activation of the occipital lobe, the rearmost area of the brain. The occipital lobe is the visual processing center of the mammalian brain and is believed to play a role in visual perception. Its marked activation during prominent visual stimulation tells researchers that something intense is happening in that area of the brain. It basically relates that the occipital lobe is working furiously.

Such activation requires energy if it is to be sustained. To provide for the required energy, the blood needs to carry more glucose and oxygen. The need for a close link between cerebral blood flow (CBF) and metabolic demand is thus of primordial importance. This close link is known as the flow-metabolism coupling. It is a distinct feature of the mature brain. One mechanism which dictates this coupling is functional hyperemia. It ensures that areas of brain activation are highly spatially correlated with areas of increased perfusion. This means that at areas of brain activation, the cerebral vasculature responds by vasodilatation to allow more blood, loaded with more glucose, to voyage through the cerebral arteries. These arteries then become welcome sources of energy and metabolites. fMRI capitalizes on the resulting increase in local blood oxygenation, CBF and cerebral blood volume (CBV).

As more blood gets pumped to areas of brain activation, the level of oxyhemoglobin in the cerebral arteries and cerebral veins increases. By extension, the ratio of oxyhemoglobin to deoxyhemoglobin (which illustrates the extent of blood oxygenation) is altered. This ratio along with CBF and cerebral blood volume quantitatively represent the blood-oxygen-level dependence (BOLD), which is what the fMRI detects. In crude terms, an fMRI scan therefore reveals those areas of the brain where more oxygenated blood is being distributed-that is areas requiring more energy.

In the brain, energy consumption has long been attributed to neural activity. As such, areas fMRI signals have been assumed to represent neural activity. Neural activity produces increases in CBF which occur in seconds and are highly restricted to areas of brain activation. What's the link between neurons and increased CBF? A widely accepted hypothesis is that glutamate receptors, activated during synaptic transmission, cause postsynaptic increases in Ca²⁺. These eventually set off enzymes which produce vasoactive agents (K⁺, H⁺, neurotransmitters, adenosine, nitric oxide, etc). These agents act on receptors on vascular smooth muscles (i.e. on blood vessels) and mediate vasodilatation, indirectly increasing CBF and provision of oxygen and metabolites.

Where specifically these vasoactive agents are produced however, is still a mystery. As such, we cannot be sure that neurons are the sole sources of the signals mediating vasodilatation. This gap in our knowledge severely dents our assumption that the response of the cerebral vasculature to brain activation exclusively reflects neural activity. Indeed, if cells other than neurons also mediate the production of these vasoactive agents, this would imply that neural activity is not the sole regulator of the cerebral vasculature. And by extension, our interpretation that fMRI locates areas of increased neural activity has to be questioned.

Actually, it is unlikely that neurons are the sole mediators of vasoactive agents. A direct effect of neurons on the cerebral vasculature is unlikely because neuronal endpoints are rarely in contact with vascular smooth muscle cells. Furthermore, extracellular diffusion of vasoactive agents from active synapses to local arterioles cannot explain the timely manner in which CBF is regulated. There are thus other cells involved in the regulation of CBF. One of them is the astrocyte.

Astrocytes are closely related to blood vessels and synapses. In fact, they have processes that are in direct contact with both blood vessels and synapses. This makes them ideal candidates for neurovascular regulation. In 2003, an increase in the amount of intracellular Ca²⁺ in astrocytic endfeet was discovered upon electrical stimulation of neuronal processes. The increase led to dilatation of local cerebral arterioles, successfully linking astrocytes with a role in neurovascular regulation.

But an increase in astrocytic Ca²⁺ is not only mobilized by neuronal activation. A number of transmitters, neuromodulators and hormones can in fact do the exact same thing, independently of synaptic transmission in neurons. Therefore, astrocytes also regulate the response of the cerebral vasculature.

Further still, studies have shown that astrocytes could also account for a significant portion of energy consumption in the brain (see references 2 and 3). Although, neurons obtain most of their energy by glycolysis, astrocytes derive much energy from oxidative metabolism and the associated release of glial transmitters, such as ATP, during Ca²⁺ signaling.

That neural activity is not the sole determinant of the cerebral vasculature, and therefore of CBF, and that it does not account for as big a share of the total energy consumption of the brain as previously thought puts our assumption that fMRI signals represent neural activity in jeopardy. By looking at an fMRI scan, we can no longer assume that the bright regions solely correspond to areas where neurons are firing. Indeed, astrocytes are also pulling the strings. How much of the response is due to astrocytes however is not known and would be of particular interest.

Image credits: Top: Scott Huettel (Duke University Photography Jim Wallace, from flickr), Bottom: Wellcome images (from flickr).

References:

1. Iadecola, C. & Nedergaard, M. Glial regulation of the cerebral microvasculature. Nature Neuroscience 10, 1369-1376 (2007).
2. Lebon, V. et al. Astroglial contribution to brain energy metabolism in humans revealed by 13C nuclear magnetic resonance spectroscopy: elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism. Journal of Neuroscience 22, 1523-1531 (2002).
3. Oz, G. et al. Neuroglial metabolism in the awake rat brain: CO₂ fixation increases with brain activity. Journal of Neuroscience 24, 11273-11279 (2004).
4. Logothetis, N.K. The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal. Philosophical Transactions of the Royal Society B: Biological Sciences 357, 1003-1037 (2002).