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Pre-emptive blood flow

Nature volume 457, pages 387388 (22 January 2009) | Download Citation

Electrical signalling among brain cells summons the local delivery of extra blood — the basis of functional brain imaging. Yet sometimes, blood is sent in anticipation of neural events that never take place.

The brain makes up only 2% of the human body mass, but because of its high energy demands it receives more than 15% of the cardiac output. When blood enters the brain, it doesn't course indiscriminately through the organ's vessels; instead, it is selectively channelled to specific regions in a need-based fashion. On page 475 of this issue, Sirotin and Das1 show that, sometimes, blood is sent to the brain's visual cortex in the absence of any stimulus, priming the neural tissue in apparent anticipation of future events.

We know a lot about the physiology of the cerebral cortex, the folded sheet of densely packed grey matter that forms the outer surface of the brain. Its neurons generate electrical impulses that carry information about stimuli and events and transmit it to other neurons. Arteries, arterioles and capillaries deliver fresh blood to neurons, and supporting glial cells surround both neurons and blood vessels, regulating blood flow and performing various housekeeping roles.

Housekeeping in the brain is a challenge, because neurons undergo sudden bursts of activity that consume energy and pollute their surroundings. Consider, for example, what happens in the cortex when we first direct our gaze to a bright stimulus. In the visual cortex — the region of the cortex specialized for vision — thousands of previously quiescent neurons suddenly erupt in a cacophony of activity, each generating hundreds of electrical impulses per second. In response to the metabolic consequences of such activity, fresh blood is directed towards neurons and glia in active regions, flushing out waste products, delivering nutrients and restoring the local milieu.

Brain mapping techniques such as functional magnetic resonance imaging (fMRI) measure blood flow (haemodynamics) rather than neural activity. The accuracy with which fMRI monitors neural functioning in the human brain depends on the precise coupling between neural activity and blood flow. Although details of how neural activity triggers changes in blood supply are a topic of active debate, it is generally assumed that the two signals are tightly coupled in both space and time.

Yet biology can provide exceptions to every rule, and Sirotin and Das1 seem to have tapped into a big one. Their study shows that cortical blood flow can depart wildly from what is expected on the basis of local neural activity. They observed this mismatch in alert rhesus monkeys by simultaneously measuring vascular and neural responses in the same region of the visual cortex. Changes in the blood supply were monitored by a sensitive video camera peering at the surface of the brain through a transparent window in the animal's skull, and local electrical responses of neurons were measured with a microelectrode. The monkeys were oblivious to all of this, focusing instead on a behavioural task that would earn them a juice reward. The task required the animals to fixate their gaze on a tiny spot on a computer monitor for several seconds at a time.

When Sirotin and Das presented the monkeys with a conventional visual stimulus under these conditions, they observed a close correspondence between neural and haemodynamic responses to the stimulus, as expected on the basis of much previous work2. The surprising finding came in trials without a visual stimulus, when the visual cortex should have been disengaged (Fig. 1).

Figure 1: Behavioural modulation of blood flow.
Figure 1

Blood flow in the visual cortex is normally modulated in step with neural responses to visual stimuli. Sirotin and Das1 show that the vascular response in this area of an alert monkey's brain is readily modulated by its expectation of the task, even in complete darkness and without accompanying neural modulation.

Here — aside from the tiny spot directing the animal where to look — the task was carried out in complete darkness. Against all expectations, however, the haemodynamic signal continued to rise and fall. Indeed, the video of the cortical surface continued to reveal the cyclical ebb and flow of cerebral blood, which accompanied simultaneous changes in blood oxygenation and arterial diameter. By contrast, during this same trial, the neural signal fell nearly silent. Individual neurons in the same patch of cortex ceased to show any changes in their rate of generating impulses, and only the faint swell of background electrical activity indicated that cortical neurons were at all stirred by the behavioural task.

So what might be the origin of this vascular priming? One possibility is that the subtle background swells led to increased blood flow through the local release of metabolic factors. Sirotin and Das argue, however, that this interpretation is unlikely because the robust haemodynamic responses they observed did not bear a reliable relationship to the neural signals they measured. Instead, this study — perhaps more than any previous work — highlights the potential role of direct, task-related neural control of vascular tone. Both glia and blood vessels receive signals from diverse types of neuron, including signals from neurons in brain centres controlling attention and arousal3. The task-based modulation of the vascular response might therefore represent input from a part of the brain that can anticipate probable neural activity in a specific brain region over the coming seconds, and so prime that region.

But how specific might such an anticipatory signal be? As the authors1 found a similar modulation in other systemic markers, such as heart rate and pupil diameter, might the observed modulation reflect an overall change in the brain's blood supply? A control experiment involving an auditory task argues against this possibility. Unlike the fixation task, periodic attention to an auditory stimulus did not elicit haemodynamic modulation in the visual cortex. This control experiment, although doing little to clarify the origin of the haemodynamic modulation, shows that such priming depends on the type of sensory stimulus that the brain expects.

The mere mismatch between blood flow and neural activity per se is not a great surprise. Indeed, the precise relationship between neural activity, metabolism and blood flow has always been difficult to pin down. Early functional imaging studies revealed a quantitative discrepancy between oxygen consumption by an activated brain region following a sensory stimulus and the corresponding blood-flow response to that region4. Simply put, much larger amounts of oxygenated blood were delivered to an active region than were required on the basis of metabolic demands. Earlier work has also shown that the correspondence between neural activity and blood-based imaging signals is highly situation-dependent5,6, highlighting the complex relationship between neural activity, metabolism and blood flow7,8,9.

Yet the neurovascular mismatch reported by Sirotin and Das1 is extreme. The clear and rhythmic haemodynamic modulation in the visual cortex spurred by a task performed in complete darkness is sure to raise eyebrows among the human fMRI research community. For one thing, most fMRI experiments involve the periodic presentation of sensory stimuli, and then rely on the temporal structure of the haemodynamic response for deducing local neural activity. The present study clearly demonstrates that some of the assumptions underlying such analysis — namely, that cyclical variations in blood flow reflect local, stimulus-driven events — may sometimes be incorrect.


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  1. David A. Leopold is in the Unit on Cognitive Neurophysiology and Imaging, Laboratory of Neuropsychology, National Institute of Mental Health, Bethesda, Maryland 20892, USA.

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