The Brain Under Anesthesia


Brain waves: This figure illustrates the differences in brain activity during anesthesia. The plots with black lines show the electrical activity recorded with EEG, while the colored plots show a spectral analysis of that activity–whether the activity is primarily high or low frequency. When the patient was awake (top), his brain activity was at a high frequency. When he was sedated during surgery (bottom), the frequency of brain waves dropped.
Emery Brown.



Researchers are looking for better ways to prevent awareness during surgery



MIT Technology Review, by Emily Singer  —  According to a study published in the New England Journal of Medicine, a while back, a commonly used device designed to prevent anesthesia awareness–the rare event when a patient is actually conscious during surgery–was largely ineffective.

The findings highlight just how little is known about the neural changes that underlie anesthesia. “The challenge is that we don’t understand the physiology and pharmacology underlying memory blocking by anesthetics,” says Beverly Orser, an anesthesiologist and scientist at the University of Toronto, who wrote an editorial accompanying the piece. “If we understood the circuits and brain regions involved in complex memory formation, we’d be in a better position to develop these monitors.”

Emery Brown, an anesthesiologist and neuroscientist at Massachusetts General Hospital, and his colleagues are using both brain imaging of human volunteers and, in animals, electrophysiology approaches–which more directly measure brain activity–to gain a deeper understanding of anesthesia. Preliminary research from his lab suggests that measuring activity at the surface of the brain may not be a reliable indicator of what’s going on deeper down, where the memory circuitry may still be functioning–and forming frightening recollections of a particular surgery.

Every year, more than 20 million people in North America undergo general anesthesia–a combination of drugs that sedate patients, paralyze their muscles, and block perception of pain. The cocktail is carefully titered to each individual and each surgery, with the aim of maintaining the patient’s crucial functions, such as heart rate and blood pressure, while keeping her blissfully unaware of the procedure.

A small number of those who get general anesthesia–about 0.1 to 0.2 percent–will experience awareness, which ranges from relatively innocuous incidents, such as later remembering a conversation between surgeons and nurses, to reports of excruciating pain while completely paralyzed. While it’s not exactly clear what triggers anesthesia awareness, an insufficient amount of drugs that quiet brain areas involved in learning and memory is thought to be part of the problem.

As recognition of the problem of anesthesia awareness has grown in recent years, so has the market for devices designed to prevent it. Several types of monitors are now commercially available. They are based on a simple concept: that anesthesia drugs quiet the cortex in a predictable manner that can be measured with electroencephalography (EEG), a technology that measures electrical activity on the surface of the head. The frequency of brain waves spikes briefly as the patient is lulled into unconsciousness, and then it slows. The devices convert EEG patterns into a single number that indicates a patient’s level of awareness, allowing physicians to administer more drugs if needed.


But Brown and others argue that devices like this give only a rudimentary measure of what’s happening in the brain. “If it’s slow, we think it’s okay to operate; if it’s fast, we think they’re waking up,” says Brown. “That’s all we’re doing.”

Brown and his colleagues are using newly developed technology that allows them to study EEG waves while a patient is simultaneously having his brain imaged with functional magnetic brain imaging, an indirect measure of brain activity that is more spatially precise than EEG. Preliminary results show that some brain areas actually become more active during the course of anesthesia. It’s not surprising that a broad-acting drug, which inactivates brain areas that are normally involved in selectively inhibiting brain activity, leads other areas become more active, says Brown. “This is the type of information we really need,” he says.

In corresponding experiments conducted on rodents, scientists used arrays of electrodes to directly measure activity in different parts of the brain. Researchers directed by Matt Wilson, a professor of brain and cognitive sciences MIT who collaborates with Brown, found that rodents that had been given an increasing dose of an anesthetic showed characteristic changes in the rhythm of brain activity in the cortex. But activity in the hippocampus, a brain area crucial in learning and memory, remained unchanged.

“If the signature [measured via EEG] is coming from the cortex, it’s not telling us what the deeper brain structures are doing, such as the arousal system, the brain stem, the amygdala, and the hippocampus,” says Brown. “If EEG cannot tell you about those structures, it’s not telling you about key systems.”








Tracking Information Flow in the Brain



When a neuron fires, it releases calcium. Alan Jasanoff at the McGovern Institute at MIT used this observation to develop a new way to visualize brain activity using fMRI. Superparamagnetic nanoparticles (illustrated here) are covered with proteins (red and green) that aggregate when calcium is released by the neuron. Aggregation of these particles can be detected by the MRI magnet.



A tiny sensor that tracks calcium levels may one day provide clearer pictures of the brain at work.


MIT Technology Review, by Jennifer Chu  —  Scientists at MIT have engineered a nano-sized calcium sensor that may eventually shed light on the intricate cell-to-cell communications that make up human thought. Alan Jasanoff and his team at the Francis Bitter Magnet Lab and McGovern Institute of Brain Research have found that tracking calcium, a key messenger in the brain, may be a more precise way of measuring neural activity, compared with current imaging techniques, such as traditional functional magnetic resonance imaging (fMRI).

FMRI uses powerful magnets to detect blood flow in the brain, allowing researchers to watch the human brain in action. Through a rapid series of snapshots, scientists can observe key areas of a person’s brain lighting up in response to a given task or command. The technology has been used to pinpoint the brain areas involved in everything from basic motor and verbal skills to murkier cognitive states like jealousy, deception, and morality.

Unfortunately, fMRI, as it is used today, has a major drawback: it measures blood flow, or hemodynamics, which is an indirect measure of neural cell activity. “It turns out hemodynamics basically introduces a delay of five seconds,” says Jasanoff. “It keeps you from being able to detect fast variation [in neural activity].”

Since neurons typically fire on the order of milliseconds, current fMRI techniques provide only a rough estimate of what the brain is doing at any given moment. FMRI scans also have a relatively low spatial resolution, measuring activity in areas of 100 microns, a volume that typically contains 10,000 neurons, each with varying activation patterns.

Efforts to fine-tune fMRI have focused on developing stronger magnets and a better understanding of blood flow and its relationship to brain activity.

But Jasanoff believes there’s a better, more precise way of tracking neural activity. He and his team are looking at calcium as a direct measure of neuronal firing. When a neuron sends an electrical impulse to another neuron, calcium-specific channels in the neuron’s membrane instantaneously open up, letting calcium flow into the cell. “It’s a very dramatic signal change,” says Jasanoff.

Fluorescent calcium sensors are already used in superficial optical imaging, but haven’t yet been applied to the deeper brain tissues that are accessible via the powerful magnets of fMRI machines. To that end, Jasanoff’s lab set about designing a calcium sensor that would be detectable via fMRI. To do this, they combined the sensor with a superparamagnetic iron oxide nanoparticle–essentially, a molecular-sized magnet that can be picked up by fMRI as high-contrast images.

The sensor itself is composed of two separate nanoparticles, each coated with a different protein: calmodulin and M13. In the presence of calcium, these two proteins bind together. “Essentially…we created two sets of Velcro balls,” says Jasanoff. “One has hooks and one has loops, and they only become Velcro balls in the presence of calcium.” The proteins come apart when calcium disappears, a property that might be useful in interpreting the flow of electrical activity in a circuit of neurons during a given task–something that’s not possible with today’s fMRI.


Jasanoff’s research is only a first step toward that goal. So far, he has tested the sensor in test-tube solutions with and without calcium, scanning the interactions with MRI. The initial results, published in a recent issue of the Proceedings of the National Academies of Sciences, are promising: scans were able to pick up high-contrast images of the Velcro-like balls clustering in the presence of calcium. Although the images were only visible after many seconds, or even minutes, Jasanoff says the sensor is highly tweakable, and he plans to improve its time response in future trials. For now, he plans to inject calcium sensors into single cells of flies and eventually rats.

Outsider observers like Greg Sorensen of Harvard Medical School are cautiously optimistic about this new generation of brain imaging, particularly for human applications. Sorensen, an associate professor of radiology, is focused on applying novel imaging techniques to the treatment of neurological diseases.

“Intracellular iron oxide particles have in some studies had an unfavorable safety profile in humans,” Sorensen says. “If we learned that this method had some risks but in exchange could identify the best treatment for, say, schizophrenia, then the risk may well be worth the benefit.”