Caution: Brain Working

For centuries, philosophers and biologists alike dreamed of watching the brain operate to see its active response to sensations, actions, or even thoughts. In some ways, functional magnetic resonance imaging (fMRI) provides such a view. This technology essentially measures blood flow to areas of the brain, and presumably neural activity, in real time. The technique could help researchers specifically map the brain. The visual cortex, for example, appears to light up when a subject sees something. Still, scientists remain unsure about exactly what the signal, the flashing spots on an fMRI screen, actually mean. Indeed, neuroscientists debate what fMRI measures and how it can best be used clinically. Paul Matthews of the University of Oxford calls it "perhaps the single most important general technique in cognitive neuroscience." But, he cautions, "It is being widely used with relatively little understanding of its fundamental basis." Data derived from the Science Watch/Hot Papers database and the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. N.K. Logothetis et al., "Neurophysiological investigation of the basis of the fMRI signal," Nature, 412:150-7, 2001. (Cited in 270 papers) G. Buccino et al., "Action observation activates premotor and parietal areas in a somatotopic manner: an fMRI study," Eur J Neurosci, 13:400-4, 2001. (Cited in 59 papers) This issue's Hot Papers1,2 approached fMRI's basic quandaries. Nikos Logothetis and his team at the Max Planck Institute for Biological Cybernetics in Tübingen, Germany, used a variety of new techniques to compare fMRI signals with the neural activity entering the area and the activity leaving it. Logothetis concluded that the illuminated areas in fMRI images most strongly correlate with neuronal inputs to the area. In a second Hot Paper published earlier, Giacomo Rizzolatti's group at the University of Parma in Italy showed that the brain area active during a motor activity, such as throwing a baseball, appears to be active when the subject views someone else engaged in the same activity. The implications go beyond motor control and brain mapping, all the way to clinical possibilities and the philosophy of self-awareness. Though they certainly raised more questions than they answered, these two papers provided new insights for a popular technology first developed 11 years ago, and first envisioned more than a century ago (see story fMRI: The Perfect Imperfect Instrument). AIRY RESULTS Most investigators rely on the fMRI method that uses a blood oxygenation level-dependent (BOLD) contrast. The signal arises from changes in magnetic characteristics of blood related to differences in the relative amounts of oxygenated and deoxygenated hemoglobin. Though many researchers correlate blood flow to neural activity, the connection hasn't been solidly determined. © Nature 2001 NEEDLE IN A BRAINSTACK: The BOLD response to rotating checkerboard patterns happens in the striate cortex close to the location of the electrode tip (N.K. Logothetis et al., Nature, 412:150-7, 2001.) In 2001, Logothetis and his team published results obtained from simultaneous recording of the BOLD signal and, using electrodes, both the local field potential and the multiunit activity of neurons in the visual cortex of monkeys.1 The local field potential reveals neural signals (inputs) coming into the area; the multiunit activity correlates with neural signals (outputs) being broadcast from the area. Generally, as a neuron receives inputs from other neurons, it processes the information and sends the output to other neurons. The experimental results showed a correlation between the BOLD signal and both neural inputs and outputs, but, the input signal, the local field potential, correlated most strongly with the BOLD measurements. Logothetis found that the fMRI signal in an area primarily measures information coming into it. "There's a spectacular match between the MRI signal and the neurological events in total," he says. For its findings and technical prowess, Logothetis's paper attracted widespread attention. Columbia University's Joy Hirsch observes, "Everybody thought this was a landmark contribution, which, of course, raises more questions about the source of the [fMRI] signal." Peter Bandettini of the National Institute of Mental Health adds, "The amazing thing about Logothetis's paper was that it was so hard to do technically. You need an incredibly precise setup." Yet, the setup had limitations. For example, Bandettini points out that placing an electrode in brain tissue could alter how neural activity affects blood flow. "It might be a minor point," he says, "but people bring it up." Other investigators say they'd like more validation of Logothetis's results. "[His] point that the BOLD signal reflects presynaptic [input] activity has extreme relevance, but it requires additional study," says Jerome Sanes of Brown Medical School, Providence, Rhode Island. As scientists learn about the mechanics behind the BOLD signal, they hope to learn more about neural activity. For example, Ralph Freeman's group at the University of California, Berkeley, recently measured the level of neural tissue oxygenation--the basis of the BOLD signal--and the electrical activity of single neurons in the visual cortex.3 They found that increases in neuronal output correlate with a decrease in the tissue's oxygen level. So, in some cases, BOLD fMRI could be a good measure of outputs, too. MIRRORING MOVEMENT While studying monkeys, Rizzolatti and his colleagues found so-called mirror neurons in the premotor cortex. These neurons get turned on when a monkey performs a specific action or sees another monkey do the same thing. "We really discovered it by chance," Rizzolatti says. Nonetheless, that good luck stimulated another experiment. "We were interested to see if the monkey system existed in humans and if it is somatotopically organized." To find out, Rizzolatti recorded fMRI signals in humans as they watched videos of other humans doing things that ranged from biting an apple to kicking a ball.2 © Blackwell Synergy 2001 THE BRAIN MAP: Researchers created a somatotopic map of sorts by observing areas of brain activity while one observes body parts in action. Lit-up areas reveal brain activity during observation of non-object-related actions (A), and object-related actions (B). Red correlates to mouth movements; green to hand movements; blue to foot movements. Overlap of colors indicates activation foci present during observation of actions made by different effectors. (G. Blinkofski et al., Eur J Neurosci, 13:400-4, 2001) As in monkeys, Rizzolatti found mirror neurons in the premotor area of the human brain. Moreover, he revealed a somatotopic order among those neurons, essentially with head-related actions at one end and feet-related actions at the other. The group also found mirror neurons in the posterior parietal lobe, located in the upper and rearward part of the brain. Rizzolatti says the primate work "really opened a lot of new avenues because it showed the coupling between sensory and motor systems." The human experiments generated a variety of reactions. Hirsch jests, "The first thing I thought was: If this is true, then we can rehabilitate people who have lost motor function by doing jumping jacks in front of them." Though a stretch, she says she wonders if mirror neurons could offer clinical applications. A competitive dancer herself, Hirsch points to the value of learning by watching. "This could be a built-in mechanism for learning motor skills." Rizzolatti's work also furthers the idea of distributed processing in the brain. In other words, many areas of the brain often work together. "The human mirror neurons show that movement and the conception of movement are highly coupled," says Matthews. To some scientists, though, Rizzolatti's work reaches beyond experimental results. "This type of paper shows how fMRI really can be used," says Bandettini. Mirror neurons may also reach beyond methods, landing squarely in the field of philosophy. "This is an example of neuroscientists finding a brain correlate of self-awareness and how it's reflected in the world," says Sanes. The work may speak more clearly about metaphysical connections made within the brain. "When I think hammer," says Matthews, "I'm recalling the elements of its 'hammerness,' one of which is action. So that activates the premotor cortex." These reflections surpass the sense of vision. In ongoing work, Rizzolatti found similar results with smells; he exposed subjects to foul odors while using fMRI to view active brain areas. Those same areas showed activity when the subjects viewed others exposed to foul odors. APPROACH WITH CAUTION Questions remain about the basics behind fMRI signals. The activity at any site in the brain can be a combination of excitatory and inhibitory inputs. Indeed, recent work at the University of Copenhagen showed that a combination of inhibitory and excitatory stimuli can increase the local field potential and cerebral blood flow.4 Thus, an fMRI signal of a given magnitude could come from an endless spectrum of combinations. Matthews and his colleagues also found that the intensity of the subject's attention changes the magnitude of the BOLD fMRI signal, even when the basic stimulus remains fixed. On the whole, Matthews says, researchers should approach with caution. "One can make inferences about what one is seeing, but one must also always include the possibility that important information could be invisible to fMRI." Mike May (mikemay@mindspring.com) is a freelance writer in Madison, Ind. References 1. N.K. Logothetis et al., "Neurophysiological investigation of the basis of the fMRI signal," Nature, 412:150-7, 2001. (Cited in 270 papers) 2. G. Buccino et al., "Action observation activates premotor and parietal areas in a somatotopic manner: an fMRI study," Eur J Neurosci, 13:400-4, 2001. (Cited in 59 papers) 3. J.K. Thompson et al., "Single-neuron activity and tissue oxygenation in the cerebral cortex," Science, 299:1070-2, 2003. 4. K. Caesar et al., "From the cover: cortex sensitivity of activity-dependent increases in cerebral blood flow," Proc Natl Acad Sci, 100:4239-44, 2003. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

Caution: Brain Working

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