George is a leader in the experimental use of TMS to alleviate depression, one of the biggest clinical hopes for the technique. In a decade of research, he has found that stimulating the prefrontal cortex can improve mood. "But where's the signal going," he says, "and how can it work to get people undepressed over time?" When he applied TMS to 14 depressed patients while they were in an fMRI scanner, he was able to confirm that subcortical areas such as the anterior cingulate - undoubtedly involved in depression - were activated as well. "I'd always believed that TMS gives us a window into some of the limbic mood regulating regions," says George. "There's no longer a question."
Still, he wants to be able to get a better picture of not only which areas are affected by the treatment, but also which areas show long-lasting changes in patients who find relief. George also hopes that this will help optimise TMS therapy.
George and Bohning are among a very select few who have managed to couple TMS with an up-and-coming technique known as diffusion tensor imaging (DTI, see "Live connections"). DTI uses the diffusion of water molecules to image connections in the brain. They have already used it to quash fears about TMS causing leakiness in the blood-brain barrier, a sort of safety fence around the brain that keeps out all but the smallest molecules. And they hope it will help reveal the underlying biology of how TMS relieves depression.
Heidi Johansen-Berg and Tim Behrens at the University of Oxford have also considered uniting TMS and DTI. The pair have already successfully begun to use DTI to map brain structure at the level of nerve fibres, and it could be fruitful to follow connections out from a point activated by TMS, says Johansen-Berg. She is particularly interested in understanding the relationship between structure and function. "Currently we use sulci and gyri [clefts and folds] as landmarks," she says. "But the relationship between folds and underlying function is not so good."
Putting DTI and fMRI together allows structure-function relationships to be tested more directly. We assume that function and structure are tightly associated, says Johansen-Berg, but until now there has been no good way to investigate that, since the only way to look at wiring was after death. Johansen-Berg and Behrens have, for example, used the combination to confirm the boundaries between the supplementary motor area, which is involved in movement, and the presupplementary motor area, which underpins higher-level cognitive tasks. Using fMRI, they compared the activity and different connections when volunteers moved their hands in a simple motor task versus when they counted backwards. Meanwhile, DTI showed where the pattern of connectivity in one region differed from the pattern in the other.
It seems most imaging methods can be mixed and matched. Computed tomography (CT) and PET scans are also proving an effective duo, mostly in an attempt to get at function and structure at the same time. Already people are whispering about bringing together PET and MRI and how that would be an even more tantalising coupling.
The quest for better understanding of how function and structure interact has come to the fore in recent years, says Paus. Five years ago people weren't paying as much attention. Now it is becoming clear that anatomy is very dynamic, that structural changes may even reflect the cumulative effect of experience. "Before that," says Paus, "they not only didn't think it was important, they also didn't have tools."
Live connections come into view
NOT so long ago, the only way to see actual physical connections in the brain was to look down a microscope at post-mortem tissue. Diffusion tensor imaging, a new technique using magnetic resonance, has changed that. A full investigation into the circuitry of living brains has now begun.
DTI measures the movement of water molecules in biological tissues. Water tends to diffuse more quickly along nerve fibres than through other tissues, though researchers are not clear exactly what determines the speed of diffusion in different parts of the brain. But a molecule of water is much more likely to diffuse along an axon, for instance, than through the fatty myelin sheath encasing it. Much as you can infer the existence of a motorway from an aeroplane at night by studying the pattern of lights below, neuroscientists can now map neural connections from the water traffic in the brain.
The technique may be able to help neurologists understand the progression of diseases such as Alzheimer's, schizophrenia and multiple sclerosis. In MS, for example, the person's immune system attacks the myelin coating on their axons. fMRI can reveal some of the damaged areas, but these don't always correspond well to a patient's disability.
Several labs are using DTI to try to see where neural pathways are disrupted in MS. For instance, a group in Italy led by Massimo Filippi at the University of Milan studied 78 people at different stages of MS. They found that DTI-based measures of damage did correlate with disability.
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