Neuropsychology and TMS
Studies of neuropsychological patients have provided some of the most important revelations of brain–behavior relationships in the past century. They have made important contributions to the backbone of our understanding of the temporal lobe memory systems, the visuo-spatial functions of the parietal lobes, the different roles of the two cerebral hemispheres, the role of occipital lobes in resolution of a few millimeters. Indeed, there are now both indirect and direct demonstrations of the considerable specificity that can be achieved by this technique. Consider the indirect case first. The spatial and functional localization of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are achieved, in part, by comparing the effects on blood flow of different task conditions. The final spatial locations of, for example, ‘the motion area’, or an area important for memory processes or processing words, are then inferred from the differences between the activations produced by task conditions that vary only in the process under consideration.
Similar inferences can be applied to TMS. Here, however, the number of sites that can be compared is more restricted. This limitation provides a conceptual constraint on the application of TMS because a hypothesis is required for every comparison. The subtraction approach follows the logic of lesion analysis in humans and non-human primates, and that of functional neuro-imaging.
In most studies of cognitive function the TMS coil will be a figure-of-eight shape, which induces a maximum electrical field that peaks under the intersection of the two windings. The efficacy of the TMS pulse depends, in part, on the orientation of the underlying cell bodies and fibers with respect to the flow of the induced current. So, to increase confidence in the localization of effective stimulation, one can compare the behavioral effect of stimulation at several stimulation sites as described above, and determine the localization of the behavior in question by subtractive inference.
Alternatively, one can use a task control. Using task controls is of particular interest in cognitive studies as it may be sufficient to show that two processes are functionally dissociated in space or time. Anatomy and function can, however, be combined in TMS studies and some recent advances in combining TMS with neuro-imaging testify to its functional precision.
The first combined studies of TMS and PET showed that TMS induced neuronal activity under the site of stimulation, but that in addition, it also had effects at anatomically connected sites distant from the coil (much as a stimulus in an imaging experiment will activate many regions of the brain). Such studies may therefore have a future use in determining the functional connectivity of the human brain. More recent work has shown that the effects of TMS at the primary site correspond impressively with the activation produced by self-induced behaviour. For example, Seibner et al.applied 2 Hz repetitive pulse TMS (rTMS) over the left sensorimotor cortex of subjects at 140% of the motor threshold. They also asked subjects to imitate the arm movement caused by the rTMS and compared changes in regional cerebral blood flow in the two conditions. Both voluntary and TMS induced movement increased blood flow in the motor cortex contralateral to the arm movement, but voluntary movement also elicited greater activity in the supplementary motor area (FIG. 1).But both conditions excited the same connected cortical areas. George and colleagues have also shown the similarity of brain activations caused by voluntary and TMS-induced movements. So it is clear that TMS could be used to examine changes in connectivity as a function of learning in cases where the areas activated by action and TMS are in correspondence.
There are, however, several constraints that should guide the design of TMS experiments.
One important constraint on TMS is that the effects of stimulation are limited to superficial cortical regions and cannot be used to investigate functions of medial cortex or subcortical structures. One should also be aware that stimulating deeper cortical structures (for example, in the sulci) may also stimulate overlying cortex.
