New Technology Poster Session
In transcranial magnetic stimulation (TMS; Nilsson et al. 1996; Walsh and Cowey, 1998), the cortex is stimulated non-invasively by strong magnetic field pulses that induce a flow of current in the tissue. TMS can be used 1) by studying the electrophysiological responses either locally or as mediated by neuro-nal path-ways from the stimulated spot (electrophysiology), 2) by disturbing ongoing neuronal signal processing in order to study cortical areas that are im-por-tant for specific tasks (temporary lesions), or 3) by treating patients with repetitive stimulation (therapy).
Magnetic stimulation is based on electromagnetic induction. In 1896, d'Arsonval reported having observed flickering lights when his head was in a changing magnetic field. Instead of having stimulated the visual cortex, d'Arsonval had stimulated the retina, which is more sensitive to induced fields than the brain.
The first successful TMS experiment was when Barker et al. (1985) stimulated the motor cortex, observing muscle responses. The early use of the technique was limited mainly to studies of neural conduction from the brain to the periphery.
In a new TMS paradigm, Amassian et al. (1989) showed that a subject's performance in a character identification task was impaired when a magnetic pulse was administered to the visual cortex between 60 and 140 ms after the onset of the visual stimulus; a temporary functional lesion had been created. Pascual-Leone et al. (1991) showed that by applying repetitive TMS (rTMS) to language areas in the dominant hemisphere, speech production can be arrested. Cohen et al. (1997) disrupted Braille reading in blind subjects with visual-cortex stimulation, obtaining evidence for the assertion (Kujala et al. 1995, Sadato et al. 1996) that the brain of the blind is modified so that the visual cortex performs some non-visual functions it would not do in the sighted. vGeorge et al. (1995) treated medication-resistant depressed patients by applying rTMS to the left dorsolateral prefrontal cortex, where neuronal activity appears to be lowered in depression. Several other authors (e.g., Pascual-Leone et al. 1996) have subsequently reported positive results on depressed patients as well as on other patient groups, but it is still too early to draw final conclusions on the efficacy of TMS therapy.
Although the head is transparent to magnetic fields at the frequencies used in TMS, the electric field generated by the changing magnetic field does depend on the conductivity structure of the head in a significant way. The most conspicuous consequence of the volume conductor geometry is that the macroscopic electric current produced by TMS is always tangential. Although the induced field can be computed directly for a coil with its axis oriented in the head's radial direction, the sphere has to be taken explicitly into account if the coil is tilted (Ilmoniemi et al. 1996).
Materials and Methods
The field strength of up to several tesla required in magnetic brain stimulation is achieved by discharging a capacitor, charged at several kilovolts, through a coil placed over the scalp; the resulting current pulse of several kiloamperes lasts less than a millisecond, the rise to maximum field strength being less than 100 microseconds; the rate of change of the magnetic field is thus on the order of 30 kT/s.
The focality of stimulation depends on the type of coil and on its distance from the head, small coils pressed against the scalp generally producing the most focal stimulation. In early magnetic stimulators, only circular coils were used; better focus can be obtained with the figure-of-eight coil (Ueno 1987). Further improvement is possible by using arrays of small coils (Ilmoniemi and Grandori 1994; Ruohonen and Ilmoniemi 1998). While focusing is possible tangentially, it is not possible to focus in depth even with combined magnetic and electric fields (Heller and van Hulsteyn 1992).
In most TMS studies, the coil is placed over the head by using external landmarks on the head or by trial and error until the desired response (e.g., thumb twitch) is generated. In contrast, in stereotactic TMS, the stimulator coil is positioned over the target location on the basis of individual MRI (Ruohonen and Ilmoniemi 1996; Krings et al. 1997a,b; Paus et al. 1997).
Because of the strong dependence of the magnetic field on the distance from the coil, even millimeter-level changes in the position or small changes in its orientation may change the induced field considerably. Therefore, stimulation amplitudes are typically selected on the basis of muscle response thresholds, but this is not possible when other than motor areas are studied. Stereotactic TMS, when made sufficiently precise, will allow one to select the level of the induced field instead of selecting stimulus amplitude as a percentage of the maximum stimulator output or on the basis of the individual motor threshold or cortical response.
To overcome the difficulties from the huge artefacts encountered by Cracco et al. (1989) and by Amassian et al. (1992), we have developed methods to eliminate the artefacts; our current EEG system, comprising a 60-electrode cap and electronics, can function without problem in the presence of the TMS pulses (Ilmoniemi et al. 1997; Virtanen et al. 1998).
The electrodes in our cap are 0.5-mm-thick Ag/AgCl rings, each interrupted with a 3-mm-wide slit to reduce the eddy currents that might otherwise cause excessive heating. In addition to heating, the TMS pulse produces a force on metallic objects; this force appears to cause an artefact in the EEG signal but fortunately the force and the artefact are also dramatically reduced when a slit is introduced.
A key feature in avoiding the stimulus artefact is a sample-and-hold circuit that keeps the amplifier output at a constant level during the pulse. Although the stimulus artefact can be dealt with by a hold period of just 1 ms, one often observes artefacts from muscles activated by the TMS pulse, in particular when the lateral aspect of the head is stimulated. These can often be handled with by a longer hold period, although at the expense of losing data.
We are developing the use of EEG mapping and source localization in conjunction with stereotactic computer-assisted TMS. By recording the cortical response just milliseconds after a TMS pulse, we can obtain an index of the local reactivity of the cortex; subsequent activity reflects also corticocortical and transcallosal connectivity.
In one set of experiments, we stimulated motor and visual cortices of volunteers (Ilmoniemi et al. 1997). The stimulation of the left sensorimotor hand area elicited an immediate strong response at the stimulated site. The activation spread to adjacent ipsilateral motor areas within 5-10 ms and to homologous regions in the opposite hemisphere within 20 ms. Similar activation patterns were generated by magnetic stimulation of the visual cortex: after the immediate ipsilateral response, the contralateral response was observed at about 20 ms. The ipsi- and contralaterally spreading neuronal activity can be seen for a period lasting up to 300 ms or more, although the interpretation of these signals is troublesome, since the loud click created by the stimulation coil produces unwanted activation of the auditory cortex.
To locate the activity underlying the observed signals, various source modelling techniques can be used. When only one area of the cortex is active, which may be a reasonable approximation in many cases, dipole modeling is appropriate. In more complicated cases, continuous current estimates are more reliable in indicating the active areas. We have used minimum-norm estimation (Hämäläinen and Ilmoniemi 1994) when observing the evolution of TMS-evoked brain activity, although original data and potential maps must always be carefully studied, at least in order to evaluate the quality of the data and to detect possible artefacts.
One advantage of EEG is that it provides direct information about the timing of signals transmitted from the stimulated site to other areas. It is also possible to combine sensory evoked potential and TMS studies (Tiitinen et al., submitted; Karhu et al., in preparation). A potentially useful application of EEG might be the early detection of approaching seizures during rapid-rate TMS treatment.
Discussion and Conclusion
TMS offers a new modality in brain mapping. While CT and MRI give us information on anatomy, MEG and EEG about electrical events, fMRI and PET about hemodynamics, PET and SPECT about metabolism and transmitter distribution, TMS can provide maps of reactivity and connectivity. In addition, TMS can be used to map areas that are important for the performance of a given task or areas that influence the activation of a muscle.
Functional connectivity and excitability of neuronal tissue are key aspects in defining how the central nervous system works. Recent advances in multimodal imaging and stimulation will allow us to characterize these properties in the intact human brain. This will help us better understand how the brain is organized functionally in normal conditions and in various diseases. For example, changes in connectivity play a central role in many types of stroke, in schitzophrenia and in demyelinating diseases such as multiple sclerosis. The possibility to study the recovery from stroke, consequences of trauma, altered excitability in epilepsies, dementias and coma may bring new tools for the diagnosis and follow-up of these diseases.
The combination of stereotactic TMS with EEG or with PET (Paus et al. 1997) gives rise to a completely new brain imaging modality. We can, for the first time, measure local reactivity of the cortex as well as functional connectivity between different brain areas.
The use of MEG and EEG together with conventional and functional MRI allows for the spatiotemporal imaging of the working human brain. The effect of TMS pulses on the neuronal network can be registered by using EEG, PET or fMRI, allowing the characterization of functional connectivity and excitability.
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|Ilmoniemi, R.J.; Karhu, J.; Ollikainen, M.; Ruohonen, J.; Tiitinen, H.; Virtanen, J.; Aronen, H.; Näätänen, R.; Katila, T.; (1998). Transcranial Magnetic Stimulation Combined with Electroencephalography. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/newtech/ilmoniemi0651/index.html|
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