To better understand the neuronal effects of transcranial magnetic stimulation (TMS), we studied how the TMS-evoked brain responses depend on stimulation intensity. We measured electroencephalographic (EEG) responses to motor-cortex TMS, estimated the intensity dependence of the overall brain response, and compared it to a theoretical model for the intensity dependence of the TMS-evoked neuronal activity. Left and right motor cortices of seven volunteers were stimulated at intensities of 60, 80, 100, and 120% of the motor threshold (MT). A figure-of-eight coil (diameter of each loop 4 cm) was used for focal stimulation. EEG was recorded with 60 scalp electrodes. The intensity of 60% of MT was sufficient to produce a distinct global mean field amplitude (GMFA) waveform in all subjects. The GMFA, reflecting the overall brain response, was composed of four peaks, appearing at 15 +/- 5 msec (Peak I), 44 +/- 10 msec (II), 102 +/- 18 msec (III), and 185 +/- 13 msec (IV). The peak amplitudes depended nonlinearly on intensity. This nonlinearity was most pronounced for Peaks I and II, whose amplitudes appeared to sample the initial part of the sigmoid-shaped curve modeling the strength of TMS-evoked neuronal activity. Although the response amplitude increased with stimulus intensity, scalp distributions of the potential were relatively similar for the four intensities. The results imply that TMS is able to evoke measurable brain activity at low stimulus intensities, probably significantly below 60% of MT. The shape of the response-stimulus intensity curve may be an indicator of the activation state of the brain.

Navigated transcranial magnetic stimulation combined with electroencephalography (nTMS-EEG), allows noninvasive studies of cortical excitability and connectivity in humans. We investigated the reproducibility of nTMS-EEG in seven healthy subjects by repeating left motor and prefrontal cortical stimulation with a 1-week interval. TMS was applied at three intensities: 90, 100, and 110% of subjects' motor threshold (MT). The TMS-compatible neuronavigation system guaranteed precise repositioning of the stimulation coil. The responses were recorded by a 60-channel whole head TMS-compatible EEG amplifier. A high overall reproducibility (r > 0.80) was evident in nTMS-EEG responses over both hemispheres for both motor and prefrontal cortical stimulation. The results suggest that nTMS-EEG is a reliable tool for studies investigating cortical excitability changes in the test-retest designs.

In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses.

Transcranial magnetic stimulation (TMS) and multichannel electroencephalography (EEG) were used for the investigation of cortical excitability preceding voluntary movement in human subjects. The study showed the practical value of the combined TMS-EEG approach in differentiating between cortical and spinal-cord mechanisms, which is difficult with conventional electromyographic measures alone. TMS induced a pronounced negativity (N100) lasting for 150-200 ms, with the amplitude maximum in the stimulated hemisphere. When TMS was applied just before the onset of the visually triggered movement, N100 was markedly attenuated, although motor evoked potentials (MEPs) became larger. We suggest that the N100 component represents an inhibitory response following TMS. This interpretation is in agreement with intracellular recordings in animals, paired-pulse TMS studies and experiments showing increased premovement excitability on the basis of MEPs. N100 was not affected only by the subsequent movement, but also by the switching from rest to the motor-task condition, which caused a slight attenuation of the N100 component; no changes, however, were found in the amplitude of MEPs, suggesting that modified excitability did not affect the output of the corticospinal pyramidal cells. By contrast to MEPs, N100 was modulated also by the presentation of the visual stimulus alone, i.e. when no movement was required. This attenuation suggests that even in a rest condition visual stimuli have an access to the sensorimotor regions of the cortex, most probably through ascending arousal brain systems.

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Recent reports on functional brain imaging in major depression have lead to an assumption that observed psychopathology might be related to an altered brain functional connectivity. Our hypothesis was that an increase in brain functional connectivity occurs in major depression. As a measure of functional connectivity, the electroencephalogram (EEG) structural synchrony approach was used in 12 medication-free depressive outpatients and 10 control subjects. Differences in the number and strength of structurally synchronized EEG patterns were compared between groups. In depressive patients the number and strength of short cortex functional connections were significantly larger for the left than for the right hemisphere, while the number and strength of long functional connections were significantly larger for the right than for the left hemisphere. Some of the functional connections were positively correlated with the severity of depression, thus being predictive. These were short-range anterior, posterior, and left hemisphere functional connections for the alpha frequency band and short-range anterior functional connections for the theta frequency band. The topology of the most representative functional connections among all patients with major depression indicated that the right anterior and left posterior brain parts may discriminate depressive patients from healthy controls. The obtained data support our hypothesis that there is an increase in brain functional connectivity in major depression. This finding was interpreted within the semantic framework, where different specialization of left (monosemantic context) and right (polysemantic context) hemispheres is functionally insufficient in patients with depression.

Neuroimaging has revealed robust large-scale patterns of high neuronal activity in the human brain in the classical eyes-closed wakeful rest condition, pointing to the presence of a baseline of sustained endogenous processing in the absence of stimulus-driven neuronal activity. This baseline state has been shown to differ in major depressive disorder. More recently, several studies have documented that despite having a complex temporal structure, baseline oscillatory activity is characterized by persistent autocorrelations for tens of seconds that are highly replicable within and across subjects. The functional significance of these long-range temporal correlations has remained unknown.We recorded neuromagnetic activity in patients with a major depressive disorder and in healthy control subjects during eyes-closed wakeful rest and quantified the long-range temporal correlations in the amplitude fluctuations of different frequency bands. We found that temporal correlations in the theta-frequency band (3-7 Hz) were almost absent in the 5-100 s time range in the patients but prominent in the control subjects. The magnitude of temporal correlations over the left temporocentral region predicted the severity of depression in the patients.These data indicate that long-range temporal correlations in theta oscillations are a salient characteristic of the healthy human brain and may have diagnostic potential in psychiatric disorders. We propose a link between the abnormal temporal structure of theta oscillations in the depressive patients and the systems-level impairments of limbic-cortical networks that have been identified in recent anatomical and functional studies of patients with major depressive disorder.

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