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Single pulses of transcranial magnetic stimulation (sTMS) restricted locally to the primary cortical areas for somatosensory and visual input, unlike the effects of repetitive stimulation, usually fail to elicit projected sensations. We tested the effect of sTMS over anterior frontal cortex in facilitating phosphenes from preceding sTMS over calcarine cortex, which alone was rarely effective in eliciting phosphenes. The combined sTMS elicited complex phosphenes, which changed with the site of frontal sTMS and the interstimulus interval. Our results show that sTMS over anterior frontal cortex also improved reporting of weakly illuminated, flashed four-letter stimuli, which permitted its statistical validation. We propose that the present demonstration of frontal cortical facilitation of visual awareness, when combined with the previous finding of projected paresthesias and sense of movement (Amassian et al, 1991 Brain 114 2505-2520), provide evidence of a general frontal opening effect on a thalamic gate. Opening this gate facilitates entry of information from primary cortical receiving areas to thalamus. Thereby, the reciprocal thalamocortical interrelations that subserve conscious awareness of sensory stimuli could be fostered.

Our objective was to determine perisaccadic gamma range oscillations in the EEG during voluntary saccades in humans. We evaluated occipital perisaccadic gamma activity both in the presence and absence of visual input, when the observer was blindfolded. We quantified gamma power in the time periods before, during, and after horizontal saccades. The corresponding EEG was evaluated for individual saccades and the wavelet transformed EEG averaged for each time window, without averaging the EEG first. We found that, in both dark and light, parietal and occipital gamma power increased during the saccade and peaked prior to reaching new fixation. We show that this is not the result of muscle activity and not the result of visual input during saccades. Saccade direction affects the laterality of gamma power over posterior electrodes. Gamma power recorded over the posterior scalp increases during a saccade. The phasic modulation of gamma by saccades in darkness--when occipital activity is decoupled from visual input--provides electrophysiological evidence that voluntary saccades affect ongoing EEG. We suggest that saccade-phasic gamma modulation may contribute to short-term plasticity required to realign the visual space to the intended fixation point of a saccade and provides a mechanism for neuronal assembly formation prior to achieving the intended saccadic goal. The wavelet-transformed perisaccadic EEG could provide an electrophysiological tool applicable in humans for the purpose of fine analysis and potential separation of stages of 'planning' and 'action'.

Objective: To determine the initial level at which the pathways for cue perception, saccades and antisaccades diverge., Methods: Two procedures: single pulse transcranial magnetic stimulation (sTMS) over posterior occiput and backward masking were used. A visual cue directed saccades to the left or right, either a pro-saccade (to the side of the cue but beyond it) or an antisaccade, i.e., contraversive saccade. No visual target was presented., Results: Latencies of the two types of saccades did not differ. Focal sTMS applied unilaterally over V1 suppressed both perception of a cue flashed 80-90ms earlier contralaterally (but not ipsilaterally) and the appropriate saccade. Masking at a delay of 100ms abolished the appropriate saccade and cue perception., Conclusions: V1 is essential for the perception of a flashed cue and for executing appropriate pro- and contraversive saccades. Masking may occur beyond V1, where the pathways for perception and for saccades at least to the next visual processing level start separating., Significance: VI is needed for rapid, accurate perceptual and motor responses to the crudest (left versus right) cues. It is unlikely that the "where" system can have a major direct input bypassing V1.

Transcranial magnetic stimulation (TMS), by providing a method of stimulating human brain without the need for surgical exposure or significant discomfort, facilitated the study of cerebral functions in both normal subjects and patients. The aspects of TMS treated include: (1) The part(s) of neurons readily direct excited by TMS; (2) the optimal relationship between the orientations of the electric field induced by TMS and the directly excited neurons; (3) the transynaptic effects of the directly excited neurons that are either distant or local; (4) the effects of repetitive versus single pulse TMS.

Objective: These experiments examined short interval paired-pulse paradigms for intracortical inhibition (ICI) and facilitation (ICF). We tested whether pairs of subthreshold conditioning stimuli interact, and whether they showed rapid periodicity similar to that observed in subthreshold I-wave interaction., Methods: Transcranial magnetic stimulation (TMS) was given over left M1 to evoke a motor-evoked potential (MEP) of approximately 1 mV peak-to-peak amplitude in the contralateral first dorsal interosseous (FDI) muscle. Each test shock (TS) was preceded by single or paired subthreshold conditioning stimuli (CS(1) and CS(2)) at short interstimulus intervals (ISIs 1-15 ms). Intensities of CS were set just below thresholds for intracortical inhibition (ICI) or intracortical facilitation (ICF)., Results: Each CS(single) alone had no effect on the test MEP, but with two CS, clear inhibition was elicited at certain intervals. With a CS(2)-TS interval of 2 ms, maximum suppression occurred if CS(1) was applied 1-2.5 ms before CS(2). This inhibitory effect tapered off gradually as the CS(2)-CS(1) interval was increased up to 13 ms. When facilitation was present with a CS(single)-TS interval of 10 ms, a small but non-significant extra-facilitation occurred at ISIs between CS(2) and CS(1) of 6-15 ms., Conclusions: Two subthreshold conditioning stimuli facilitate inhibition that lacks the rapid periodicity typical of I-wave interaction. The data would be compatible with a model in which synaptic inputs converge on a common inhibitory interneurone.

Objective and Methods: Direct (D) and transynaptic, (i.e. indirect) (I) corticospinal tract (CT) discharges were simultaneously recorded epidurally with muscle motor evoked potentials (MEPs) in patients under different levels of anesthesia. The effects of the one, two or more equal electrical stimuli, applied transcranially or directly to the motor cortex, were studied at different interstimulus intervals (ISIs) to determine the optimal conditions for eliciting I and MEP responses., Results and Conclusion: At anesthetic levels permiting large D and I responses to single stimuli, optimal D and I wave facilitation and MEPs occurred with two stimuli at ISIs greater than 4 ms (e.g. at 5.9 and 8 ms). When single electrical stimuli elicit only a D response, optimal MEP responses are determined by the number of stimuli and the recovery of CT fibers excitability (e.g. at an ISI of 4 ms).

Direct (D) corticospinal tract discharges were recorded epidurally in patients at anesthetic depths suppressing indirect (I) activity and were elicited by two equal transcranial electrical stimuli. The recovery of amplitude of the second D wave (D2) was a function of the interstimulus interval (ISI) and the stimulus duration. For example, with a 100 micros pulse, there was no response at an ISI of 1.1 ms, but partial recovery occurred with a 500 micros pulse. This indicates a relative refractory component at this ISI. Both D2 amplitude and conduction time recovered completely using a 4 ms ISI, with evidence of increased amplitude and reduced conduction time (supernormality) at longer ISIs. These findings are relevant in explaining high frequency D and I discharges and facilitation of motor responses by two transcranial magnetic pulses. Furthermore, these data help to understand why an ISI of 4 ms would be optimal in eliciting limb muscle responses when a short train of transcranial stimuli elicits only D waves in anesthetized patients (Deletis et al., Clin Neurophysiol 112 (2001) 445).

Single-pulse magnetic coil stimulation (Cadwell MES 10) over the cranium induces without pain an electric pulse in the underlying cerebral cortex. Stimulation over the motor cortex can elicit a muscle twitch. In 10 subjects, we tested whether motor cortical stimulation could also elicit skin sympathetic nerve activity (SSNA; n = 8) and muscle sympathetic nerve activity (MSNA; n = 5) in the peroneal nerve. Focal motor cortical stimulation predictably elicited bursts of SSNA but not MSNA; with successive stimuli, the SSNA responses did not readily extinguish (94% of discharges to the motor cortex evoked SSNA responses) and had predictable latencies [739 +/- 33 (SE) to 895 +/- 13 ms]. The SSNA responses were similar after stimulation of dominant and nondominant sides. Focal stimulation posterior to the motor cortex elicited extinguishable SSNA responses. In three of six subjects, anterior cortical stimulation evoked SSNA responses similar to those seen with motor cortex stimulation but without detectable movement; in the other subjects, anterior stimulation evoked less SSNA discharge than that seen with motor cortex stimulation. Contrasting with motor cortical stimulation, evoked SSNA responses were more readily extinguished with 1) peripheral stimulation that directly elicited forearm muscle activation accompanied by electromyograms similar to those with motor cortical stimulation; 2) auditory stimulation by the click of the energized coil when off the head; and 3) in preliminary experiments, finger afferent stimulation sufficient to cause tingling. Our findings are consistent with the hypothesis that motor cortex stimulation can cause activation of both alpha-motoneurons and SSNA.

The fact that TMS of cerebral cortex is associated with inhibitory as well as excitatory properties is important because it makes it possible to investigate interconnections between cortical areas and tracing these functional interconnections by a noninvasive excitation or inhibition and temporary interference with the flow of impulses in the cerebral cortex. An important tool is thereby added to the analysis of higher cortical functions.

Pairs of threshold magnetic stimuli were applied over the motor cortex at interstimulus intervals of 1-6 ms, and EMG responses recorded from the relaxed or active first dorsal interosseous muscle of 7 normal subjects. In relaxed subjects, when the interval between the stimuli was around 1.0-1.5 ms, 2.5-3.0 ms or 4.5 ms or later, the size of the response to the pair of stimuli was much greater than the algebraic sum of the response to each stimulus alone. During contraction, fewer peaks of facilitation were observed. Facilitation was evident if the stimuli were 0.9-1.1 times threshold in the relaxed state, and 1.0-1.1 times threshold during voluntary contraction. Experiments using either magnetic followed by anodal electric stimulation, or pairs of anodal electric stimuli, suggested that the facilitation most likely occurred within the cerebral motor cortex. Given the timings at which facilitation is prominent, it seems likely that it reflects interactions between circuits normally responsible for production of I-waves.

Using principles derived from electric field measurements and studies of phrenic nerve in vitro, neuromagnetic stimuli in humans were predicted to excite selective low threshold sites in proximal and distal cauda equina. Physical models, in which induced electric fields were recorded in a segment of human lumbosacral spine immersed in a saline filled tank, supported this prediction. Conclusions from the model were tested and confirmed in normal human subjects. Ipsilateral motor evoked potentials were elicited in lower limb muscles and striated sphincters by magnetic coil (MC) stimulation of both proximal and distal cauda equina. Over proximal cauda equina a vertically oriented MC junction and cranially directed induced current elicited a newly identified compound muscle action potential (CMAP). The F response latency and lack of attenuation when the target muscle was vibrated suggest that the proximal response is a directly elicited M response arising near or at the rootlet exit zone of the conus medullaris. Over distal cauda equina, lumbar roots were optimally excited by a horizontally oriented MC junction, and sacral roots by an approximately vertically oriented MC junction, eliciting CMAPs with similar appearance but shorter latency consistent with the known intrathecal lengths of the lower lumbar and sacral nerve roots. The induced current was usually most effective when directed towards the spinal fluid filled thecal sac. Normal subjects showed stable CMAP onset latencies elicited at proximal and distal cauda equina despite wide variation in amplitude. Thus, cauda equina conduction time can be directly calculated. This new method may improve the detection and classification of peripheral neuropathies affecting lower limbs and striated sphincters.

It is hoped that this survey conveys a sense of the many positive uses of focal and nonfocal MC stimulation already manifest within a decade of its introduction. As with other techniques of investigating brain function, MC stimulation has its relative advantages and disadvantages. The precision of defining the site of MC effects currently is inferior to that achieved with PET scanning, but the precision of timing of effects is superior, being on the order of milliseconds. Perhaps the special value of MC stimulation is in moving closer to specifying cause-effect relationships, through interference or facilitatory effects, than when techniques yielding more circumstantial evidence are used. However, it is the testing and cross-validation of the conclusions from the different modes of neuroscientific inquiry that we look to in synthesizing explanations of brain function.