Cerebral function revealed by transcranial magnetic stimulation.

Although transcranial magnetic stimulation (TMS) has been introduced only recently, it is safe and provides a painless, inexpensive noninvasive method for the evaluation of brain function. Determining central motor conduction time (CMCT) permits assessment of the corticospinal pathways. Mapping the central representation of muscles provides a method for investigating the cortical reorganization that follows training, amputation and injury to the central nervous system. Such studies of human plasticity may have important implications for neurorehabilitation. TMS also provides a method whereby cortical excitability can be noninvasively evaluated, which is likely to have important implications in the study of epilepsy, movement disorders and related conditions. TMS is useful in tracking the flow of information from one brain region to another and in investigations of cognition and functional localization, thereby complementing information obtained using functional imaging techniques, which have superior spatial but inferior temporal resolution. Finally, TMS is currently being investigated as a method for establishing cerebral dominance and as a therapeutic tool in the treatment of depression. Investigations for treatment of other neurologic and psychiatric conditions are likely to be undertaken.

Interconnections between cortical areas revealed by transcranial magnetic stimulation.

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.

Transcranial magnetic stimulation in study of the visual pathway.

The authors critically reviewed experiments in which transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) of the higher visual pathway were used. Topics include basic mechanisms of neural excitation by TMS and their relevance to the visual pathway (excitatory and inhibitory effects), TMS and rTMS of calcarine cortex (suppression, unmasking, and phosphenes), TMS of V5 (suppression), TMS and rTMS of higher level temporoparietooccipital areas (perceptual errors, unmasking, and inattention), the role of frontal lobe output in visual perception, and vocalization of perceived visual stimuli (role of consciousness of linguistic symbols).

Some positive effects of transcranial magnetic stimulation.

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.

The polarity of the induced electric field influences magnetic coil inhibition of human visual cortex: implications for the site of excitation.

Human perception of 3 briefly flashed letters in a horizontal array that subtends a visual angle of 3 degrees or less is reduced by a magnetic coil (MC) pulse given, e.g., 90 msec later. Either a round or a double square MC is effective when the lower windings or central junction region, respectively, are tangential to the skull overlying calcarine cortex and symmetrical across the midline. The modeled, induced electric field has peak amplitude at the midline, but the peak spatial derivatives lie many centimeters laterally. Thus, the foveal representation near the midline is closer to the peak electric field than to its peak spatial derivatives, i.e., excitation of calcarine cortex differs from excitation of a straight nerve. With an MC pulse that induces an electric field which is substantially monophasic in amplitude, the lateral-most letter (usually the right-hand letter) in the trigram is preferentially suppressed when the electric field in the contralateral occipital lobe is directed towards the midline. Inferences from using peripheral nerve models imply that medially located bends in geniculo-calcarine or corticofugal fibers are the relevant sites of excitation in visual suppression; end excitation of fiber arborizations or apical dendrites is considered less likely. This conclusion is supported by the fact that the induced electric field polarity in paracentral lobule for optimally eliciting foot movements is opposite to that for visual suppression, the major bends occurring at different portions of the fiber trajectories in the two systems.

Measurement of information processing delays in human visual cortex with repetitive magnetic coil stimulation.

Previous work disclosed that single magnetic coil (MC) pulses applied over human calcarine cortex could suppress perception of letters briefly presented, e.g. 80-100 ms earlier. Although individual MC stimuli presented 0-60 ms, or more than 140 ms after the visual stimulus were apparently ineffective, combinations of 2 or 3 MC pulses at such intervals temporarily depressed visual perception. Thus, progressing of such language information could be slowed, without being abolished. By contrast, when the first MC pulse was delivered 120 ms or later, a second MC pulse 40 ms later had no detectable effect, implying that calcarine cortex had already transmitted the information. Perceptual recovery of 5-character words initially occurred no earlier than that of random letters, nor or random letters vs. arbitrary linear patterns, implying that the processing delays in calcarine cortex were similar.

Unmasking human visual perception with the magnetic coil and its relationship to hemispheric asymmetry.

Visual suppression by a magnetic coil (MC) pulse delivered over human calcarine cortex after a transient visual stimulus 80-100 ms earlier has been used to suppress the representation of a 'masking' visual stimulus and thus to unmask a 'target' visual stimulus given, e.g., 100 ms before the mask. The resulting target unmasking as a function of the interval between mask and MC pulse is approximately the inverse of the visual suppression curve. Arbitrary visual linear patterns can similarly be unmasked. At the long target-mask interval used, the site of masking is deduced to lie beyond calcarine cortex. In several right-handed subjects tested, powerful MC stimulation of the left (but not right) temporo-parieto-occipital cortex also led to (weaker) unmasking.

Familial rectal pain: a type of reflex epilepsy?

We studied 2 members of a family suffering from paroxysmal attacks elicited by tactile stimuli. The attacks consist of burning pain of the stimulated body part, followed by either complete collapse or tonic posturing. Noxious stimuli provoke episodes regardless of their somatic location, whereas it is only necessary for nonnoxious stimuli to be applied to specific trigger zones, such as the rectum, to provoke attacks. Episodes are most commonly precipitated by bowel movement, leading to extreme fear of defecation and resultant fecal retention. An ictal electroencephalographic video recording revealed only slowing of the background; however, serum prolactin was significantly elevated postictally. The attacks were completely suppressed by carbamazepine and resumed on discontinuing the medication. These attacks may represent a form of reflex epilepsy manifested by autonomic nervous system dysfunction.

Cerebello-frontal cortical projections in humans studied with the magnetic coil.

Focal stimulation over human cerebellum with a figure 8 magnetic coil (MC) results in an evoked wave recorded from bipolar scalp electrodes on the interaural line and more anteriorly. In 3 subjects, the wave responses along the interaural line had latencies of 8.8-13.8 msec, lasted 17.4-29.0 msec and had a maximum amplitude of 14.4-26.8 microV. The responses were recorded more anteriorly from leads midway between the interaural line and frontal leads; responses recorded from frontal leads were up to 3.5 msec later. The evoked wave was preceded by a diphasic EMG response with a latency of 1.2-2.0 msec. Analysis of the averaged responses recorded by adjoining bipolar leads indicated that the response was predominantly surface positive and crossed. Control experiments eliminated eye movement and somatosensory input as explanations of the evoked response, thereby identifying it as a cortical response. The surface positive wave in humans was compared with the responses recorded in cat and monkey to cerebellar stimulation. The responses in humans could reflect dysfacilitation through MC activation of Purkinje cells, or feed-forward facilitation through transsynaptic or antidromic activation of dentate neurons. The latency of the surface positive wave exceeds that of cerebellar inhibition of MC elicited hand muscle responses, but the discrepancy is at least partly accounted for by the extra delay required to set up the indirect cortico-spinal component required for motoneuron discharge. Estimates made of the cerebello-frontal cortical and peripheral feedback loop times suggest that the central has less than one quarter the delay of the peripheral loop, which would be especially advantageous during fast skilled movements of the fingers.

Paraesthesias are elicited by single pulse, magnetic coil stimulation of motor cortex in susceptible humans.

A minority of normal humans experience paraesthesias (usually tingling) projected to the contralateral hand in response to individual transcranial magnetic coil (MC) pulses. The cortical source of the paraesthesias was sought by comparing their incidence with that of muscle responses to focal MC stimulation with either a figure 8 MC or with edge stimulation of a tilted round MC in 4 susceptible subjects. In all 4, paraesthesias were best felt with MC stimulation either at, or anterior to sites yielding movement, implying an initial source in precentral gyrus (and possible premotor cortex), rather than parietal cortex. In the two subjects exhibiting the strongest paraesthesias, the threshold for the paraesthesias was less than that for movement in the relaxed arm. The optimal site of the paraesthesias within the hand was usually in the digits, but differed among subjects. Motor responses and paraesthesias following a given stimulus occurred at different sites in the hand, implying that excitation of differing sets of motor cortical neurons subserved sensory and motor responses. In only one subject were the paraesthesias sufficiently reproducible to warrant interacting electrical digital and transcranial MC pulses. The data suggested that central processing of the response to the MC pulse is slowed by an antecedent digital stimulus, but the delay for perception of each type of stimulus does not greatly differ. The central sense of movement (Amassian et al., 1989a) elicited by MC stimulation of motor cortex is compared with the paraesthesias. Both are attributed to brief, high frequency discharge by motor cortical neurons accessing the perceptual system more readily than after excitation of post-central gyrus, which requires prolonged repetitive stimulation (Libet et al., 1964). Given also the normal pattern of muscle responses in the 4 subjects, their paraesthesias are best explained by a heightened sensitivity of the perceptual system to the motor cortical response to MC stimulation.

Intraoperative recordings of spinal somatosensory evoked potentials to tibial nerve and sural nerve stimulation.

Somatosensory evoked potentials (SSEPs) to stimulation of the tibial nerve at the knee (TN-K) and ankle (TN-A), and the sural nerve at the ankle (SN-A), were recorded from 3 or 4 spinal levels during surgery for scoliosis in 11 neurologically normal subjects. With stimulation of all 3 nerves, the propagation velocity along the spine was nonlinear: it was faster over cauda equina and midthoracic cord than over caudal spinal cord. Over the mid-thoracic cord, TN-K SSEP propagation was faster than that of TN-A and SN-A SSEPs, whereas over the caudal spinal cord these values were similar on stimulation of all 3 nerves. These data suggest that fast conducting second order afferent fiber systems contribute to spinal cord SSEPs evoked by stimulating both mixed and cutaneous peripheral nerves.

Stimulation of the human nervous system using the magnetic coil.

The magnetic coil (MC) is a unique probe that can be used to elucidate basic neurophysiological mechanisms in humans. Either by excitation or inhibition of responding neural elements, we have been able to investigate: (1) the distribution of the electric field induced within isotropic and anisotropic volume conductors by round and figure-eight MCs; (2) the theoretical relationship between electric field distribution and excitation of distal peripheral nerve, nerve root, cranial nerve, and motor cortex; (3) the effect of focal MC stimulation of motor and visual systems; (4) perturbation of sequential digit movements by MC stimulation of human premotor cortex; (5) activation of frontal motor areas related to speech; (6) elicitation of a sense of movement in an ischemic paralyzed limb by focal MC cortical stimulation; and (7) the effect of stimulation of the human visual system to (a) suppress and unmask visual perception using single MC stimuli and (b) prolong visual suppression using short trains of MC stimuli. In the future, prolongation of MC action by using repetitive stimuli should be useful in further investigating functions concerned with language, speech, and cognition.

Magnetic coil stimulation of human visual cortex: studies of perception.

The effects of magnetic coil (MC) stimulation of human visual cortex on the foveal perception of briefly presented letter trigrams include: (1) letters were nearly always reported correctly at visual stimulus-MC pulse intervals less than 60-80 msec or greater than 120-140 msec. Thus, by 120-140 msec, information related to letter recognition is relayed from calcarine cortex. (2) Presentation of equiluminant chromatic stimuli (specifically green letters against a red background) results in suppression curves which commence at longer latencies than those obtained with achromatic stimuli. (3) At a stimulus-MC pulse interval of 100 msec, shifting the MC laterally or rostrally resulted in suppression of the contralateral or caudal-most letter respectively. This implies a focal, topographical effect on visual cortex. (4) Two trigram stimuli separated in time (e.g. 100 msec) resulted in classical backward masking in which S1 (the target) was suppressed by S2 (the mask), using an S2/S1 luminance-contrast ratio of 4:1. When the MC was subsequently discharged 80-100 msec after S2, and S2 was suppressed, the response to S1 was easily retrieved (unmasked). Presumably, by 160 msec, S1 has been transmitted to the next processing, extrastriate level. (5) The unmasking phenomenon has been used to track information flow from visual cortex to higher cortical centers (e.g. Wernicke's, Broca's, and related areas). (6) Using a prototype repetitive stimulator, a consecutive train of single MC pulses given 70, 143 and 216 msec following a brief alphabetic trigram stimulus elicited a significant reduction in letter perception. This notably contrasts with the absence of suppression when a single MC pulse was given 70 or 143 msec following presentation of the alphabetic trigram. The results with 3 pulses suggest that the first MC pulse (at 70 msec) delays but requires repetition to prevent processing and/or transmission of information from visual cortex.

Matching focal and non-focal magnetic coil stimulation to properties of human nervous system: mapping motor unit fields in motor cortex contrasted with altering sequential digit movements by premotor-SMA stimulation.

Possible classifications of effects of magnetic coil (MC) stimulation are discussed, with the conclusion that the most useful is focal versus non-focal excitation. The mode of excitation of peripheral motor axons by the longitudinal-orthogonally orientated round MC is deduced from the insignificant latency shift in motor unit response when the current direction is reversed either by rotating the coil or by a switching device. A hypothesis is advanced of how peak membrane current entry and exit could occur only 1-3 nodes apart. The mode of excitation of cerebral cortex is more complex. Related to the orientation of the round MC, corticospinal neurons are: (1) directly excited and; or (2) indirectly excited through stimulation of corticocortical and other presynaptic inputs. Although the round MC can directly excite monkey corticospinal neurons at two sites, i.e. the initial segment and the node, the node is believed to be the main target in humans. The meaning of 'focality' of excitation is discussed as applied to MC stimulation of peripheral nerve and cerebral cortex. A potential conflict exists between focality and magnitude of response to MC excitation. However, by appropriately orientating the round MC, activation of all motor axons in one nerve (e.g., the median nerve at the wrist) can be achieved without coactivation of another (e.g., the ulnar nerve). By contrast, no orientation of the round MC, or use of a specially designed MC (e.g., double coil) over motor cortex permits all members of a defined set to be activated in isolation. Nevertheless, some members of the set can be activated in isolation with the MC over motor cortex. Response properties of individual motor units in the extensors of the digits when focally stimulating motor cortex with the figure '8' MC include: (1) Responses are variable to a given stimulus a little above threshold. Comparing responses by individual motor units with that of the population, or with other simultaneously recorded units revealed both coherent and independent sources of variability. (2) The scalp field from which the motor units could be driven by suprathreshold stimulation was of the order of 4-6 cm2. The fields were elongated in the antero-posterior axis, possibly related to the similar orientation of the junction region of the figure '8' MC. (3) Motor units initially excited by threshold MC stimulation were typically recruited early during voluntary contraction (confirming Hess et al. 1987).(ABSTRACT TRUNCATED AT 400 WORDS)

Brain stimulation revisited.

The results of the following selected studies using magnetic coil (MC) stimulation are presented: (1) evidence for focality of MC stimulation, (2) MC stimulation of frontal areas related to speech, (3) transcallosal responses evoked by MC stimulation, and (4) suppression of visual perception with MC stimulation over occipital cortex. The authors served as subjects, and in most studies a standard Cadwell stimulator and round MC were used. Using a more vertical, rather than tangential, MC orientation and threshold stimulation, nearly isolated movements of individual digits were elicited implying focal cortical excitation. MC stimulation of frontal areas of either hemisphere elicited electromyography in contralateral laryngeal muscles. The shortest latency responses that were often accompanied by arm movement were thought to be elicited from intermediate areas of precentral gyrus and longer latency responses, from near Broca's area, extreme lateral precentral gyrus, and the supplementary motor area. MC stimulation over the occipital cortex resulted in suppression of visual perception of letters briefly flashed on a screen. The topography of suppression implicated the geniculocalcarine system as the site of MC effect. Focal MC stimulation of posterior frontal cerebral cortex elicited a transcallosal response from contralateral homologous cortex with a latency similar to that obtained with focal anodic stimulation but with considerably less excitation of cranial muscles.

Comparison of human transcallosal responses evoked by magnetic coil and electrical stimulation.

Human transcallosal responses (TCRs) were elicited by focal magnetic coil (MC) stimulation of homologous sites in contralateral frontal cortex and compared with those to focal anodic stimulation. With MC stimulation, the TCR consisted of an initially positive wave with an onset latency of 8.8-12.2 msec, a duration of 7-15 msec, and an amplitude which reached up to 20 microV, sometimes followed by a broad low amplitude negative wave. With anodic stimulation, a similar response was obtained in which the positive wave was similar in latency and maximum amplitude, but had a greater duration. With anodic stimulation, not only was the TCR threshold below that for contralateral movement, but it reached substantial size at intensities below motor threshold. With MC stimulation, contralateral arm movement and scalp corticomotor potentials were observed when the MC was displaced posteriorly towards the central sulcus. Unlike with anodic stimulation, the MC evoked TCR was usually not preceded by a prominent EMG potential from temporalis muscle and was not associated with subject discomfort. The TCR provides unique information concerning the functional integrity of callosal projection neurons, their axons and transsynaptic processes in recipient cortex. This information may prove useful in the evaluation of intrinsic cerebral mechanisms and in establishing cortical viability.