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These studies investigated whether a single electrical stimulus over the thoracic spine activates corticospinal axons projecting to human leg muscles. Transcranial magnetic stimulation of the motor cortex and electrical stimulation over the thoracic spine were paired at seven interstimulus intervals, and surface electromyographic responses were recorded from rectus femoris, tibialis anterior, and soleus. The interstimulus intervals (ISIs) were set so that the first descending volley evoked by cortical stimulation had not arrived at (positive ISIs), was at the same level as (0 ISI) or had passed (negative ISIs) the site of activation of descending axons by the thoracic stimulation at the moment of its delivery. Compared with the responses to motor cortical stimulation alone, responses to paired stimuli were larger at negative ISIs but reduced at positive ISIs in all three leg muscles. This depression of responses at positive ISIs is consistent with an occlusive interaction in which an antidromic volley evoked by the thoracic stimulation collides with descending volleys evoked by cortical stimulation. The cortical and spinal stimuli activate some of the same corticospinal axons. Thus it is possible to examine the excitability of lower limb motoneuron pools to corticospinal inputs without the confounding effects of changes occurring within the motor cortex.

Changes in the strength of corticospinal projections to muscles in the upper and lower limbs are induced in conscious humans after paired associative stimulation (PAS) to the motor cortex. We tested whether an intervention of PAS consisting of 90 low-frequency (0.1-Hz) stimuli to the common peroneal nerve combined with suprathreshold transcranial magnetic stimulation (TMS) produces specific changes to the motor-evoked potentials (MEPs) in lower leg muscles if the afferent volley from peripheral stimulation is timed to arrive at the motor cortex after TMS-induced firing of corticospinal neurons. Unlike PAS in the hand, MEP facilitation in the leg was produced when sensory inputs were estimated to arrive at the motor cortex over a range of 15 to 90 ms after cortical stimulation. We examined whether this broad range of facilitation occurred as a result of prolonged subthreshold excitability of the motor cortex after a single pulse of suprathreshold TMS so that coincident excitation from sensory inputs arriving many milliseconds after TMS can occur. We found that significant facilitation of MEP responses (>200%) occurred when the motor cortex was conditioned with suprathreshold TMS tens of milliseconds earlier. Likewise, it was possible to induce strong MEP facilitation (85% at 60 min) when afferent inputs were directly paired with subthreshold TMS. We argue that in the leg motor cortex, facilitation of MEP responses from PAS occurred over a large range of interstimulus intervals as a result of the paired activation of sensory inputs with sustained, subthreshold activity of cortical neurons that follow a pulse of suprathreshold TMS.

Electrical stimulation of the motor cortex in monkeys can evoke complex, multijoint movements including movements of the arm and hand. In this study, we examined these movements in detail and tested whether they showed adaptability to differing circumstances such as to a weight added to the hand. Electrical microstimulation was applied to motor cortex using pulse trains of 500-ms duration (matching the approximate duration of a reach). Arm movement was measured using a high-resolution three-dimensional tracking system. Movement latencies averaged 80.2 ms. Speed profiles were typically smooth and bell-shaped, and the peak speed covaried with movement distance. Stimulation generally evoked a specific final hand position. The convergence of the hand from disparate starting positions to a narrow range of final positions was statistically significant for every site tested (91/91). When a weight was fixed to the hand, for some stimulation sites (74%), the evoked movement appeared to compensate for the weight in that the hand was lifted to a similar final location. For other stimulation sites (26%), the weight caused a significant reduction in final hand height. For about one-half of the sites (54%), the variation in movement of each joint appeared to compensate for the variation in the other joints in a manner that stabilized the hand in a restricted region of space. These findings suggest that at least some of the stimulation-evoked movements reflect relatively high-level, adaptable motor plans.

Transcranial magnetic stimulation (TMS) is a unique method in neuroscience used to stimulate focal regions of the human brain. As TMS gains popularity in experimental and clinical domains, techniques for controlling the extent of brain stimulation are becoming increasingly important. At present, TMS intensity is typically calibrated to the excitability of the human motor cortex, a measure referred to as motor threshold (MT). Although TMS is commonly applied to nonmotor regions, most applications do not consider the effect of changes in distance between the stimulating device and underlying neural tissue. Here we show that for every millimeter from the stimulating coil, an additional 3% of TMS output is required to induce an equivalent level of brain stimulation at the motor cortex. This abrupt spatial gradient will have crucial consequences when TMS is applied to nonmotor regions because of substantial variance in scalp-cortex distances over different regions of the head. Stimulation protocols that do not account for cortical distance therefore risk substantial under- or overstimulation. We describe a simple method for adjusting MT to account for variations in cortical distance, thus providing a more accurate calibration than unadjusted MT for the safe and effective application of TMS in clinical and experimental neuroscience.

We studied the effects of 1-Hz repetitive transcranial magnetic stimulation (rTMS) on the excitability of interhemispheric connections in 13 right-handed healthy volunteers. TMS was performed using figure-eight coils, and surface electromyography (EMG) was recorded from both first dorsal interosseous (FDI) muscles. A paired-pulse method with a conditioning stimulus (CS) to the motor cortex (M1) followed by a test stimulus to the opposite M1 was used to study the interhemispheric inhibition (ppIHI). Both CS and TS were adjusted to produce motor-evoked potentials of approximately 1 mV in the contralateral FDI muscles. After baseline measurement of right-to-left IHI (pre-RIHI) and left-to-right IHI (pre-LIHI), rTMS was applied over left M1 at 1 Hz with 900 stimuli at 115% of resting motor threshold. After rTMS, ppIHI was studied using both the pre-rTMS CS (post-RIHI and post-LIHI) and an adjusted post-rTMS CS set to produce 1-mV motor evoked potentials (MEPs; post-RIHI(adj) and post-LIHI(adj)). The TS was set to produce 1-mV MEPs. There was a significant reduction in post-LIHI (P = 0.0049) and post-LIHI(adj) (P = 0.0169) compared with pre-LIHI at both interstimulus intervals of 10 and 40 ms. Post-RIHI was significantly reduced compared with pre-RIHI (P = 0.0015) but pre-RIHI and post-RIHI(adj) were not significantly different. We conclude that 1-Hz rTMS reduces IHI in both directions but is predominantly from the stimulated to the unstimulated hemisphere. Low-frequency rTMS may be used to modulate the excitability of IHI circuits. Treatment protocols using low-frequency rTMS to reduce cortical excitability in neurological and psychiatric conditions need to take into account their effects on IHI.

We used microstimulation to examine the contribution of the motor cortex to the structure and timing of the hindlimb step cycle during locomotion in the intact cat. Stimulation was applied to the hindlimb representation of the motor cortex in 34 sites in three cats using either standard glass-insulated microelectrodes (16 sites in 1 cat) or chronically implanted microwire electrodes (18 sites in 2 cats). Stimulation at just suprathreshold intensities with the cat at rest produced multi-joint movements at a majority of sites (21/34, 62%) but evoked responses restricted to a single joint, normally the ankle, at the other 13/34 (38%) sites. Stimulation during locomotion generally evoked larger responses than the same stimulation at rest and frequently activated additional muscles. Stimulation at all 34 sites evoked phase-dependent responses in which stimulation in swing produced transient increases in activity in flexor muscles while stimulation during stance produced transient decreases in activity in extensors. Stimulation with long (200 ms) trains of stimuli in swing produced an increased level of activity and duration of flexor muscles without producing changes in cycle duration. In contrast, stimulation during stance decreased the duration of the extensor muscle activity and initiated a new and premature period of swing, resetting the step cycle. Stimulation of the pyramidal tract in two of these three cats as well as in two additional ones produced similar effects. The results show that the motor cortex is capable of influencing hindlimb activity during locomotion in a similar manner to that seen for the forelimb.

We have used the technique of spatial facilitation to examine the interactions between the signals conveyed by the corticospinal tract and those of cutaneous afferents in the hindlimb of the intact, walking cat. Microstimulation was applied to 20 cortical sites in the hindlimb representation of the motor cortex and to three different cutaneous nerves innervating the hindpaw in four cats. Conditioning stimuli to the motor cortex induced both facilitation and depression of cutaneous reflexes evoked by stimulation of nerves in the hindlimb contralateral to the cortical stimulation site. Facilitation was most frequently evoked by conditioning stimuli in the range of 10-30 ms before the cutaneous stimulation; depression was normally evoked by shorter and longer conditioning delays. Similar changes were observed after conditioning stimuli to the pyramidal tract, suggesting that the changes were independent of any changes in cortical excitability. Modulation of reflex activity varied according to the muscle under study, the cutaneous nerve used to evoke the reflex and the cortical site used to condition the reflex. Together, these results suggest that there is spatial convergence of corticospinal and cutaneous afferent activity and that this convergence is mediated by distinct subpopulations of spinal interneurons.

Transcranial magnetic stimulation (TMS) is commonly used to activate or inactivate specific cortical areas in a noninvasive manner. Because of technical constraints, the precise effects of TMS on cortical circuits are difficult to assess experimentally. Here, this issue is investigated by constructing a detailed model of a portion of the thalamocortical system and examining the effects of the simulated delivery of a TMS pulse. The model, which incorporates a large number of physiological and anatomical constraints, includes 33,000 spiking neurons arranged in a 3-layered motor cortex and over 5 million intra- and interlayer synaptic connections. The model was validated by reproducing several results from the experimental literature. These include the frequency, timing, dose response, and pharmacological modulation of epidurally recorded responses to TMS (the so-called I-waves), as well as paired-pulse response curves consistent with data from several experimental studies. The modeled responses to simulated TMS pulses in different experimental paradigms provide a detailed, self-consistent account of the neural and synaptic activities evoked by TMS within prototypical cortical circuits.

In the cat, the motor representation in motor cortex develops between wk 8 and wk 13. Motor map development is accompanied by a decrease in the current thresholds for evoking movements with a concomitant increase in the number of effective sites, an increase in the distal representation, and the representation of multijoint synergies. In this study we used intracortical microstimulation in anesthetized cats to examine how forelimb motor experiences influence development of map characteristics. To promote skilled movements during wks 8-13, animals were engaged in daily performance of a prehension task. Forelimb movements were prevented by intramuscular botulinum toxin injection or restraint. To determine whether experience-dependent changes were permanent, we examined the map in different animals between 1 wk and 1 yr after cessation of testing. Promoting forelimb use resulted in an increase in the number of sites from which multiple joint effects were produced by stimulation and the number of joints represented at those sites. The effect was maximal at 1 wk after cessation of testing, and became progressively less at 1 mo and at 4 mo. Preventing limb use resulted in a decreased number of effective sites, an increase in current thresholds for evoking responses, and a decreased representation of joints at multijoint sites. Our findings show that the motor map can respond to novel motor demands as it is forming during development but that it reverts back to one with the properties of a map in a control animal if those demands are not maintained in the animal's behavioral repertoire.

Although evidence suggests that the contribution of the presupplementary motor area (pre-SMA) to voluntary motor control is effector-nonselective, the question of how electrical stimulation of the pre-SMA affects eye movements remains unanswered. To address this issue, stimulus effects of the pre-SMA of monkeys on saccade initiation were investigated during performance of a visually guided saccade task with an instructed delay period. This report describes two major findings. First, when stimuli with currents of < or =80 microA were applied before the presentation of a go signal, the reaction time (RT) of an upcoming saccade shortened with comparable effects on ipsi- and contraversive saccades. Second, stimuli that were delivered after the go signal lengthened the RT; this resulted in greater effects on ipsiversive saccades. In addition, the stimulation yielded a mild impairment of saccade accuracy, particularly when the stimulation was delivered after the go signal. By themselves, however, these stimuli did not directly elicit eye movements. Therefore the stimulus effects appeared only in the context of the behavioral task and were dependent on the phase of the task. These findings provide additional support for the hypothesis that the involvement of the pre-SMA in motor control can be linked to either eye or arm motor system dependent on behavioral context.

Learning of motor skills may occur as a consequence of changes in the efficacy of synaptic connections in the primary motor cortex. We investigated if learning in a reaching task affects the excitability, short-term plasticity, and long-term plasticity of horizontal connections in layers II-III of the motor cortex. Because training in this task requires animals to be food-deprived, we compared the trained animals with similarly food-deprived untrained animals and normal controls. The results show that the excitability, short-term plasticity, and long-term plasticity of the studied horizontal connections were unaffected by motor learning. However, stress-related effects produced by food deprivation and handling significantly enhanced the expression of long-term depression in these pathways. These results are compatible with the hypothesis that the acquisition of a complex motor skill produces bi-directional changes in synaptic strength that are distributed throughout the complex neural networks of motor cortex, which remains synaptically balanced during learning. The results are incompatible with the idea that learning causes large unidirectional changes in the population response of these neural networks, which may occur instead during certain behavioral states, such as stress.

Transcranial magnetic stimulation (TMS) of the motor cortex can interrupt voluntary contralateral rhythmic limb movements. Using the method of "resetting index" (RI), our study investigated the TMS effect on different types of bimanual movements. Six normal subjects participated. For unimanual movement, each subject tapped either the right or left index finger at a comfortable rate. For bimanual movement, index fingers of both hands tapped in the same (in-phase) direction or in the opposite (antiphase) direction. TMS was applied to each hemisphere separately at various intensities from 0.5 to 1.5 times motor threshold (MT). TMS interruption of rhythm was quantified by RI. For the unimanual movements, TMS disrupted both contralateral and ipsilateral rhythmic hand movements, although the effect was much less in the ipsilateral hand. For the bimanual in-phase task, TMS could simultaneously reset the rhythmic movements of both hands, but the effect on the contralateral hand was less and the effect on the ipsilateral hand was more compared with the unimanual tasks. Similar effects were seen from right and left hemisphere stimulation. TMS had little effect on the bimanual antiphase task. The equal effect of right and left hemisphere stimulation indicates that neither motor cortex is dominant for simple bimanual in-phase movement. The smaller influence of contralateral stimulation and the greater effect of ipsilateral stimulation during bimanual in-phase movement compared with unimanual movement suggest hemispheric coupling. The antiphase movements were resistant to TMS disruption, and this suggests that control of rhythm differs in the 2 tasks. TMS produced a transient asynchrony of movements on the 2 sides, indicating that both motor cortices might be downstream of the clocking command or that the clocking is a consequence of the 2 hemispheres communicating equally with each other.