Repetitive Paired-pulse Stimulation Research Articles

T022 Shaping the temporal characteristics of transcranial magnetic stimulation

The pulse waveform of transcranial magnetic stimulation (TMS) affects the degree to which various neuronal elements and populations are activated as well as the strength of neuromodulation resulting from repetitive TMS. Conventional TMS devices allow very limited pulse waveform adjustment; therefore we developed TMS devices with controllable pulse parameters (cTMS). So far cTMS has been used, by our and other groups, to study strength-duration curves in motor cortex and the associated neural membrane time constants; pulse-width dependence of motor input–output curves, cortical neuron recruitment, paired-pulse paradigms, and scalp sensation; and pulse-shape dependence of neuromodulatory effects. These studies show that changing the pulse width, shape, and/or direction may alter the neural elements that are preferentially activated in cortex, as evidenced by differences in motor evoked potential latencies and membrane time constants. These parameters also affect the changes of neural excitability resulting from 1 Hz and intermittent theta burst stimulation. For the 1 Hz protocol, the near rectangular cTMS pulses produced stronger inhibition than conventional sinusoidal pulses, with unidirectional cTMS pulses having the strongest effect. As well, cTMS has been used to optimize new repetitive paired-pulse stimulation protocols. cTMS was also used to show that the slope of motor input–output curves depends on pulse width via the same mechanism driving the strength-duration relationship of motor threshold. Finally, the pulse width affects the perceived scalp sensation of TMS, with briefer pulses feeling sharper and slightly more uncomfortable than longer pulses. In parallel with exploring the capabilities afforded by cTMS, we are developing a next generation ultraflexible TMS device called a modular pulse synthesizer (MPS) that would allow the generation of essentially any pulse shape and pulse sequence/train within the energy levels practical for TMS. The development and adoption of cTMS and MPS could enable expanded utilization of the temporal characteristics of TMS as a means of enhancing functional targeting, noninvasive biomarkers, neuromodulatory potency, and tolerability.

Strength-Duration Relationship in Paired-pulse Transcranial Magnetic Stimulation (TMS) and Its Implications for Repetitive TMS.

Paired-pulse protocols have played a pivotal role in neuroscience research using transcranial magnetic stimulation (TMS). Stimulus parameters have been optimized over the years. More recently, pulse width (PW) has been introduced to this field as a new parameter, which may further fine-tune paired-pulse protocols. The relationship between the PW and effectiveness of a stimulus is known as the "strength-duration relationship". To test the "strength-duration relationship", so as to improve paired-pulse TMS protocols, and to apply the results to develop new repetitive TMS (rTMS) methods. Four protocols were investigated separately: short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), short-interval intracortical facilitation (SICF) and long-interval intracortical inhibition (LICI). First, various stimulus parameters were tested to identify those yielding the largest facilitation or inhibition of the motor evoked potential (MEP) in each participant. Using these parameters, paired-pulse stimulations were repeated every five seconds for 30 minutes (repetitive paired-pulse stimulation, rPPS). The after-effects of rPPS were measured using MEP amplitude as an index of motor-cortical excitability. Altogether, the effect of changing PW was similar to that of changing the stimulus intensity in the conventional settings. The best parameters were different for each participant. When these parameters were used, rPPS based on either SICF or ICF induced an increase in MEP amplitude. PW was introduced as a new parameter in paired-pulse TMS. Modulation of PW influenced the results of paired-pulse protocols. rPPS using facilitatory protocols can be a good candidate to induce enhancement of motor-cortical excitability.

Repetitive Paired-pulse Transcranial Magnetic Stimulation Over the Visual Cortex Selectively Inhibits Focal Flash VEPs

BackgroundThe human visual system processes different aspects of visual information such as luminance and contrast via multiple channels. We previously used repetitive paired-pulse stimulation (rPPS) over the visual cortex to elicit a disinhibitory effect on the visual recovery function of paired pattern-reversal (PR) visual evoked potentials (VEPs). ObjectiveWe tested the hypothesis that different visual channels exhibit diverse response patterns after rPPS over the visual cortex. Thus, we examined how rPPS influenced each channel of the visual cortex. MethodsWe employed rPPS with a 1.5-ms interstimulus interval over the visual cortex at the stimulus intensity of the visual masking effect. Focal flash (FF) and PR-VEPs (check size, 15 min) were recorded to evaluate the response properties of visual channels in 10 healthy subjects. Visual stimuli were presented for the lower half-field that subtended 6° in radius. The amplitudes and latencies of each VEP were compared before and after rPPS for up to 30 min. ResultsFollowing rPPS, N1-P1 and P1-N2 amplitudes of FF-VEPs decreased linearly up to 30 min. In contrast, the amplitudes of PR-VEPs were not significantly changed. Latencies of FF- and PR-VEPs were also unchanged. ConclusionsModulation of FF-VEPs by rPPS suggests that rPPS selectively induced an inhibitory effect on the luminance channel. Therefore, rPPS may be a promising tool for exploring plastic changes in the visual cortex.

Long-term synaptic depression in the adult entorhinal cortex in vivo.

The piriform cortex provides a major input to the entorhinal cortex. Mechanisms of long-term depression (LTD) of synaptic transmission in this pathway may affect olfactory and mnemonic processing. We have investigated stimulation parameters for the induction of homosynaptic LTD and depotentiation in this pathway using evoked synaptic field potential recordings in the awake rat. In this study, 15 min of 1-Hz stimulation induced a transient (< 5 min) depression of evoked responses but did not induce LTD or depotentiation. To determine whether inhibitory and/or facilitatory mechanisms contribute to LTD induction, repetitive delivery of pairs of stimulation pulses was also assessed. Repetitive paired-pulse stimulation with a 10-ms interval between pulses, which activates inhibitory mechanisms during the second response, did not reliably induce LTD. However, repetitive paired-pulse stimulation using a 30-ms interval, which evokes marked paired-pulse facilitation, resulted in synaptic depression that lasted > or = 1 day, and which was reversible by tetanization. The selective induction of LTD by stimulation that evokes paired-pulse facilitation suggests that strong synaptic activation is required for LTD induction. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (0.1 mg/kg) blocked the induction of LTD, indicating that NMDA receptor activation is required for LTD induction in this pathway. These results indicate that LTD in piriform cortex inputs to the entorhinal cortex in the awake rat is effectively induced by strong repetitive synaptic stimulation, and that this form of LTD is dependent on activation of NMDA receptors.

NMDA receptor-dependent long-term synaptic depression in the entorhinal cortex in vitro.

The entorhinal cortex receives a large projection from the piriform (primary olfactory) cortex and, in turn, provides the hippocampal formation with most of its cortical sensory input. Synaptic plasticity in this pathway may therefore affect the processing of olfactory information and memory encoding. We have recently found that long-term synaptic depression (LTD) can be induced in this pathway in vivo by repetitive paired-pulse stimulation but not by low-frequency (1 Hz) stimulation with single pulses. Here, we have used field potential recordings to investigate the stimulation parameters and transmitter receptors required for the induction of LTD in the rat entorhinal cortex in vitro. The effectiveness of low-frequency stimulation (900 pulses at 1 or 5 Hz) and repeated delivery of pairs of stimulation pulses (30-ms interpulse interval) was assessed. Only repeated paired-pulse stimulation resulted in lasting LTD, and a low-intensity paired-pulse stimulation protocol that induces LTD in vivo was only effective in the presence of the GABA(A) receptor antagonist bicuculline (50 microM). LTD could also be induced in normal ACSF, however, by increasing the number of pulse-pairs delivered and by increasing the stimulation intensity during LTD induction. The induction of LTD was blocked by constant bath application of the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist d-2-amino-5-phosphonovalerate (50 microM), indicating that LTD is dependent on NMDA receptor activation. However, LTD was not blocked by the group I/II mGluR antagonist (RS)-alpha-ethyl-4-carboxyphenylglycine (500 microM) or by bicuculline (50 microM). The induction of LTD in the entorhinal cortex in vitro is therefore dependent on intense stimulation that recruits activation of NMDA receptors, but does not require concurrent activation of mGluRs or inhibitory synaptic inputs.

Distributed synaptic modification in neural networks induced by patterned stimulation.

Activity-dependent changes in synaptic efficacy or connectivity are critical for the development, signal processing and learning and memory functions of the nervous system. Repetitive correlated spiking of pre- and postsynaptic neurons can induce a persistent increase or decrease in synaptic strength, depending on the timing of the pre- and postsynaptic excitation. Previous studies on such synaptic modifications have focused on synapses made by the stimulated neuron. Here we examine, in networks of cultured hippocampal neurons, whether and how localized stimulation can modify synapses that are remote from the stimulated neuron. We found that repetitive paired-pulse stimulation of a single neuron for brief periods induces persistent strengthening or weakening of specific polysynaptic pathways in a manner that depends on the interpulse interval. These changes can be accounted for by correlated pre- and postsynaptic excitation at distant synaptic sites, resulting from different transmission delays along separate pathways. Thus, through such a 'delay-line' mechanism, temporal information coded in the timing of individual spikes can be converted into and stored as spatially distributed patterns of persistent synaptic modifications in a neural network.