Simulation of transcranial magnetic stimulation in head model with morphologically-realistic cortical neurons

BackgroundTranscranial magnetic stimulation (TMS) enables non-invasive modulation of brain activity with both clinical and research applications, but fundamental questions remain about the neural types and elements TMS activates and how stimulation parameters affect the neural response.ObjectiveTo develop a multi-scale computational model to quantify the effect of TMS parameters on the direct response of individual neurons.MethodsWe integrated morphologically-realistic neuronal models with TMS-induced electric fields computed in a finite element model of a human head to quantify the cortical response to TMS with several combinations of pulse waveforms and current directions.ResultsTMS activated with lowest intensity intracortical axonal terminations in the superficial gyral crown and lip regions. Layer 5 pyramidal cells had the lowest thresholds, but layer 2/3 pyramidal cells and inhibitory basket cells were also activated at most intensities. Direct activation of layers 1 and 6 was unlikely. Neural activation was largely driven by the field magnitude, rather than the field component normal to the cortical surface. Varying the induced current direction caused a waveform-dependent shift in the activation site and provided a potential mechanism for experimentally observed differences in thresholds and latencies of muscle responses.ConclusionsThis biophysically-based simulation provides a novel method to elucidate mechanisms and inform parameter selection of TMS and other cortical stimulation modalities. It also serves as a foundation for more detailed network models of the response to TMS, which may include endogenous activity, synaptic connectivity, inputs from intrinsic and extrinsic axonal projections, and corticofugal axons in white matter.     

Ongoing brain rhythms shape I-wave properties in a computational model

Background

Responses to transcranial magnetic stimulation (TMS) are notoriously variable. Previous studies have observed a dependence of TMS-induced responses on ongoing brain activity, for instance sensorimotor rhythms. This suggests an opportunity for the development of more effective stimulation protocols through closed-loop TMS-EEG. However, it is not yet clear how features of ongoing activity affect the responses of cortical circuits to TMS.

I-waves in motor cortex.

I-waves refer to high-frequency (approximately 600 Hz) repetitive discharge of corticospinal fibers produced by single-pulse stimulation of the motor cortex. First detected in animal preparations, this multiple discharge can also be recorded in humans with epidural electrodes over the spinal cord, and with recently developed noninvasive paired-pulse transcranial magnetic stimulation protocols. The exact nature of the generation of I-waves is still unclear, but there is convincing evidence that they originate in the motor cortex, mainly through activation of corticocortical projections onto corticospinal neurons. The ability to measure I-waves in human motor cortex allows one to test the integrity and excitability of the underlying corticocortical circuits in health and disease.     

Corticospinal volleys evoked by transcranial stimulation of the brain in conscious humans

Abstract

The direct recording in conscious humans of corticospinal volleys evoked by different magnetic and electric techniques of transcranial stimulation demonstrates that it is possible to activate neurones of the motor cortex in several different ways. Lateral electrical stimulation of the motor cortex preferentially activates the axons of corticospinal neurones in the subcortical white matter, and evokes a D-wave in pyramidal tract. The way of activation of corticospinal neurones using magnetic stimulation depends on the direction of the electrical current induced in the brain and on the shape of the coil. Monophasic magnetic stimulation with a focal figure-of-eight coil inducing posterior–anterior current in the brain activates corticospinal neurones trans-synaptically recruiting an I1-wave, with later I-waves appearing in sequence at higher intensities and a D-wave at very high intensities. If the induced current is rotated to the anterior–posterior direction late I-waves are preferentially recruited and when a D-wave is recruited, it has a later onset than the electrical D-wave, suggesting an activation nearer the cell body of the pyramidal neurones. A latero–medial induced current activates both corticospinal axons at the same point as electrical stimulation evoking a D wave and cortico–cortical axons evoking I-waves. A nonfocal large circular coil centered at the vertex is capable of activating pyramidal neurones both at the initial segment and transsynaptically evoking a D wave with a longer latency than the electrical D-wave and I-waves. Using a biphasic magnetic stimulation, both phases of the biphasic pulse are capable of activating descending motor output and the pattern of recruitment of descending activity depends on the intensity of the stimulus and the relative threshold of each volley to each direction of current flow.     

Influence of Waveform and Current Direction on Short-Interval Intracortical Facilitation: A Paired-Pulse TMS Study

BackgroundTranscranial magnetic stimulation (TMS) of the human primary motor hand area (M1-HAND) can produce multiple descending volleys in fast-conducting corticospinal neurons, especially so-called indirect waves (I-waves) resulting from trans-synaptic excitation. Facilitatory interaction between these I-waves can be studied non-invasively using a paired-pulse paradigm referred to as short-interval intracortical facilitation (SICF).Objective/hypothesisWe examined whether SICF depends on waveform and current direction of the TMS pulses.MethodsIn young healthy volunteers, we applied single- and paired-pulse TMS to M1-HAND. We probed SICF by pairs of monophasic or half-sine pulses at suprathreshold stimulation intensity and inter-stimulus intervals (ISIs) between 1.0 and 5.0 ms. For monophasic paired-pulse stimulation, both pulses had either a posterior–anterior (PA) or anterior–posterior (AP) current direction (AP–AP or PA–PA), whereas current direction was reversed between first and second pulse for half-sine paired-pulse stimulation (PA–AP and AP–PA).ResultsMonophasic AP–AP stimulation resulted in stronger early SICF at 1.4 ms relative to late SICF at 2.8 and 4.4 ms, whereas monophasic PA–PA stimulation produced SICF of comparable size at all three peaks. With half-sine stimulation the third SICF peak was reduced for PA–AP current orientation compared with AP–PA.ConclusionSICF elicited using monophasic as well as half-sine pulses is affected by current direction at clearly suprathreshold intensities. The impact of current orientation is stronger for monophasic compared with half-sine pulses. The direction-specific effect of paired-pulse TMS on the strength of early versus late SICF shows that different cortical circuits mediate early and late SICF.     

Preferential Activation of Unique Motor Cortical Networks With Transcranial Magnetic Stimulation: A Review of the Physiological,Functional, and Clinical Evidence

ObjectivesThe corticospinal volley produced by application of transcranial magnetic stimulation (TMS) over primary motor cortex consists of a number of waves generated by trans-synaptic input from interneuronal circuits. These indirect (I)-waves mediate the sensitivity of TMS to cortical plasticity and intracortical excitability and can be assessed by altering the direction of cortical current induced by TMS. While this methodological approach has been conventionally viewed as preferentially recruiting early or late I-wave inputs from a given populations of neurons, growing evidence suggests recruitment of different neuronal populations, and this would strongly influence interpretation and application of these measures. The aim of this review is therefore to consider the physiological, functional, and clinical evidence for the independence of the neuronal circuits activated by different current directions.Materials and MethodsTo provide the relevant context, we begin with an overview of TMS methodology, focusing on the different techniques used to quantify I-waves. We then comprehensively review the literature that has used variations in coil orientation to investigate the I-wave circuits, grouping studies based on the neurophysiological, functional, and clinical relevance of their outcomes.ResultsReview of the existing literature reveals significant evidence supporting the idea that varying current direction can recruit different neuronal populations having unique functionally and clinically relevant characteristics.ConclusionsFurther research providing greater characterization of the I-wave circuits activated with different current directions is required. This will facilitate the development of interventions that are able to modulate specific intracortical circuits, which will be an important application of TMS.     

Generalized periodic discharges after acute cerebral ischemia: Reflection of selective synaptic failure?

ObjectivesGeneralized periodic discharges (GPDs) can be observed in the electroencephalogram (EEG) of patients after acute cerebral ischemia and reflect pathological neuronal synchronization. Whether GPDs represent ictal activity, which can be treated with anti-epileptic drugs, or severe ischemic damage, in which treatment is futile, is unknown. We hypothesize that GPDs result from selective ischemic damage of glutamatergic synapses, which are known to be relatively vulnerable to effects of ischemia.MethodsWe employed a macroscopic model of cortical dynamics in which we increasingly eliminated glutamatergic synapses. We compared the output of the model with clinical EEG recordings in patients showing GPDs after cardiac arrest.ResultsSelective elimination of glutamatergic synapses from pyramidal cells to inhibitory interneurons led to simulated GPDs whose waveshape and frequency matched those of patients showing GPDs after cardiac arrest. Mere reduction of glutamatergic synapses between pyramidal cells themselves did not result in GPDs.ConclusionsSelective ischemic damage of glutamatergic synapses on inhibitory cortical interneurons leads to the generation of ischemia induced GPDs. Disinhibition of cortical pyramidal neurons is a candidate mechanism.SignificanceThis study increases the insight in the pathophysiological mechanisms underlying the generation GPDS after acute cerebral ischemia.     

Conditioning the Cortical Silent Period with Paired Transcranial Magnetic Stimulation

BackgroundA single supra-threshold pulse of transcranial magnetic stimulation (TMS) over human motor cortex elicits multiple descending volleys (I-waves) that generate a motor evoked potential (MEP) followed by a period of electromyographic silence in the tonically contracted target muscle (silent period; SP). A sub-threshold conditioning stimulus (CS) delivered at inter-pulse intervals (IPIs) of 1-5 ms after a supra-threshold test stimulus (TS) conditions I-waves elicited by TS and can increase MEP amplitude (short-interval intracortical facilitation; SICF), however its effect on the SP remains unknown.ObjectiveWe investigated whether it is possible to modulate the SP resulting from a TS by delivering a sub-threshold CS 1–5 ms later.MethodsPaired-pulse TMS was delivered while subjects performed slight contraction of the first dorsal interosseous muscle. SICF and SP duration were measured at each IPI and compared to amplitude-matched MEPs evoked by single-pulse TMS.ResultsPaired stimulation at IPI 2–5 ms prolonged the SP by 21 ± 3% (P < 0.001) but had no effect on MEP amplitude. At shorter IPIs the CS increased MEP amplitude (by 170 ± 31%), but the SP was not prolonged when compared to an amplitude-matched single-pulse stimulus.ConclusionThe SP can be modified by a CS applied during the early phase of its genesis. We suggest that this is in keeping with an early GABA_A contribution to the SP, and it is possible that this new conditioning paradigm may offer another means for probing the excitability of cortical inhibitory networks in human motor cortex.     

Basic mechanisms of TMS.

Transcranial magnetic stimulation (TMS) is now established as an important noninvasive measure for neurophysiologic investigation of the central and peripheral nervous systems in humans. Magnetic stimulation can be used for stimulating peripheral nerves with a similar mechanism of activation as for electrical stimulation. When TMS is applied to the cerebral cortex, however, some features emerge that distinguish it from transcranial electrical stimulation. One of the most important features is designated the D and I wave hypothesis, which is now widely accepted as a mechanism of TMS of the motor cortex. Transcranial electrical stimulation excites the pyramidal tract axons directly, either at the initial segment of the neuron or at proximal internodes in the subcortical white matter, giving rise to D (direct) waves, whereas TMS excites the pyramidal neurons transsynaptically, giving rise to I (indirect) waves. There are still other phenomena with mechanisms that remain to be elucidated. First, not only excitatory effects but also inhibitory effects can be elicited by TMS of the cerebral cortex (e.g., the silent period and intracortical inhibition). The inhibitory effect may also be used to investigate cerebral functions other than the motor cortex, such as the visual, sensory cortices, and the frontal eye field, from which no overt response like the motor evoked potential can be elicited. Second, there is an abundance of intraregional functional connectivities among different cortical areas that can also be revealed by TMS, or TMS in combination with neuroimaging techniques. Last, repetitive transcranial stimulation exerts a lasting effect on brain function even after the stimulation has ceased. With further investigation of the neural mechanisms of TMS, these techniques will open up new possibilities for investigating the physiologic function of the brain as well as opportunities for clinical application.     

Modulation of motor learning by a paired associative stimulation protocol inducing LTD-like effects

BackgroundPaired associative stimulation (PAS) induces long-term potentiation (LTP)-like effects when interstimulus intervals (ISIs) between electrical peripheral nerve stimulation and transcranial magnetic stimulation (TMS) to M1 are approximately 21–25 ms (PAS_LTP). It was previously reported that two forms of motor learning (i.e., mode-free and model-based learning) can be differentially modulated by PAS_LTP depending on the different synaptic inputs to corticospinal neurons (CSNs), which relate to posterior-to-anterior (PA) or anterior-to-posterior (AP) currents induced by TMS (PA or AP inputs, respectively). However, the effects of long-term depression (LTD)-inducing PAS with an ISI of approximately 10 ms (PAS_LTD) on motor learning and its dependency on current direction have not yet been tested.ObjectiveTo investigate whether, and how, PAS_LTD affects distinct types of motor learning.MethodsEighteen healthy volunteers participated. We adopted the standard PAS using suprathreshold TMS with the target muscle relaxed, as well as subthreshold PAS during voluntary contraction, which was suggested to selectively recruit PA or AP inputs depending on the orientation of the TMS coil. We examined the effects of suprathreshold and subthreshold PAS_LTD on the performance of model-free and model-based learning, as well as the corticospinal excitability, indexed as the amplitudes of motor evoked potentials (MEPs).ResultsPAS_LTD inhibited model-free learning and MEPs only when subthreshold AP currents were applied. The PAS_LTD protocols tested here showed no effects on model-based learning.ConclusionsPAS_LTD affected model-free learning, presumably by modulating CSN excitability changes, rather than PA inputs, which are thought to be related to model-free learning.     

I-wave origin and modulation

The human motor cortex can be activated by transcranial magnetic stimulation (TMS) evoking a high-frequency repetitive discharge of corticospinal neurones. The exact physiologic mechanisms producing the corticospinal activity still remain unclear because of the complexity of the interactions between the currents induced in the brain and the circuits of cerebral cortex, composed of multiple excitatory and inhibitory neurons and axons of different size, location, orientation and function. The aim of current paper is to evaluate whether the main characteristics of the activity evoked by single- and paired-pulse and repetitive TMS, can be accounted by the interaction of the induced currents in the brain with the key anatomic features of a simple cortical circuit composed of the superficial population of excitatory pyramidal neurons of layers II and III, the large pyramidal neurons in layer V, and the inhibitory GABA cells. This circuit represents the minimum architecture necessary for capturing the most essential cortical input-output operations of neocortex. The interaction between the induced currents in the brain and this simple model of cortical circuitry might explain the characteristics and nature of the repetitive discharge evoked by TMS, including its regular and rhythmic nature and its dose-dependency and pharmacologic modulation. The integrative properties of the circuit also provide a good framework for the interpretation of the changes in the cortical output produced by paired and repetitive TMS.     

Repetitive Transcranial Magnetic Stimulation Elicits Rate-Dependent Brain Network Responses in Non-Human Primates

BackgroundTranscranial magnetic stimulation (TMS) has the potential to treat brain disorders by tonically modulating firing patterns in disease-specific neural circuits. The selection of treatment parameters for clinical repetitive transcranial magnetic stimulation (rTMS) trials has not been rule based, likely contributing to the variability of observed outcomes.ObjectiveTo utilize our newly developed baboon (Papio hamadryas anubis) model of rTMS during position-emission tomography (PET) to quantify the brain's rate–response functions in the motor system during rTMS.MethodsWe delivered image-guided, suprathreshold rTMS at 3 Hz, 5 Hz, 10 Hz, 15 Hz and rest (in separate randomized sessions) to the primary motor cortex (M1) of the lightly anesthetized baboon during PET imaging; we also administered a (reversible) paralytic to eliminate any somatosensory feedback due to rTMS-induced muscle contractions. Each rTMS/PET session was analyzed using normalized cerebral blood flow (CBF) measurements; statistical parametric images and the resulting areas of significance underwent post-hoc analysis to determine any rate-specific rTMS effects throughout the motor network.ResultsThe motor system's rate–response curves were unimodal and system wide—with all nodes in the network showing highly similar rate response functions—and an optimal network stimulation frequency of 5 Hz.Conclusion(s)These findings suggest that non-invasive brain stimulation may be more efficiently delivered at (system-specific) optimal frequencies throughout the targeted network and that functional imaging in non-human primates is a promising strategy for identifying the optimal treatment parameters for TMS clinical trials in specific brain regions and/or networks.     

Associative plasticity in intracortical inhibitory circuits in human motor cortex

ObjectivePaired associative stimulation (PAS) is a transcranial magnetic stimulation technique inducing Hebbian-like synaptic plasticity in the human motor cortex (M1). PAS is produced by repetitive pairing of a peripheral nerve shock and a transcranial magnetic stimulus (TMS). Its effect is assessed by a change in size of a motor evoked response (MEP). MEP size results from excitatory and inhibitory influences exerted on cortical pyramidal cells, but no robust effects on inhibitory networks have been demonstrated so far.MethodIn 38 healthy volunteers, we assessed whether a PAS intervention influences three intracortical inhibitory circuits: short (SICI) and long (LICI) intracortical inhibitions reflecting activity of GABA_A and GABA_B interneurons, respectively, and long afferent inhibition (LAI) reflecting activity of somatosensory inputs.ResultsAfter PAS, MEP sizes, LICI and LAI levels were significantly changed while changes of SICI were inconsistent. The changes in LICI and LAI lasted 45 min after PAS. Their direction depended on the delay between the arrival time of the afferent volley at the cortex and the TMS-induced cortical activation during the PAS.ConclusionsPAS influences inhibitory circuits in M1.SignificancePAS paradigms can demonstrate Hebbian-like plasticity at selected inhibitory networks as well as excitatory networks.     

In vitro characterization of intrinsic properties and local synaptic inputs to pyramidal neurons in macaque primary motor cortex

Primates (including humans) have a highly developed corticospinal tract, and specialized motor cortical areas which differ in key ways from rodents. Much work on motor cortex has therefore used macaque monkeys as a good animal model for human motor control. However, there is a paucity of data describing the fundamental functional architecture of primate primary motor cortex, which is best addressed with in vitro approaches. In this study we examined the cellular properties and the micro‐circuitry of the adult macaque primary motor cortex by carrying out in‐vitro intracellular recordings. We aimed to characterize the basic properties of the cortical circuitry by studying the intrinsic properties of its pyramidal neurons and their physiological interconnectivity. We studied the passive and active electrophysiological properties of pyramidal neurons in both superficial and deep cortical layers. Both superficial and deep pyramidal neurons exhibited bursting behaviour that could act as powerful excitation for downstream targets. Synaptic connections were lamina specific. Neurons in the deep layers had convergent excitatory inputs from all cortical layers whereas superficial neurons had only significant inputs from superficial layers. This sheds light on the functional architecture of the primate primary motor cortex and how its output is shaped. We also took the unique opportunity in our recording technique to characterize the relationship between intracellular and extracellular spike waveforms, with implications for cell‐type identification in studies in awake behaving monkey. Our results will aid the interpretation of primate studies into motor control involving extracellular spike recordings and electrical stimulation in primary motor cortex.     

Multi-scale modeling toolbox for single neuron and subcellular activity under Transcranial Magnetic Stimulation

BackgroundTranscranial Magnetic Stimulation (TMS) is a widely used non-invasive brain stimulation method. However, its mechanism of action and the neural response to TMS are still poorly understood. Multi-scale modeling can complement experimental research to study the subcellular neural effects of TMS. At the macroscopic level, sophisticated numerical models exist to estimate the induced electric fields. However, multi-scale computational modeling approaches to predict TMS cellular and subcellular responses, crucial to understanding TMS plasticity inducing protocols, are not available so far.ObjectiveWe develop an open-source multi-scale toolbox Neuron Modeling for TMS (NeMo-TMS) to address this problem.MethodsNeMo-TMS generates accurate neuron models from morphological reconstructions, couples them to the external electric fields induced by TMS, and simulates the cellular and subcellular responses of single-pulse and repetitive TMS.ResultsWe provide examples showing some of the capabilities of the toolbox.ConclusionNeMo-TMS toolbox allows researchers a previously not available level of detail and precision in realistically modeling the physical and physiological effects of TMS.     

Rotational field TMS: Comparison with conventional TMS based on motor evoked potentials and thresholds in the hand and leg motor cortices

BackgroundTranscranial magnetic stimulation (TMS) is a rapidly expanding technology utilized in research and neuropsychiatric treatments. Yet, conventional TMS configurations affect primarily neurons that are aligned parallel to the induced electric field by a fixed coil, making the activation orientation-specific. A novel method termed rotational field TMS (rfTMS), where two orthogonal coils are operated with a 90° phase shift, produces rotation of the electric field vector over almost a complete cycle, and may stimulate larger portion of the neuronal population within a given brain area.ObjectiveTo compare the physiological effects of rfTMS and conventional unidirectional TMS (udTMS) in the motor cortex.MethodsHand and leg resting motor thresholds (rMT), and motor evoked potential (MEP) amplitudes and latencies (at 120% of rMT), were measured using a dual-coil array based on the H7-coil, in 8 healthy volunteers following stimulation at different orientations of either udTMS or rfTMS.ResultsFor both target areas rfTMS produced significantly lower rMTs and much higher MEPs than those induced by udTMS, for comparable induced electric field amplitude. Both hand and leg rMTs were orientation-dependent.ConclusionsrfTMS induces stronger physiologic effects in targeted brain regions at significantly lower intensities. Importantly, given the activation of a much larger population of neurons within a certain brain area, repeated application of rfTMS may induce different neuroplastic effects in neural networks, opening novel research and clinical opportunities.     

Synaptic Input and ACh Modulation Regulate Dendritic Ca2+ Spike Duration in Pyramidal Neurons,Directly Affecting Their Somatic Output

Nonlinear synaptic integration in dendrites is a fundamental aspect of neural computation. One such key mechanism is the Ca²⁺ spike at the apical tuft of pyramidal neurons. Characterized by a plateau potential sustained for tens of milliseconds, the Ca²⁺ spike amplifies excitatory input, facilitates somatic action potentials (APs), and promotes synaptic plasticity. Despite its essential role, the mechanisms regulating it are largely unknown. Using a compartmental model of a layer 5 pyramidal cell (L5PC), we explored the plateau and termination phases of the Ca²⁺ spike under input current perturbations, long-step current-injections, and variations in the dendritic high-voltage-activated Ca²⁺ conductance (that occur during cholinergic modulation). We found that, surprisingly, timed excitatory input can shorten the Ca²⁺ spike duration while inhibitory input can either elongate or terminate it. A significant elongation also occurs when the high-voltage-activated Ca²⁺ channels (Ca_HVA) conductance is increased. To mechanistically understand these phenomena, we analyzed the currents involved in the spike. The plateau and termination phases are almost exclusively controlled by the Ca_HVA inward current and the I_m outward K⁺ current. We reduced the full model to a single-compartment model that faithfully preserved the responses of the Ca²⁺ spike to interventions and consisted of two dynamic variables: the membrane potential and the K⁺-channel activation level. A phase-plane analysis of the reduced model provides testable predictions for modulating the Ca²⁺ spike and reveals various dynamical regimes that explain the robust nature of the spike. Regulating the duration of the Ca²⁺ spike significantly impacts the cell synaptic-plasticity window and, as we show, its input-output relationship.SIGNIFICANCE STATEMENT Pyramidal neurons are the cortex''s principal projection neurons. In their apical tuft, dendritic Ca²⁺ spikes significantly impact information processing, synaptic plasticity, and the cell''s input-output relationship. Therefore, it is essential to understand the mechanisms regulating them. Using a compartmental model of a layer 5 pyramidal cell (L5PC), we explored the Ca²⁺ spike responses to synaptic perturbations and cholinergic modulation. We showed a counterintuitive phenomenon: early excitatory input shortens the spike, whereas weak inhibition elongates it. Also, we demonstrated that acetylcholine (ACh) extends the spike. Through a reduced model containing only the membrane potential and the K⁺-channel activation level, we explained these phenomena using a phase-plane analysis. Our work provides new information about the robustness of the Ca²⁺ spike and its controlling mechanisms.     

Electrical Low Frequency Stimulation of the Kindling Site Preserves the Electrophysiological Properties of the Rat Hippocampal CA1 Pyramidal Neurons From the Destructive Effects of Amygdala Kindling: The Basis for a Possible Promising Epilepsy Therapy

BackgroundDeep brain stimulation (DBS) has emerged as a potential therapeutic strategy in the treatment of neurological disorders including epilepsy. However, the cellular mechanism responsible for the effects of DBS remains largely undefined. Therefore, using electrophysiological approach, we aimed to determine the antiepileptic effects and restorative potential of low frequency stimulation (LFS) on amygdala kindling-induced changes in electrophysiological properties of rat hippocampal CA1 pyramidal neurons.MethodsAnimals were kindled by electrical stimulation of amygdala in a rapid kindling manner (12 times per day). In one group of animals, immediately after termination of daily 12 rapid kindling stimulations, the kindling site was subjected to 4 packages of LFS at intervals of 5 min (each package contained 200 monophasic square-wave pulses, 0.1 ms pulse duration at 1 Hz). Whole cell patch clamp recording under current clamp conditions was performed on visually identified pyramidal neurons in hippocampal slice preparations obtained from amygdala-kindled rats and the rats receiving LFS.ResultsKindling of the right basolateral amygdala profoundly affected spontaneous firing behavior and repetitive discharge characteristics of pyramidal neuronal electrophysiological properties. Application of LFS at the kindling site almost completely prevented the development of epilepsy and the disruptive effects of kindling on neuronal electrical activity through restoration of the normal electrophysiological characteristics.ConclusionsThe results of this study implied that application of LFS during kindling acquisition prevents the kindling induced changes in functional electrical properties of CA1 pyramidal neurons, suggesting that this action may be involved in the antiepileptogenic mechanism of LFS.     

Suppression by topiramate of epileptiform burst discharges in hippocampal CA3 neurons of spontaneously epileptic rat in vitro

Topiramate, a novel antiepileptic drug, inhibits the seizures of spontaneously epileptic rat (SER), a double mutant (zi/zi, tm/tm) which exhibits both tonic convulsion and absence-like seizures from the age of 8-weeks. Hippocampal CA3 pyramidal neurons in SER show a long-lasting depolarization shift with accompanying repetitive firing when a single electrostimulation is delivered to the mossy fibers in vitro. The effects of topiramate on the excitability of CA3 pyramidal neurons in SER were examined to elucidate the mechanism underlying the antiepileptic action. Intracellular recordings were performed in 23 hippocampal slice preparations of 16 SER aged 8–17 weeks. Topiramate (10–100 μM) dose-dependently inhibited the depolarizing shifts with repetitive firing induced by mossy fiber stimulation without affecting the first spike and resting membrane potentials in hippocampal CA3 neurons of SER. Higher dose of topiramate (100 μM) sometimes inhibited the first spike, and decreased excitatory postsynaptic potentials in the SER CA3 neurons. However, topiramate up to 100 μM did not affect the single action potential elicited by the stimulation in the hippocampal CA3 neurons of age-matched Wistar rat devoid of the seizure. Application of topiramate (100 μM) did not significantly affect the firing induced by depolarizing pulse applied in the CA3 neurons of the SER. In addition, topiramate (100 μM) had no effects on the Ca²⁺ spike induced by intracellularly applied depolarizing pulse in the presence of tetrodotoxin and tetraethylammonium. In contrast, a dose-dependent inhibition of depolarization and repetitive firing induced by bath application of glutamate in CA3 pyramidal neurons was obtained with topiramate (10–100 μM). Furthermore, topiramate (100 μM) decreased the number of miniature postsynaptic potential of CA3 pyramidal neurons of SER. In patch clamp whole cell recording using acutely dissociated hippocampal CA3 neurons from SER aged 8-weeks and age-matched normal Wistar rats, there were no remarkable effects on voltage dependent Ca²⁺ current with topiramate up to 300 μM in either animal; the current was completely blocked by Cd²⁺ at a concentration of 1 mM. These findings suggest that topiramate inhibits release of glutamate from the nerve terminals and/or abnormal firing of the CA3 pyramidal neurons of SER by mainly blocking glutamate receptors in the neurons.     

Non-linear input-output properties of the cortical networks mediating TMS-induced short-interval intracortical inhibition in humans

The effects of transcranial magnetic stimulation (TMS) on post-discharge histograms of single motor units in the first dorsal interosseous have been tested to estimate the input-output properties of cortical network-mediating short-interval intracortical inhibition (SICI) to pyramidal cells of the human primary motor cortex. SICI was studied using the paired pulse paradigm (2-ms interval): test TMS intensity was varied to evoke peaks of different size in post-discharge histograms, reflecting the corticospinal excitatory post-synaptic potential in the relevant spinal motoneuron, and conditioning TMS intensity was constant (0.6 × the resting motor threshold). Navigated brain stimulation was used to monitor the coil position. A linear relationship was observed between test peak size and test TMS intensity, reflecting linear summation of excitatory inputs induced by TMS. SICI was estimated using the difference between conditioned (produced by the paired pulses) and test peaks (produced by the isolated test pulse). Although the conditioning intensity (activating cortical inhibitory interneurons mediating SICI) was kept constant throughout the experiments, the level of SICI changed with the test peak size, in a non-linear fashion, suggesting that low-threshold cortical neurons (excitatory interneurons/pyramidal cells) are less sensitive to SICI than those of higher threshold. These findings provide the first experimental evidence, under physiological conditions, for non-linear input/output properties of a complex cortical network. Consequently, changes in the recruitment gain of cortical inhibitory interneurons can greatly modify the excitability of pyramidal cells and their response to afferent inputs.