Comparison of motor effects following subcortical electrical stimulation through electrodes in the globus pallidus internus and cortical transcranial magnetic stimulation

Current concepts of transcranial magnetic stimulation (TMS) over the primary motor cortex are still under debate as to whether inhibitory motor effects are exclusively of cortical origin. To further elucidate a potential subcortical influence on motor effects, we combined TMS and unilateral subcortical electrical stimulation (SES) of the corticospinal tract. SES was performed through implanted depth electrodes in eight patients treated with deep brain stimulation (DBS) for severe dystonia. Chronaxie, conduction velocity (CV) of the stimulated fibres and poststimulus time histograms of single motor unit recordings were calculated to provide evidence of an activation of large diameter myelinated fibres by SES. Excitatory and inhibitory motor effects recorded bilaterally from the first dorsal interosseus muscle were measured after SES and focal TMS of the motor cortex. This allowed us to compare motor effects of subcortical (direct) and cortical (mainly indirect) activation of corticospinal neurons. SES activated a fast conducting monosynaptic pathway to the alpha motoneuron. Motor responses elicited by SES had significantly shorter onset latency and shorter duration of the contralateral silent period compared to TMS induced motor effects. Spinal excitability as assessed by H-reflex was significantly reduced during the silent period after SES. No ipsilateral motor effects could be elicited by SES while TMS was followed by an ipsilateral inhibition. The results suggest that SES activated the corticospinal neurons at the level of the internal capsule. Comparison of SES and TMS induced motor effects reveals that the first part of the TMS induced contralateral silent period should be of spinal origin while its later part is due to cortical inhibitory mechanisms. Furthermore, the present results suggest that the ipsilateral inhibition is predominantly mediated via transcallosal pathways.This paper is dedicated to Bernd-Ulrich Meyer, who died in a plane accident     

High frequency stimulation or elevated K+ depresses neuronal activity in the rat entopeduncular nucleus

High frequency stimulation (HFS) is applied to many brain regions to treat a variety of neurological disorders/diseases, yet the mechanism(s) underlying its effects remains unclear. While some studies showed that HFS inhibits the stimulated nucleus, others report excitation. In this in vitro study, we stimulated the rat globus pallidus interna (entopeduncular nucleus, EP), a commonly stimulated area for Parkinson's disease, to investigate the effect of HFS-induced elevation of extracellular potassium (K(+)(e)) on rat EP neuronal activity. Whole-cell patch-clamp recordings and [K(+)](e) measurements were obtained in rat EP brain slices before, during and after HFS. After HFS (150 Hz, 10 s), [K(+)](e) increased from 2.5-9.6+/-1.4 mM, the resting membrane potential of EP neurons depolarized by 11.1+/-2.5 mV, spiking activity was significantly depressed, and input resistance decreased by 25+/-6%. The GABA(A) receptor blocker, gabazine, did not prevent these effects. The bath perfusion of 6 or 10 mM K(+), with or without synaptic blockers, mimicked the HFS-mediated effects: inhibition of spike activity, a 20+/-9% decrease in input resistance and a 17.4+/-3.0 mV depolarization. This depolarization exceeded predicted values of elevated [K(+)](e) on the resting membrane potential. A depolarization block did not fully account for the K(+)-induced inhibition of EP neuronal activity. Taken together, our results show that HFS-induced elevation of [K(+)](e) decreased EP neuronal activity by the activation of an ion conductance resulting in membrane depolarization, independent of synaptic involvement. These findings could explain the inhibitory effects of HFS on neurons of the stimulated nucleus.     

Mechanisms regulating the activity of facial nucleus motoneurons—III. Synaptic influences from the cerebral cortex and subcortical structures

Peculiarities of synaptic processes in facial motoneurons evoked by stimulation of various regions of the cerebral cortex and subcortical structures were studied in acute experiments on cats by intracellular recording technique. Stimulation of the motor cortex as well as gyrus proreus and pyramidal tract was shown to evoke polysynaptic excitatory and inhibitory postsynaptic potentials in facial motoneurons. Stimulation of the lateral hypothalamus produced exclusively excitatory polysynaptic effects. It was also found that stimulation of the head of nucleus caudatus and globus pallidus evokes a polysynaptic activation in facial motoneurons, while stimulation of nucleus amygdala centralis leads to mono- and polysynaptic excitation of these neurons. Convergence of the above effects on the same motoneurons is shown to exist. Possible pathways and mechanisms of descending influences on the activity of facial motoneurons is discussed.     

Patterns of functional synaptic connections in organized cultures of cerebellum

Organized cultures of mouse cerebellum with separated regions containing cortical, deep nuclear neurons and brain stem neurons from the peduncular zone were used for electrophysiological studies of axonal projections and synaptic interactions. Responses of single neurons of each of the regions were recorded extracellularly and intracellularly during localized electrical stimulation of other parts of the explant, and indicated extensive synaptic interactions. Cortical stimulation inhibited deep nuclear neurons, apparently monosynaptically, and frequently caused antidromic activation of these cells. Synaptic responses of brain stem neurons to cortical stimulation were usually excitatory, but these were often succeeded by inhibitory potentials. Since brain stem cells were often antidromically activated, the excitatory synaptic responses may be mediated by collaterals of antidromically stimulated brain stem axons. Stimulation of the deep nuclear region could evoke inhibitory or excitatory potentials in cortical neurons, the most frequent response being an excitatory postsynaptic potential which was followed in about 2 ms by an inhibitory potential. Most excitatory and some inhibitory postsynaptic potentials followed high frequency stimulation with constant latencies.The results indicate that within these cultures there are rich synaptic interconnections, many of which follow patterns resembling those seen in the intact brain. The monosynaptic inhibitory projection from the cortex to the deep nuclei and collateral inhibition by Purkinje cell axons appear to be features of cerebellar function that are reproduced in this culture model. In addition, a projection from the deep nuclei to the cortex recently described in the intact cerebellum is also present in the cultures and gives postsynaptic potential responses typical of excitatory afferents to the cerebellar cortex. Such cultures appear useful as an experimental model for the study of synaptic mechanisms or the effects of drugs in the mammalian CNS.     

Brain-derived neurotrophic factor-mediated retrograde signaling required for the induction of long-term potentiation at inhibitory synapses of visual cortical pyramidal neurons

High-frequency stimulation (HFS) induces long-term potentiation (LTP) at inhibitory synapses of layer 5 pyramidal neurons in developing rat visual cortex. This LTP requires postsynaptic Ca²⁺ rise for induction, while the maintenance mechanism is present at the presynaptic site, suggesting presynaptic LTP expression and the necessity of retrograde signaling. We investigated whether the supposed signal is mediated by brain-derived neurotrophic factor (BDNF), which is expressed in pyramidal neurons but not inhibitory interneurons. LTP did not occur when HFS was applied in the presence of the Trk receptor tyrosine kinase inhibitor K252a in the perfusion medium. HFS produced LTP when bath application of K252a was started after HFS or when K252a was loaded into postsynaptic cells. LTP did not occur in the presence of TrkB-IgG scavenging BDNF or function-blocking anti-BDNF antibody in the medium. In cells loaded with the Ca²⁺ chelator BAPTA, the addition of BDNF to the medium enabled HFS to induce LTP without affecting baseline synaptic transmission. These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB, leading to LTP. Because BDNF, expressed activity dependently, regulates the maturation of cortical inhibition, inhibitory LTP may contribute to this developmental process, and hence experience-dependent functional maturation of visual cortex.     

The facilitating effect of systemic administration of Kv7/M channel blocker XE991 on LTP induction in the hippocampal CA1 area independent of muscarinic activation

A large amount of in vitro studies demonstrate suppression of M-current in hippocampal neurons by Kv7/M channel blocker results in depolarization of membrane potential and release of neurotransmitters, such as acetylcholine and glutamate, suggesting that Kv7/M channel may play important roles in regulating synaptic plasticity. In the present study, we examined the in vivo effect of Kv7/M channel inhibition on the long-term potentiation (LTP) induction at basal dendrites in hippocampal CA1 area of urethane-anaesthetized rats. The Kv7/M channel was inhibited by intraperitoneal injection of XE991 (10 mg/kg) and the LTP of field excitatory postsynaptic potential (fEPSP) was induced by supra-threshold high frequency stimulation (S1 HFS). A weak protocol which was just below the threshold for evoking LTP was used as sub-threshold high frequency stimulation (S2 HFS). XE991 did not significantly alter the slope of fEPSP and the magnitude of LTP induced by S1 HFS, suggesting that Kv7/M channel inhibition had little or no effect on glutamatergic transmission under basal conditions. However, XE991 could make S2 HFS evoke LTP even after the application of the muscarinic cholinergic (mACh) receptor antagonist scopolamine, suggesting that Kv7/M channel inhibition lowered the threshold for LTP induction and the effect was independent of muscarinic activation. Based on the above findings, we concluded that the facilitating effect of XE991 on LTP induction is not mediated by its ability to enhance the release of acetylcholine; therefore, Kv7/M channel blockers may provide a therapeutic benefit to cholinergic deficiency-related cognitive impairment, e.g., Alzheimer's disease.     

Neuronal electrical high frequency stimulation modulates presynaptic GABAergic physiology

Electrical high frequency deep brain stimulation (DBS) of the globus pallidus internus (GPi) or the subthalamic nucleus (STN) has dramatic beneficial motor effects in advanced Parkinson's disease (PD). However, the mechanisms underlying these clinical results remain unclear. It is proposed that the gamma-aminobutyric acid (GABA) system is involved in the effectiveness of DBS. To prove this hypothesis, rat striatal slices were stimulated electrically (130 Hz) in vitro; GABA and glutamate (GLU) outflow from striatal slices of normal or kainic acid-lesioned rats were measured after o-phthaldialdehyde sulphite derivatization using HPLC with electrochemical detection. Our results could demonstrate that high frequency stimulation (HFS) did not modulate basal GABA outflow in the perfusate. In the presence of submaximal concentrations of the voltage-gated sodium channel opener veratridine, HFS significantly enhanced GABA outflow. When the GABA transporter inhibitor, nipecotic acid, was added to the incubation medium, the HFS effects decreased to nearly control values. Destruction of striatal GABAergic neurons by kainic acid completely reversed the effects of HFS on GABA outflow. In the present study no effect of HFS on glutamate outflow was observed under any condition. These results suggest that HFS has a specific effect on GABAergic neuronal terminals resulting in an enhancement of extracellular GABA in the caudate nucleus. This effect is probably due to an inhibitory effect of HFS on the GABA uptake system rather than to stimulation of vesicular GABA release from GABAergic neurons, which are both associated with the presynaptic GABAergic physiology.     

Network activity evoked by neocortical stimulation in area 36 of the guinea pig perirhinal cortex.

The perirhinal cortex is a key structure involved in memory consolidation and retrieval. In spite of the extensive anatomical studies that describe the intrinsic and extrinsic associative connections of the perirhinal cortex, the activity generated within such a network has been poorly investigated. We describe here the pattern of synaptic interactions that subtend the responses evoked in area 36 of the perirhinal cortex by neocortical and local stimulation. The experiments were carried out in the in vitro isolated guinea pig brain. The synaptic perirhinal circuit was reconstructed by integrating results obtained during intracellular recordings from layer II-III neurons with simultaneous current source density analysis of laminar profiles performed with 16-channel silicon probes. Both neocortical and local stimulation of area 36 determined a brief monosynaptic excitatory potential in layer II-III neurons, followed by a biphasic synaptic inhibitory potential possibly mediated by a feed-forward inhibitory circuit at sites close to the stimulation electrode and a late excitatory postsynaptic potential (EPSP) that propagated at distance within area 36 along the rhinal sulcus. During a paired-pulse stimulation test, the inhibitory postsynaptic potential (IPSP) and the late EPSP were abolished in the second conditioned response, suggesting that they are generated by poli-synaptic circuits. Current source density analysis of the field responses demonstrated that 1) the monosynaptic activity was generated in layers II-III and 2) the sink associated to the disynaptic responses was localized within the superficial layer of area 36. We conclude that the neocortical input induces a brief monosynaptic excitation in area 36 of the perirhinal cortex, that is curtailed by a prominent inhibition and generates a recurrent excitatory associative response that travels at distance within area 36 itself. The results suggest that the perirhinal cortex network has the potentials to integrate multimodal incoming neocortical information on its way to the hippocampus.     

Spinal input to thalamic VL neurons: evidence for direct spinothalamic effects.

1. The postsynaptic actions of afferents ascending in the ventrolateral quadrant and dorsal columns of the spinal cord were studied in neurons in the ventrolateral nucleus of the thalamus (VL) (n = 138) by use of intracellular recording procedures. Neurons were identified by their monosynaptic input from the cerebellum and, when possible, their antidromic activation from the motor cortex. The possible occurrence of monosynaptic transmission along spinothalamic fibers was investigated by estimating the intrathalamic delay time of postsynaptic responses and by examining the occurrence of temporal facilitation to double-shock stimulation. The experiments were performed in cats anesthetized with alpha-chloralose. 2. The majority of neurons (86%) responded with excitatory or inhibitory postsynaptic potentials to stimulation of the ascending paths. The response latencies of excitation on stimulation of the ventral quadrants at C3 ranged from 2.9 to 18 ms. Evidence for monosynaptic excitation after stimulation of (spinothalamic) afferents ascending in the ventrolateral quadrants was obtained for a number of neurons (n = 30). For these neurons, estimated intrathalamic delays were less than 1 ms and/or the neurons did not display temporal facilitation to double shocks. All the shortest latency responses (from C3) showed evidence of monosynaptic transmission. It is estimated that approximately 19-39% of neurons sampled may receive monosynaptic input. The spinal conduction velocities of the direct projections ranged from 10 to 35 m/s (median 20 m/s). 3. Much of the ascending input was mediated polysynaptically. For afferents ascending in the ventrolateral quadrant, estimated intrathalamic delays were greater than 1.5 ms and/or the postsynaptic responses displayed temporal facilitation to double shocks. The shortest latency from C3 of a polysynaptic response was 5 ms. Spatial interactions were observed between polysynaptic inputs from the ventrolateral quadrants and the dorsal columns, indicating that at least some of the pathways to VL are shared. 4. The data show that many neurons in the VL receive input ascending from the spinal cord via direct and indirect routes. Somatosensory information reaching VL could serve to adjust, during the course of movement execution, the cerebellar commands relayed by VL to the motor cortex.     

Postsynaptic control of the induction of long-term changes in efficacy of transmission at neocortical synapses in slices of rat brain

1. Long-term potentiation (LTP) is an enduring, activity-induced increase in the efficacy of synaptic transmission, which has been considered as a possible neural substrate for learning. Recent experiments have shown that LTP can be induced in hippocampal CA1 neurons when a presynaptic volley is paired repetitively with depolarization of the postsynaptic cell, brought about with intracellularly applied depolarizing current pulses (20, 33). We have repeated these experiments in neocortical neurons, in transverse slices of rat sensorimotor cortex in vitro. 2. Stable intracellular recordings were obtained from 28 neurons (mean resting potential -78 mV, mean spike amplitude 95 mV, mean input resistance 41 M omega) mostly in layers V and VI. Two different afferent pathways were stimulated alternately at 0.2 Hz to evoke subthreshold composite excitatory postsynaptic potentials (EPSPs). One micromolar bicuculline methiodide was added to the bathing medium in most experiments. 3. Repetitive pairing of one afferent volley with a coincident intracellular depolarizing current pulse (100-200 ms long) of a magnitude sufficient to make the neuron fire 6 to 13 action potentials/pulse, gave rise after 30-50 pairings in 4 neurons to a significant enduring increase in the amplitude of the paired EPSP. The increase persisted without decrement for as long as the recording continued (range 15-50 min after the pairing ended) but the amplitude of the unpaired EPSP was unchanged. During the LTP, the membrane potential and the apparent input resistance of the postsynaptic neurons were also unchanged. 4. In two cells a significant prolonged depression of the paired EPSP was induced while the unpaired EPSP was unaffected. Membrane potential and input resistance were not changed. In the remaining 22 cells neither the paired nor the unpaired EPSP was altered. 5. Brief, tetanic stimulation was applied to one afferent pathway in 11 of the neurons in which postsynaptic stimulation had been ineffective. A variety of effects was produced (LTP, depression, or posttetanic potentiation). All the effects of tetanic stimulation were confined to the stimulated pathway. 6. We conclude that LTP can be produced in some neocortical neurons by pairing a presynaptic volley with postsynaptic depolarization, in an experimental paradigm that conforms to Hebb's (17) model of associative conditioning. Depression of the paired EPSP was produced in other cells with the same experimental design.(ABSTRACT TRUNCATED AT 400 WORDS)     

Developmental changes in presynaptic muscarinic modulation of excitatory and inhibitory neurotransmission in rat piriform cortex in vitro: relevance to epileptiform bursting susceptibility

Suppression of depolarizing postsynaptic potentials and isolated GABA-A receptor-mediated fast inhibitory postsynaptic potentials by the muscarinic acetylcholine receptor agonist, oxotremorine-M (10 microM), was investigated in adult and immature (P14-P30) rat piriform cortical (PC) slices using intracellular recording. Depolarizing postsynaptic potentials evoked by layers II-III stimulation underwent concentration-dependent inhibition in oxotremorine-M that was most likely presynaptic and M2 muscarinic acetylcholine receptor-mediated in immature, but M1-mediated in adult (P40-P80) slices; percentage inhibition was smaller in immature than in adult piriform cortex. In contrast, compared with adults, layer Ia-evoked depolarizing postsynaptic potentials in immature piriform cortex slices in oxotremorine-M, showed a prolonged multiphasic depolarization with superimposed fast transients and spikes, and an increased 'all-or-nothing' character. Isolated N-methyl-d-aspartate receptor-mediated layer Ia depolarizing postsynaptic potentials (although significantly larger in immature slices) were however, unaffected by oxotremorine-M, but blocked by dl-2-amino-5-phosphonovaleric acid. Fast inhibitory postsynaptic potentials evoked by layer Ib or layers II-III-fiber stimulation in immature slices were significantly smaller than in adults, despite similar estimated mean reversal potentials ( approximately -69 and -70 mV respectively). In oxotremorine-M, only layer Ib-fast inhibitory postsynaptic potentials were suppressed; suppression was again most likely presynaptic M2-mediated in immature slices, but M1-mediated in adults. The degree of fast inhibitory postsynaptic potential suppression was however, greater in immature than in adult piriform cortex. Our results demonstrate some important physiological and pharmacological differences between excitatory and inhibitory synaptic systems in adult and immature piriform cortex that could contribute toward the increased susceptibility of this region to muscarinic agonist-induced epileptiform activity in immature brain slices.     

Comparison of the effects of neurokinin-3 receptor blockade on two forms of slow synaptic transmission in myenteric AH neurons

AH neurons are intrinsic sensory neurons of the intestine that exhibit two types of slow synaptic event: slow excitatory postsynaptic potentials which increase their excitability for about 2-4 min, and sustained slow postsynaptic excitation which can persist for several hours, and may be involved in long-term changes in the sensitivity of the intestine to sensory stimuli. The effects of the neurokinin-3 tachykinin receptor antagonist, SR142801, on these two types of synaptic event in AH neurons of the myenteric ganglia of guinea-pig small intestine were compared. Slow excitatory postsynaptic potentials were evoked by stimulation of synaptic inputs at 10-20 Hz for 1s, and sustained slow postsynaptic excitation was evoked by stimulation of inputs at 1Hz for 4 min. SR142801 (1microM) reduced the amplitude of the slow excitatory postsynaptic potential to 26% of control, and also reduced the increase in input resistance and the extent of anode break excitation associated with the slow excitatory postsynaptic potential. In contrast, SR142801 did not reduce the increase in excitability, the increase in input resistance or the depolarisation that occur during the sustained slow postsynaptic excitation. SR142801 did not change the resting membrane potential or the resting input resistance.We conclude that tachykinins, acting through neurokinin-3 receptors, are involved in the generation of the slow excitatory postsynaptic potential, but not in the sustained slow postsynaptic excitation, and that the release of transmitters from synaptic inputs to AH neurons is frequency coded.     

Multiparametric corticofugal modulation of collicular duration-tuned neurons: modulation in the amplitude domain

The subcortical auditory nuclei contain not only neurons tuned to a specific frequency but also those tuned to multiple parameters characterizing a sound. All these neurons are potentially subject to modulation by descending fibers from the auditory cortex (corticofugal modulation). In the past, we electrically stimulated cortical duration-tuned neurons of the big brown bat, Eptesicus fuscus, and found that its collicular duration-tuned neurons were corticofugally modulated in the frequency and time (duration) domains. In the current paper, we report that they were also corticofugally modulated in the amplitude (intensity) domain. We found the following collicular changes evoked by focal cortical electric stimulation. 1) Corticofugal modulation in the amplitude domain differed depending on whether recorded collicular neurons matched in best frequency (BF) with stimulated cortical neurons. BF-matched neurons decreased their thresholds, whereas BF-unmatched neurons increased their thresholds: the larger the BF difference between the recorded collicular and stimulated cortical neurons, the larger the threshold increase. 2) In general, the dynamic range for amplitude coding was larger in the inferior colliculus than in the auditory cortex. BF-matched neurons increased their dynamic ranges and response magnitude, whereas BF-unmatched neurons decreased them. 3) Single duration-tuned neurons were simultaneously modulated by cortical electric stimulation in the amplitude, frequency and time domains. 4) Corticofugal modulation in these three domains indicates that the contrast of the neural representation of repeatedly delivered sound stimuli is increased.     

Activity-dependent synaptic plasticity in the supraoptic nucleus of the rat hypothalamus

Activity-dependent long-term synaptic changes were investigated at glutamatergic synapses in the supraoptic nucleus (SON) of the rat hypothalamus. In acute hypothalamic slices, high frequency stimulation (HFS) of afferent fibres caused long-term potentiation (LTP) of the amplitude of AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) recorded with the whole-cell patch-clamp technique. LTP was also obtained in response to membrane depolarization paired with mild afferent stimulation. On the other hand, stimulating the inputs at 5 Hz for 3 min at resting membrane potential caused long-term depression (LTD) of excitatory transmission in the SON. These forms of synaptic plasticity required the activation of NMDA receptors since they were abolished in the presence of d -AP5 or ifenprodil, two selective blockers of these receptors. Analysis of paired-pulse facilitation and trial-to-trial variability indicated that LTP and LTD were not associated with changes in the probability of transmitter release, thereby suggesting that the locus of expression of these phenomena was postsynaptic. Using sharp microelectrode recordings in a hypothalamic explant preparation, we found that HFS also generates LTP at functionally defined glutamatergic synapses formed between the organum vasculosum lamina terminalis and SON neurons. Taken together, our findings indicate that glutamatergic synapses in the SON exhibit activity-dependent long-term synaptic changes similar to those prevailing in other brain areas. Such forms of plasticity could play an important role in the context of physiological responses, like dehydration or lactation, where the activity of presynaptic glutamatergic neurons is strongly increased.     

Excitability of corticospinal neurons during tonic muscle contractions in man

Summary A magnetic stimulus applied to the human scalp over the motor cortex causes a short latency contraction of contralateral limb muscles. This is presumed to result from the indirect excitation of corticospinal neurons with monosynaptic connections to motoneurons. The excitability of these cortical neurons can be estimated from the magnitude of the postsynaptic potentials produced in spinal motoneurons by a given magnetic stimulus. In man the characteristics of these postsynaptic potentials can be derived from changes in the firing probability of single motor units. When a subject increases the level of a sustained voluntary contraction the excitability of the corticospinal neurons estimated in this way becomes less. We conclude that the additional synaptic input to motoneurons required to maintain a stronger muscle contraction comes from fiber systems other than the population of fast corticospinal neurons activated by magnetic stimulation.     

闭环式电刺激抑制痫样棘波发放的机制研究

脑深部刺激（DBS）在临床癫痫病的治疗中备受关注,可能替代癫痫病灶的切除手术。但是,癫痫的发作机制多种多样,需要针对性地设计DBS的刺激模式和参数,才能获得较好的疗效。对于γ\|氨基丁酸受体的拮抗剂印防己毒素在麻醉大鼠海马CA1区诱导的痫样发放,采用短促的高频刺激（HFS）脉冲串;并利用闭环式的刺激模式,在各个爆发式发放期间,将脉冲串施加于CA1区的传入轴突束Schaffer侧支。9只大鼠的实验结果表明,100 Hz以上的0.3 s时长HFS可以抑制Burst中60%~70%的棘波发放。而且,在HFS抑制棘波发放期间,CA1区神经元不能响应其传出轴突束上施加的逆向刺激脉冲的激励作用,表明在此期间神经元失去了产生动作电位的能力。由此可以推测,HFS抑制棘波发放的机制可能是神经元细胞膜发生了去极化阻滞。该研究的发现对于开发DBS治疗癫痫的闭环刺激新模式具有重要的指导意义。     

Responses of myenteric S neurones to low frequency stimulation of their synaptic inputs

Previous experiments have shown that prolonged low frequency stimulation of presynaptic inputs causes excitation of AH neurones that considerably outlasts the period of stimulation in the guinea-pig small intestine. The present experiments compare the responses of S neurones (which are motor neurones and interneurones) with responses of AH neurones (intrinsic primary afferent neurones) to low frequency stimulation of synaptic inputs. Neurones in the myenteric plexus of isolated segments of guinea-pig small intestine were recorded from with intracellular microelectrodes. During their impalement, the neurones were filled with a marker dye and they were later processed to reveal their shapes and immunohistochemical properties. One group of neurones, inhibitory motor neurones to the circular muscle, was depolarised by stimulation of synaptic inputs at 1 Hz for 100 s to 4 min. With 4-min trains of stimuli, peak depolarisation was 21+/-2 mV (mean+/-S.E.M.), which was reached at about 110 s. Depolarisation was accompanied by increased excitability; before stimulation, a test intracellular pulse (500 ms) triggered 3 action potentials, at the peak of excitability this reached 16 action potentials. Depolarisation began to decline immediately at the end of stimulation. This contrasts with responses of AH neurones, in which depolarisation persisted after the end of the stimulus (peak depolarisation at 300 s). The excitation and depolarisation of inhibitory motor neurones was blocked by the neurokinin 1 tachykinin receptor antagonist, SR140333 (100 nM), but excitation of AH neurones was not affected. Small or no responses to 1 Hz stimulation were recorded from descending filamentous interneurones, longitudinal muscle motor neurones and excitatory circular muscle motor neurones. In conclusion, this study indicates that sustained slow postsynaptic excitation only occurs in AH neurones, and that one type of S neurones, inhibitory motor neurones to the circular muscle, responds substantially, but not beyond the period of stimulation, to activation of synaptic inputs at 1 Hz. This slow excitatory postsynaptic potential evoked by low frequency stimulation is mediated by tachykinins.     

Excitatory synaptic potentials in neurons of the deep nuclei in olivo-cerebellar slice cultures.

Excitatory postsynaptic potentials evoked in neurons of the deep cerebellar nuclei, either by electrical stimulation within the nuclei in cerebellar slice cultures or by electrical stimulation of olivary explants in olivo-cerebellar co-cultures, were investigated in the rat by means of intracellular recordings. In neurons of the deep cerebellar nuclei, stimulation of the nuclear tissue, as well as stimulation of the olivary tissue, induced a fast rising excitatory postsynaptic potential, followed by an inhibitory postsynaptic potential and a long-lasting excitation. The fast rising excitatory postsynaptic potential and the following inhibitory postsynaptic potential were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione. The remaining depolarization was abolished by D-(-)-2-amino-5-phosphonovalerate, suggesting that this potential was mediated by N-methyl-D-aspartate receptors. With only D-(-)-2-amino-5-phosphonovalerate added to the bath, the slow excitation was depressed, whereas the fast excitatory and inhibitory postsynaptic potentials were not affected. In the presence of bicuculline, the 6-cyano-7-nitroquinoxaline-2,3-dione- and the D-(-)-2-amino-5-phosphonovalerate-sensitive excitatory postsynaptic potentials elicited by stimulation of the olivary tissue had the same latency, and were both graded with stimulation strength. The time-to-peak and the duration of the D-(-)-2-amino-5-phosphonovalerate-sensitive excitatory postsynaptic potentials were considerably longer than those of the 6-cyano-7-nitroquinoxaline-2,3-dione-sensitive excitatory postsynaptic potentials.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cholinergic-mediated response enhancement in barrel cortex layer V pyramidal neurons

Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions, but the underlying cellular mechanisms are largely unknown. We analyzed the effects of acetylcholine (ACh) on synaptic transmission and cell excitability in rat "barrel cortex" layer V (L5) pyramidal neurons in vitro. ACh through nicotinic and M1 muscarinic receptors enhanced excitatory postsynaptic currents and through nicotinic and M2 muscarinic receptors reduced inhibitory postsynaptic currents. These effects increased excitability and contributed to the generation of Ca(2+) spikes and bursts of action potentials (APs) when inputs in basal dendrites were stimulated. Ca(2+) spikes were mediated by activation of NMDA receptors (NMDARs) and L-type voltage-gated Ca(2+) channels. Additionally, we demonstrate in vivo that basal forebrain stimulation induced an atropine-sensitive increase of L5 AP responses evoked by vibrissa deflection, an effect mainly due to the enhancement of an NMDAR component. Therefore, ACh modified the excitatory/inhibitory balance and switched L5 pyramidal neurons to a bursting mode that caused a potent and sustained response enhancement with possible fundamental consequences for the function of the barrel cortex.     

5 Hz repetitive TMS increases anticipatory motor activity in the human cortex

In the present study, we analyzed how high-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor hand area (M1-Hand) shapes anticipatory motor activity in frontal areas as indexed by the contingent negative variation (CNV). Eight right-handed volunteers received real or sham 5Hz rTMS at an intensity of 90% resting motor threshold (1,500 stimuli per session). Real but not sham rTMS to left M1-Hand induced a site-specific increase in amplitude of the late component of the CNV at the electrode C3 overlaying the site of stimulation. The increase in pre-movement activity in the stimulated cortex may reflect an increase in facilitatory drive from connected motor areas, enhanced responsiveness of the stimulated cortex to these inputs or both.