变间隔的脉冲改变高频刺激对于脑神经元的作用

通常采用恒定电脉冲间隔的高频刺激(high-frequency stimulation,HFS),进行深部脑刺激治疗帕金森氏症等运动障碍疾病.为了开发适用于不同脑疾病治疗的新刺激模式,近年来脉冲间隔(inter-pulse-interval,IPI)变化的变频刺激模式受到关注.已有研究表明,即使具有相同的平均电脉冲频率,变频刺激与恒频刺激的治疗效果也不同.我们推测,变频刺激的短小IPI变化就足以改变HFS对于神经元的作用.为了验证此推测,本文在大鼠海马CA1区锥体神经元的输入轴突纤维上交替施加恒频刺激(100或133 Hz,即IPI=10 ms或7.5 ms)和随机变频刺激(100～200 Hz,即IPI=5～10 ms,平均频率为133 Hz),记录并分析刺激下游神经元群体的诱发电位,用于定量评价神经元对于恒频和变频刺激的响应.实验结果表明,持续的恒频刺激使得神经元的响应从最初的同步发放形成的群峰电位(population spike,PS)转变为非同步的动作电位发放(即单元锋电位).但是,当刺激切换为变频模式时,却又可以诱发神经元群体同步产生动作电位,重新形成PS波.并且,变频刺激诱发的PS幅值和神经元发放的同步程度可达基线的单脉冲刺激诱发波的水平.但是,PS的发生率只有脉冲刺激频率的7%左右,表明在持续的变频刺激时,多个脉冲累积的作用才能诱发这种同步的神经元发放.而且PS的出现与前导IPI的长度之间存在一定关系.神经元的轴突和突触等结构对于高频刺激的非线性响应可能是变频刺激诱发同步活动的原因.这些结果表明,变频刺激序列中短小的间隔变化可以产生与恒定间隔不同的调控作用.本文的结果对于揭示脑刺激的作用机制,促进新型刺激模式的开发及其在不同类型脑疾病治疗中的应用具有重要意义.     

Manifestations of dynamic coding of the amplitude-modulated sounds on the level of auditory nerve fibres

Average firing rate of the auditory nerve fiber as function of the level of the tone with the frequency equal to characteristic frequency of the fibers, can be defined as an input-output characteristic. It is known that the steepening of the input-output characteristic of the real auditory nerve fiber is more, and the width is less than the spontaneous activity of the fiber. The latter characterizes fiber's ability to generate spikes, if the stimulus is absent. However it is known, that the real auditory nerve fibers with low spontaneous activity reproduce amplitude modulation of the signals much better, than the fibers with high spontaneous activity. From the results of simulation experiments, it follows that the dynamic properties of the auditory nerve fibers, providing fine tuning or adaptation of a fiber threshold under the stimulus level but not the static input-output characteristics, are the reason of fibers reproduction of stimuli amplitude modulations. However the auditory nerve fibers with high spontaneous activity due to abrupt input-output characteristic are capable to reproduce modulations of sounds whose levels are lower than a threshold of the fiber, if a weak signal adds to a weak broadband noise. This is a phenomenon of stochastic resonance found in the reactions of auditory nerve fibers.     

Selective depressant action of antidromic impulses on gustatory nerve signals

The depressant action of antidromic volleys of impulses on gustatory nerve signals from the tongues of bullfrogs was studied. Electrical stimulation of the glossopharyngeal nerve at a rate of 100 Hz for 10 s and at supramaximal intensity slightly depressed the integrated glossopharyngeal nerve responses to quinine and to mechanical taps to the tongue. The same antidromic stimuli resulted in a 30-40% reduction in the responses to salt, acid, water, and warmed saline, but depressed greater than 80% of the afferent impulses firing spontaneously. The magnitude of responses to quinine and NaCl and the number of spontaneous discharges decreased gradually with an increase in either the frequency or the duration of antidromic stimuli. Similar results were obtained with intensities above the threshold for exciting gustatory and slowly adapting mechanosensitive fibers. The time required to recover from termination of the antidromic stimuli to two-thirds of the maximal amount of depression ranged between 6 and 7 min, with no significant differences among the depressions. The possible mechanisms involved in the antidromic depression of gustatory nerve signals are discussed.     

A new analytical method of studying post-synaptic currents.

A powerful methodology for analyzing post-synaptic currents recorded from central neurons is presented. An unknown quantity of transmitter molecules released from presynaptic terminals by electrical stimulation of nerve fibers generates a post-synaptic response at the synaptic site. The current induced at the synaptic junction is assumed to rise rapidly and decay slowly with its peak amplitude being proportional to the number of released transmitter molecules. The signal so generated is then distorted by the cable properties of the dendrite, modeled as a time-invariant, linear filter with unknown parameters. The response recorded from the cell body of the neuron following the electrical stimulation is contaminated by zero-mean, white, Gaussian noise. The parameters of the signal are then evaluated from the observation sequence using a quasi-profile likelihood estimation procedure. These parameter values are then employed to deconvolve each measured post-synaptic response to produce an optimal estimate of the transmembrane current flux. From these estimates we derive the amplitude of the synaptic current and the relative amount of transmitter molecules that elicited each response. The underlying amplitude fluctuations in the entire data sequence are investigated using a non-parametric technique based on kernel smoothing procedures. The effectiveness of the new methodology is illustrated in various simulation examples.     

Differentiated pressor and sympathetic responses to dual brain stimulation: ventromedial hypothalamus versus locus coeruleus

Sensitivity of the ventromedial hypothalamus (VMH) to electrical stimulation was compared with that of the locus coeruleus (LC) in urethane-anesthetized rats. Based not only on current strengths required to elicit threshold effects, but also on magnitude of pressor responses to suprathreshold stimulation, the LC was consistently more sensitive than the VMH. Despite this greater pressor sensitivity, splanchnic nerve firing increased almost equally upon stimulation of either brain area. Similar comparisons made in other rats following bilateral adrenalectomy or pretreatment with a vasopressin antagonist showed no significant alteration of pressor and sympathetic responsiveness to stimulation of either the LC or the VMH. When frequency of neural firing was recorded from a lumbar sympathetic trunk instead of the splanchnic nerve, increases in sympathetic nerve activity produced by LC stimulation were significantly larger than those produced from the VMH. The results suggest that greater pressor sensitivity of the LC is due, at least in part, to stronger constriction in vascular beds innervated by the lumbar sympathetic chains.     

Synchronized firing in the retina

Synchronized firing in neural populations has been proposed to constitute an elementary aspect of the neural code, but a complete understanding of its origins and significance has been elusive. Synchronized firing has been extensively documented in retinal ganglion cells, the output neurons of the retina. However, differences in synchronized firing across species and cell types have led to varied conclusions about its mechanisms and role in visual signaling. Recent work on two identified cell populations in the primate retina, the ON-parasol and OFF-parasol cells, permits a more unified understanding. Intracellular recordings reveal that synchronized firing in these cell types arises primarily from common synaptic input to adjacent pairs of cells. Statistical analysis indicates that local pairwise interactions can explain the pattern of synchronized firing in the entire parasol cell population. Computational analysis reveals that the aggregate impact of synchronized firing on the visual signal is substantial. Thus, in the parasol cells, the origin and impact of synchronized firing on the neural code may be understood as locally shared input which influences the visual signals transmitted from eye to brain.     

The muscle sound properties of different muscle fiber types during voluntary and electrically induced contractions.

Soundmyogram (SMG) and electromyogram signals were recorded simultaneously from the relatively fast medial gastrocnemius (MG) and slow soleus (SOL) during voluntary and electrically induced contractions. Using a spike-triggered averaging technique, the averaged elementary sound and corresponding MU spikes were also obtained from about 35 different MUs identified. The rms-SMG of MG increased as a function of force (P < 0.01). On the contrary, these values for SOL increased up to 60% MVC (P < 0.01), but decreased at 80% MVC. The relationship between the peak to peak amplitude of SMG and MU spike indicated significant positive correlations (r = 0.631 to approximately 0.657, P < 0.01). During electrical stimulation at 5 Hz, the SMG power spectral peak frequency (PF) was matched with stimulation frequency in both muscles. At higher stimulation frequencies, e.g., > 15 Hz, only in the MG was SMG-PF synchronized with stimulation frequency; the slow SOL did not show such synchronization. Our data suggest that the SMG frequency components might reflect active motor unit firing rates, and that the SMG amplitude depends upon mechanical properties of contraction, muscle fiber composition, and firing rate during voluntary and electrically induced contractions.     

Some effects of superior laryngeal nerve stimulation on sympathetic preganglionic neuron firing

Repetitive electrical stimulation of afferent fibers in the superior laryngeal nerve (SLN) evoked depressant or excitatory effects on sympathetic preganglionic neurons of the cervical trunk in Nembutal-anesthetized, paralyzed, artifically ventilated cats. The depressant effect, which consisted of suppression of the inspiration-synchronous discharge of units with such firing pattern, was obtained at low strength and frequency of stimulation (e.g. 600 mV, 30 Hz) and was absent at end-tidal CO2 values below threshold for phrenic nerve activity. The excitatory effect required higher intensity and frequency of stimulation and was CO2 independent. The depressant effect on sympathetic preganglionic neurons with inspiratory firing pattern seemed a replica of the inspiration-inhibitory effect observed on phrenic motoneurons. Hence, it could be attributed to the known inhibition by the SLN of central inspiratory activity, if it is assumed that this is a common driver for phrenic motoneurons and some sympathetic preganglionic neurons. The excitatory effect, on the other hand, appears to be due to connections of SLN afferents with sympathetic preganglionic neurons, independent of the respiratory center.     

Electromyography of the opercularis muscle of Rana catesbeiana: An amphibian tonic muscle

The opercularis muscle of Rana catesbeiana originates on the suprascapular cartilage of the shoulder girdle and inserts on the otic opercular element. It is part of the levator scapulae musculature and lies dorsomedial to the levator scapulae superior and inferior muscles. Bipolar electrode recordings from all three muscles show electrical activity linked to cyclical firing of the posterior intermandibularis muscle, an important ventilatory muscle. The opercularis muscle shows low amplitude, erratic signals when animals are sumerged. Upon emergence of the snout region, the opercularis muscle shows rhythmic low amplitude activity at twice the rate of buccal pumping. Lung ventilation is synchronized with this rhythm and at ventilation the opercularis muscle shows higher amplitude activity. Upon submergence, opercularis activity again shows low level activity with no rhythmic pattern. Opercularis muscle activity has a major low frequency component (about 30 Hz) that probably corresponds to activity of tonic muscle fibers. Higher frequency signals (about 200–250 Hz) comparable to those of the levator scapulae muscles are also present and probably represent activity of phasic muscle fibers. Activity of the opercularis muscle is correlated with conditions in which aerial respiration is possible, and this pattern of activity supports an opercularis role in aerial hearing and/or detection of substrate vibrations. As far as we know, this is the first report of electromyographic analysis of a vertebrate tonic muscle.     

The influence of an unmyelinated terminal on repetitive firing of a mammalian receptor afferent fiber

The distal end of a myelinated receptor afferent fiber consists of an unmyelinated terminal membrane which is assumed to be the site of sensory transduction, whereas the action potential encoding appears at a distal node of Ranvier. In the present paper a model of a mammalian myelinated nerve fiber was augmented by an unmyelinated terminal segment into which stimulating current was injected thus modelling the situation at a myelinated receptor afferent fiber. It was found that the introduction of the unmyelinated terminal reduces the repetitive firing rate shown by the model. However, also the amplitude of the spikes at the site of action potential generation diminishes through the large electrical load which the unmyelinated terminal imposes onto the active parts of the nerve fiber model. This "loss" of spike amplitude can abolish the ability of the model to show repetitive activity, if the unmyelinated terminal increases in size. On the other hand, the incorporation of sodium channels into the terminal membrane compensates the spike amplitude reduction introduced by the electrical load of that membrane. This allows repetitive firing at a lower frequency than would be possible for a model with an equivalent sodium-channel-free terminal. The results show that the unmyelinated terminal present at the distal end of myelinated receptor afferent fibers has not only the ability to provide sensory transduction but evokes also a reduction in the discharge rate of the encoding membrane.     

c-Fos expression in rat brain stem and spinal cord in response to activation of cardiac ischemia-sensitive afferent neurons and electrostimulatory modulation

The purpose of this study was to identify central neuronal sites activated by stimulation of cardiac ischemia-sensitive afferent neurons and determine whether electrical stimulation of left vagal afferent fibers modified the pattern of neuronal activation. Fos-like immunoreactivity (Fos-LI) was used as an index of neuronal activation in selected levels of cervical and thoracic spinal cord and brain stem. Adult Sprague-Dawley rats were anesthetized with urethane and underwent intrapericardial infusion of an "inflammatory exudate solution" (IES) containing algogenic substances that are released during ischemia (10 mM adenosine, bradykinin, prostaglandin E2, and 5-hydroxytryptamine) or occlusion of the left anterior descending coronary artery (CoAO) to activate cardiac ischemia-sensitive (nociceptive) afferent fibers. IES and CoAO increased Fos-LI above resting levels in dorsal horns in laminae I-V at C2 and T4 and in the caudal nucleus tractus solitarius. Dorsal rhizotomy virtually eliminated Fos-LI in the spinal cord as well as the brain stem. Neuromodulation of the ischemic signal by electrical stimulation of the central end of the left thoracic vagus excited neurons at the cervical and brain stem level but inhibited neurons at the thoracic spinal cord during IES or CoAO. These results suggest that stimulation of the left thoracic vagus excites descending inhibitory pathways. Inhibition at the thoracic spinal level that suppresses the ischemic (nociceptive) input signal may occur by a short-loop descending pathway via signals from cervical propriospinal circuits and/or a longer-loop descending pathway via signals from the nucleus tractus solitarius.     

Encoding of a spectrally-complex communication sound in the bullfrog's auditory nerve

1. A population study of eighth nerve responses in the bullfrog, Rana catesbeiana, was undertaken to analyze how the eighth nerve codes the complex spectral and temporal structure of the species-specific advertisement call over a biologically-realistic range of intensities. Synthetic advertisement calls were generated by Fourier synthesis and presented to individual eighth nerve fibers of anesthetized bullfrogs. Fiber responses were analyzed by calculating rate responses based on post-stimulus-time (PST) histograms and temporal responses based on Fourier transforms of period histograms. 2. At stimulus intensities of 70 and 80 dB SPL, normalized rate responses provide a fairly good representation of the complex spectral structure of the stimulus, particularly in the low- and mid-frequency range. At higher intensities, rate responses saturate, and very little of the spectral structure of the complex stimulus can be seen in the profile of rate responses of the population. 3. Both AP and BP fibers phase-lock strongly to the fundamental (100 Hz) of the complex stimulus. These effects are relatively resistant to changes in stimulus intensity. Only a small number of fibers synchronize to the low-frequency spectral energy in the stimulus. The underlying spectral complexity of the stimulus is not accurately reflected in the timing of fiber firing, presumably because firing is 'captured' by the fundamental frequency. 4. Plots of average localized synchronized rate (ALSR), which combine both spectral and temporal information, show a similar, low-pass shape at all stimulus intensities. ALSR plots do not generally provide an accurate representation of the structure of the advertisement call. 5. The data suggest that anuran peripheral auditory fibers may be particularly sensitive to the amplitude envelope of sounds.     

The three isoforms of nitric oxide synthase distinctively affect mouse nocifensive behavior

Nitric oxide synthases (NOSs) have been shown to modulate thermal hyperalgesia and mechanical hypersensitivity in inflammatory and neuropathic pain. However, little is known about the effect of NOSs on baseline function of sensory nerve fibers. Using genetic deficiency and pharmacologic inhibition of NOSs, we examined the impact of the three isoforms NOS1, NOS2, and NOS3 on baseline nocifensive behavior by measuring current vocalization threshold in response to electrical stimulation at 5, 250, 2000 Hz that preferentially stimulate C, Aδ, and Aβ fibers. In response to 5, 250 and 2000 Hz, NOS1-deficient animals had significantly higher current vocalization thresholds compared with wild-type. Genetic deficiency of NOS2 was associated with higher current vocalization thresholds in response to 5 Hz (C-fiber) stimulation. In contrast, NOS3-deficient animals had an overall weak trend toward lower current vocalization thresholds at 5 Hz and significantly lower current vocalization threshold compared with wild-type animals at 250 and 2000 Hz. Therefore, NOSs distinctively affect baseline mouse current vocalization threshold and appear to play a role on nocifensive response to electrical stimulation of sensory nerve fibers.     

Does the frequency content of the surface mechanomyographic signal reflect motor unit firing rates? A brief review.

The purpose of this review is to examine the literature that has investigated the potential relationship between mechanomyographic (MMG) frequency and motor unit firing rates. Several different experimental designs/methodologies have been used to address this issue, including: repetitive electrical stimulation, voluntary muscle actions in muscles with different fiber type compositions, fatiguing and non-fatiguing isometric or dynamic muscle actions, and voluntary muscle actions in young versus elderly subjects and healthy individuals versus subjects with a neuromuscular disease(s). Generally speaking, the results from these investigations have suggested that MMG frequency is related to the rate of motor unit activation and the contractile properties (contraction and relaxation times) of the muscle fibers. Other studies, however, have reported that MMG mean power frequency (MPF) does not always follow the expected pattern of firing rate modulation (e.g. motor unit firing rates generally increase with torque during isometric muscle actions, but MMG MPF may remain stable or even decrease). In addition, there are several factors that may affect the frequency content of the MMG signal during a voluntary muscle action (i.e. muscle stiffness, intramuscular fluid pressure, etc.), independent of changes in motor unit firing rates. Despite the potential influences of these factors, most of the evidence has suggested that the frequency domain of the MMG signal contains some information regarding motor unit firing rates. It is likely, however, that this information is qualitative, rather than quantitative in nature, and reflects the global motor unit firing rate, rather than the firing rates of a particular group of motor units.     

多巴胺对急性间歇性低氧诱导的大鼠颈动脉体低氧敏感性的影响*

目的: 观察急性间歇性低氧刺激后大鼠颈动脉体对低氧的敏感性以及多巴胺对颈动脉体低氧敏感性的影响。方法: 将分离SD大鼠的颈动脉体-窦神经移入到孵育槽,然后把分离的窦神经吸入到记录的玻璃电极中行电信号记录。记录基线部分缓冲液充入气体为95% O₂+ 5% CO₂混合气,低氧应激给予5% O₂+ 5% CO₂+ 90% N₂混合气,低氧刺激给予30 s,95% O₂ + 5% CO₂给予90 s,共10个循环,每组实验大鼠数量n大于等于5。结果: 大鼠离体的颈动脉体,给予急性间歇性低氧应激,再给予低氧刺激,窦神经较之前低氧刺激放电活动增强。但加入多巴胺后,可以抑制窦神经对低氧的反应,急性间歇性低氧后,多巴胺对窦神经的低氧放电活动抑制作用加强。结论: 大鼠颈动脉体给予急性间歇性低氧可增强窦神经对低氧的反应,多巴胺可抑制急性低氧诱导的颈动脉体对低氧敏感性的增强。     

EFFECTS OF ELECTRICAL STIMULATION OF CHORDA TYMPANI ON GLOSSOPHARYNGEAL NERVE RESPONSE TO THE FOLIATE PAPILLAE STIMULATION

The foliate papillae of the rat are dually innervated by thechorda tympani and the glossopharyngeal nerves. The effectsof electrical stimulation of the distal end of the cut chordatympani on the spontaneous discharges and the gustatory responsesof the glossopharyngeal nerve fibers were examined in the ratwhile gustatory stimuli were applied to the foliate papillae.Activities of 5 out of 35 taste units in the glossopharyngealnerve were influenced by this procedure. Three units showedan inhibitory effect, 1 unit showed an excitatory effect and1 unit changed its firing pattern. These facts may be derivedfrom alterations of the blood circulation in the vicinity ofthe taste receptor cells innervated by the glossopharyngealnerve fibers.     

Neuropeptide Y co-exists and co-operates with noradrenaline in perivascular nerve fibers

Neuropeptide Y (NPY)-immunoreactive nerve fibers were numerous around arteries and few around veins. NPY probably co-exists with noradrenaline in such fibers since chemical or surgical sympathectomy eliminated both NPY and noradrenaline from perivascular nerve fibers and since double staining demonstrated dopamine-beta-hydroxylase, the enzyme that catalyzes the conversion of dopamine to noradrenaline, and NPY in the same perivascular nerve fibers. Studies on isolated blood vessels indicated that NPY is not a particularly potent contractile agent in vitro. NPY greatly enhanced the adrenergically mediate contractile response to electrical stimulation and to application of adrenaline, noradrenaline or histamine, as studied in the isolated rabbit gastro-epiploic and femoral arteries. The potentiating effect of NPY on the response to electrical stimulation is probably not presynaptic since NPY affected neither the spontaneous nor the electrically evoked release of [3H]noradrenaline from perivascular sympathetic nerve fibers.     

Conduction Properties Distinguish Unmyelinated Sympathetic Efferent Fibers and Unmyelinated Primary Afferent Fibers in the Monkey

Background

Different classes of unmyelinated nerve fibers appear to exhibit distinct conductive properties. We sought a criterion based on conduction properties for distinguishing sympathetic efferents and unmyelinated, primary afferents in peripheral nerves.

Methodology/Principal Findings

In anesthetized monkey, centrifugal or centripetal recordings were made from single unmyelinated nerve fibers in the peroneal or sural nerve, and electrical stimuli were applied to either the sciatic nerve or the cutaneous nerve endings, respectively. In centrifugal recordings, electrical stimulation at the sympathetic chain and dorsal root was used to determine the fiber''s origin. In centrifugal recordings, sympathetic fibers exhibited absolute speeding of conduction to a single pair of electrical stimuli separated by 50 ms; the second action potential was conducted faster (0.61 0.16%) than the first unconditioned action potential. This was never observed in primary afferents. Following 2 Hz stimulation (3 min), activity-dependent slowing of conduction in the sympathetics (8.6 0.5%) was greater than in one afferent group (6.7 0.5%) but substantially less than in a second afferent group (29.4 1.9%). In centripetal recordings, most mechanically-insensitive fibers also exhibited absolute speeding to twin pulse stimulation. The subset that did not show this absolute speeding was responsive to chemical stimuli (histamine, capsaicin) and likely consists of mechanically-insensitive afferents. During repetitive twin pulse stimulation, mechanosensitive afferents developed speeding, and speeding in sympathetic fibers increased.

Conclusions/Significance

The presence of absolute speeding provides a criterion by which sympathetic efferents can be differentiated from primary afferents. The differences in conduction properties between sympathetics and afferents likely reflect differential expression of voltage-sensitive ion channels.