Patterns of spontaneous activity in unstructured and minimally structured spinal networks in culture

The rhythmic activity observed in locomotion is generated by local neuronal networks in the spinal cord. The alternating patterns are produced by reciprocal connections between these networks. Synchronous rhythmic activity, but not alternation, can be reproduced in disinhibited networks of dissociated spinal neurons of rats. This suggests that a specific network architecture is required for pattern generation but not for rhythm generation. Here we were interested in the recruitment of neurons to produce population bursts in unstructured and minimally structured cultures of rat spinal cord grown on multielectrode arrays. We tested whether two networks, connected by a small number of axons, could be functionally separated into two units and generate more complex patterns such as alternation. In the unstructured cultures, we found that the recruitment of the neurons into bursting populations is divided into two steps: the fast recruitment of a trigger network, consisting of intrinsically firing cells connected in networks with short delays, and slow recruitment of the rest of the network. One or several trigger networks were observed in a single culture and could account for variable patterns of propagation. In the minimally structured cultures, a functional separation between loosely connected networks was achieved. Such separation led either to an independent bursting between the networks or to synchronized bursting with long and variable delays. However, no qualitatively novel pattern such as alternation could be generated. In addition, we found that the strength of reciprocal inhibitory connections was modulated by spontaneous activity.     

Sensitivity of human auditory evoked potentials to the harmonicity of complex tones: evidence for dissociated cortical processes of spectral and periodicity analysis

A strong subjective tendency exists for simultaneous sound frequencies forming an harmonic series (integer multiples of the fundamental) to "group" together into a unified auditory percept whose pitch is similar to that of the fundamental. The aim of the study was to determine whether cortical auditory evoked potentials (AEPs) to complex tones differ according to whether the component frequencies of the stimuli are harmonically related or not. AEPs were recorded to continuous complex tones comprising four or more sinusoids. The vertex-maximal "change-potentials" (CP1, CN1, CP2), recorded to a stimulus cycle comprising one harmonic and five inharmonic complexes changing every second, showed no sensitivity to harmonicity, although an additional mismatch negativity was possibly present to the harmonic complex. In a second study the CP2 was significantly attenuated when an harmonic complex changed to a new one in the presence of an unchanging sinusoidal background tone, harmonically related to the first complex but not to the second, and thus becoming perceptually distinct. This, however, might be caused by lateral inhibitory effects not related to harmonicity. In a third experiment, when four concurrent sinusoidal tones came to rest on steady frequencies after a 5-s period of 16/s pseudo-random frequency changes, fronto-centrally maximal "mismatch-potentials" (MN1, MP2), were recorded. Both the MN1 and the MP2 were significantly shorter in latency when the steady frequencies formed an harmonic complex. Since the harmonic complex had a short overall periodicity, equal to that of the fundamental, while that of the inharmonic complex was much longer, the effect might be explained if the latencies of the mismatch-potential are related to periodicity. The perceptual grouping of harmonically related frequencies appears not to be a function of spectral domain analysis, reflected in the change-potentials, but of periodicity analysis, reflected in the mismatch-potentials Electronic Publication     

Effects of inhibition of neuronal nitric oxide synthase on NMDA-induced changes in cerebral blood flow and oxygen consumption

This study was performed to determine whether neuronal nitric oxide synthase (nNOS) is involved in altering regional cerebral blood flow (rCBF) and oxygen consumption during N-methyl-D-aspartate (NMDA) receptor stimulation. A craniotomy was performed in rats, under isoflurane anesthesia, to expose the cerebral cortex. For the control group (n=7), an NMDA patch (10^–3 M) was applied to the exposed cortex (ipsilateral cortex, IC) for 10 min before determining rCBF and O₂ consumption. The patch was changed every 5 min. To block nNOS, 7-nitroindazole (7-NI, 25 mg/kg i.p.) was administered 30 min before NMDA application (7-NI group, n=7). The autoradiographic technique was used to determine rCBF and regional O₂ consumption was measured using cryomicrospectrophotometry. Blood pressure, heart rate, blood gases, and hemoglobin were similar between the two groups. In the control group, rCBF (108±32 ml/100 g per min) and O₂ consumption (4.8±0.8 ml O₂/100 g per min) of the IC where NMDA was applied were higher than those of the contralateral cortex (CC) (78±16 ml/100 g per min and 3.1±0.4 ml O₂/100 g per min, respectively). Neither rCBF nor O₂ consumption of the IC of the 7-NI group was statistically different from that of the CC. However, O₂ consumption of the IC of the 7-NI group was lower (3.9±1.0 ml O₂/100 g per min) than that of the IC of the control group. Our data demonstrated that a direct cortical application of NMDA increased O₂ consumption and rCBF, and that pretreatment with 7-NI not only attenuated the effects of NMDA on rCBF but also decreased the O₂ consumption during NMDA receptor stimulation. Electronic Publication     

Auditory cortical and hippocampal local-field potentials to frequency deviant tones in urethane-anesthetized rats: An unexpected role of the sound frequencies themselves

The human brain can automatically detect auditory changes, as indexed by the mismatch negativity of event-related potentials. The mechanisms that underlie this response are poorly understood. We recorded primary auditory cortical and hippocampal (dentate gyrus, CA1) local-field potentials to serial tones in urethane-anesthetized rats. In an oddball condition, a rare (deviant) tone (p = 0.11) randomly replaced a repeated (standard) tone. The deviant tone was either lower (2200, 2700, 3200, 3700 Hz) or higher (4300, 4800, 5300, 5800 Hz) in frequency than the standard tone (4000 Hz). In an equiprobability control condition, all nine tones were presented at random (p = 0.11). Differential responses to deviant tones relative to the standard tone were found in the auditory cortex and the dentate gyrus but not in CA1. Only in the dentate gyrus, the responses were found to be standard- (i.e., oddball condition-) specific. In the auditory cortex, the sound frequencies themselves sufficed to explain their generation. These findings tentatively suggest dissociation among non-contextual afferent, contextual afferent and auditory change detection processes. Most importantly, they remind us about the importance of strict control of physical sound features in mismatch negativity studies in animals.     

N1, P2 and T-complex of the auditory brain event-related potentials to tones with varying rise times in adults with and without dyslexia

Dyslexia is a learning difficulty affecting the acquisition of fluent reading and spelling skills due to poor phonological processing. Underlying deficits in processing sound rise time have also been found in children and adults with dyslexia. However, the neural basis for these deficits is unknown. In the present study event-related potentials were used to index neural processing and examine the effect of rise time manipulation on the obligatory N1, T-complex and P2 responses in English speaking adults with and without dyslexia. The Tb wave of the T-complex showed differences between groups, with the amplitudes for Tb becoming less negative with increased rise time for the participants with dyslexia only. Frontocentral N1 and P2 did not show group effects. Enhanced Tb amplitude that is modulated by rise time could indicate altered neural networks at the lateral surface of the superior temporal gyrus in adults with dyslexia.     

Temporal prominence of auditory evoked potentials (N1 wave) in 4-8-year-old children

Cortical auditory evoked potentials (N1 wave) were studied in 24 adults (12 men, 12 women) and 20 children (12 boys, 8 girls; age: 4-8 years). In adults, this wave was recorded with maximal amplitude at frontocentral sites, peaking at about 100 ms poststimulation, whereas in children the auditory response displayed maximal amplitude at the midtemporal sites, with a positive wave at about 100 ms and a large negative wave at approximately 170 ms. Moreover, the modulatory effects of intensity on N1 amplitude were prominent at frontocentral sites in adults and at temporal sites in children. Frontocentral negative response was also recorded in children but was smaller in amplitude and longer in peak latency (around 140 ms) than in adults; responses were of greater amplitude at the frontal site than at the vertex before 6 years of age, whereas the reverse was more often found after this age. These data suggest great differences with age in the neural generators contributing to auditory evoked potentials recorded in the N1 latency range.     

Auditory and somatosensory evoked potentials in a case of "locked-in" syndrome: a clinical and pathological study

Brainstem auditory evoked potentials were bilaterally normal, and somatosensory evoked potentials were unilaterally abnormal in a patient with a large pontine infarct causing a "locked-in" syndrome. In the post mortem examination, the lesion extended unilaterally into the pontine tegmentum, partially involving the left medial lemniscus. The P14 potential was absent and the N20 potential was diminished in amplitude with right median nerve stimulation. The origin of the P14 potential has been debated in the literature. This case provides evidence for the P14 generator being located at the pontine level, in relation to a lemniscal area above the decussation of the somatosensory pathway. Evoked potentials can help to determine the tegmental extension of the pontine infarcts in the "locked-in" syndrome, especially in patients unable to cooperate with clinical examination.     

Event-related potentials to tones in the absence and presence of sleep spindles

The present study focused on event-related potentials to tones in the presence and absence of sleep spindles. Six undergraduates were studied throughout an experimental night, following an adaptation session. The event-related potentials to tone stimuli were averaged for each subject. Separate averages were determined for trials on which no sleep spindle occurred 2 s before or after a tone and trials in which spindle activity was present. Both voltage distribution maps and multivariate analysis of the waveforms produced significant differences between these conditions, which could be seen as a higher initial positive component and sustained positivity over the averaged epoch in the presence of spindles. Spectral analysis indicated that this result could not solely be ascribed to residual sigma activity in the spindle-present average. The results may provide insights into the functional role of sleep spindles in humans in addition to that suggested by a neurophysiological model of inhibition.     

Retinal electrophysiology for toxicology studies: Applications and limits of ERG in animals and ex vivo recordings

Assessing retinal drug toxicity is becoming increasingly important as different molecules are now developed for the treatment of neurodegenerative diseases and vascular disorders. In pharmacology and toxicology, the electroretinogram (ERG) and the multielectrode array (MEA) recording techniques can be used to quantify the possible side effects of retino-active xenobiotics. Toxicity testing requires the use of rodent as well as non-rodent models for extrapolation to the human model when determining risk and safety. Animal species differ in their retinal anatomo-physiology: most rodents used in toxicology studies are essentially nocturnal species, whereas the non-rodent laboratory species normally used (e.g. dogs, pigs and monkeys) are diurnal. The ratio between the photoreceptor populations which varies from species to species, should be considered when designing the experiment protocol and the interpretation. The described ERG procedures are designed to comply with all applicable good laboratory practice standards. Use of these procedures should yield an acceptable level of intra- and inter-subject variability for compiling a historical database, and for detecting possible retinal toxicity in animal studies. They could therefore be used as specific and standardized tools for screening of potential retinotoxic molecules in drug discovery and development in order to compare methods and results with those obtained in human electrophysiological assessments. Recording of ganglion cell light responses on ex vivo retina with the MEA technique can further demonstrate how retino-active xenobiotics affect retinal visual information processing by eliminating potential obstacles related to bioavailability and blood barrier permeability.     

Brain event-related potentials to complex tones in depressed patients: Relations to perceptual asymmetry and clinical features

Brain event-related potentials (ERPs) to probe tones in a dichotic complex tone test were recorded from right-handed depressed patients (n= 44) and normal subjects (n= 19) at homologous sites over left and right hemispheres (F3, F4; C3, C4; P3, P4; O1, O2). There were no differences between groups in N1 or P2 amplitude, but patients had smaller P3 amplitude than did normal subjects. Depressed patients failed to show either the left ear advantage or behavior-related hemispheric asymmetry of P3 seen for normal subjects. Depressed patients also showed less differences in hemispheric asymmetry between same and different judgments. These findings indicate that the abnormal behavioral asymmetry for dichotic pitch discrimination in depressed patients reflects a reduction in hemispheric asymmetry and is related to relatively late stages of cognitive processing.     

PKA参与脊髓背角C-纤维诱发电位LTP的诱导和早期维持

目的: 探讨环一磷酸腺苷依赖的蛋白激酶 (PKA) 在脊髓背角C-纤维诱发电位长时程增强(LTP)的诱导和维持中的作用。方法:细胞外记录技术在脊髓腰膨大部记录背角浅层神经元C-纤维诱发电位。 结果:(1) 8-Br-cAMP诱发脊髓背角C-纤维诱发电位LTP,且8-Br-cAMP-诱导的 LTP 遮蔽强直刺激诱导的LTP。(2) PKA的选择性抑制剂Rp-CPT-cAMPS阻断C-纤维诱发电位LTP的诱导和时间依赖性翻转C-纤维诱发电位LTP。(3)蛋白质合成抑制剂茴香霉素彻底阻断8-Br-cAMP诱发的 LTP。(4)MAPK选择性抑制剂PD98059阻断8-Br-cAMP诱发的LTP。 结论:脊髓背角神经元存在PKA信号途径,并参与脊髓背角C-纤维诱发LTP的诱导和早期维持。     

Event-related potentials and selective attention to tones moving in location and pitch: an examination of movement velocity

Event-related potentials (ERPs) were recorded from subjects who listened selectively to one of two classes of tone pips that arose from separate, virtual sound sources moving in spatial location and pitch. In different runs the speeds of the moving sources were varied; for the slow speed, the two classes of tones were easily separable, but for the moderate and fast speeds selective listening was difficult without practice. A prolonged negative shift of the ERP, beginning around 60 ms poststimulus and lasting over 300 ms, was observed when the eliciting tones were selectively attended. However, no differences at any phase of the negative ERPs were found as a function of movement velocity, in contrast to the decline of target detection performance for the fast speed. The results were interpreted as indicating that anticipation, based on contextual information, can play an important role in early input selection.     

Auditory event-related potentials in humans and rats: effects of task manipulation

The purpose of this study was to compare components of the rat and human auditory event-related potential (ERP) as generated in active oddball and passive single-stimulus tasks. The rats were trained to discriminate between target and standard stimuli in an oddball task, whereas the human subjects received instructions. Task effects on various ERP components were found in both species. Interestingly, effects on the P3 component were similar in the species with regard to amplitude: Target stimuli elicited a higher amplitude in the oddball task than did standard stimuli. This might indicate that the P3 shares the same characteristics between species. However, the first four components occurred 1.82 times earlier in rats than in humans, expecting a P3 of about 200 ms in rats. The P3 in rats appeared at 380 ms. We conclude that either the relation between human and rat peak latencies is not linear, or the P3 in rats is not the equivalent of the human P3.     

Topographic recordings of auditory evoked potentials to speech: Subcortical and cortical responses

Topographies of speech auditory brainstem response (speech ABR), a fine electrophysiological marker of speech encoding, have never been described. Yet, they could provide useful information to assess speech ABR generators and better characterize populations of interest (e.g., musicians, dyslexics). We present here a novel methodology of topographic speech ABR recording, using a 32‐channel low sampling rate (5 kHz) EEG system. Quality of speech ABRs obtained with this conventional multichannel EEG system were compared to that of signals simultaneously recorded with a high sampling rate (13.3 kHz) EEG system. Correlations between speech ABRs recorded with the two systems revealed highly similar signals, without any significant difference between their signal‐to‐noise ratios (SNRs). Moreover, an advanced denoising method for multichannel data (denoising source separation) significantly improved SNR and allowed topography of speech ABR to be recovered.     

The dynamic allocation of attention to emotion: Simultaneous and independent evidence from the late positive potential and steady state visual evoked potentials

Emotional stimuli capture and hold attention without explicit instruction. The late positive potential (LPP) component of the event related potential can be used to track motivated attention toward emotional stimuli, and is larger for emotional compared to neutral pictures. In the frequency domain, the steady state visual evoked potential (ssVEP) has also been used to track attention to stimuli flickering at a particular frequency. Like the LPP, the ssVEP is also larger for emotional compared to neutral pictures. Prior work suggests that both the LPP and ssVEP are sensitive to “top-down” manipulations of attention, however the LPP and ssVEP have not previously been examined using the same attentional manipulation in the same participants. In the present study, LPP and ssVEP amplitudes were simultaneously elicited by unpleasant and neutral pictures. Partway through picture presentation, participants’ attention was directed toward an arousing or non-arousing region of unpleasant pictures. In line with prior work, the LPP was reduced when attention was directed toward non-arousing compared to arousing regions of unpleasant pictures; similar results were observed for the ssVEP. Thus, both electrocortical measures index affective salience and are sensitive to directed (here: spatial) attention. Variation in the LPP and ssVEP was unrelated, suggesting that these measures are not redundant with each other and may capture different neurophysiological aspects of affective stimulus processing and attention.     

A Visual study of surface potentials and Laplacians due to distributed neocortical sources: Computer simulations and evoked potentials

Summary A "picture book" of surface potentials, Laplacians, and magnetic fields due to distributed, neocortical sources is presented. The mathematically simulated data is based on 4200 current sources at the macrocolumn scale. Estimated scalp surface maps are based on the three-concentic spheres model of the head. Emphasis is placed on the effects of sampling with a limited number of electrodes, the choice of reference electrode, and the use of the spline Laplacian to improve spatial resolution. The spline Laplacian is applied to median and ulnar nerve somatosensory evoked potentials and to auditory evoked potentials including P300. Substantial improvement in spatial resolution over conventional methods is obtained. The implementation of practical high resolution EEG systems based on the spline Laplacian is considered.The authors greatfully acknowledge the technical assistance of Chris Fritton, Laurie Orth, and Chiraprakash Nayak. This research was supported by NIH grant RO1 NS24314.Invited paper, Submitted to Brain Topography, July, 1991     

TMS modulation of visual and auditory processing in the posterior parietal cortex

The activity patterns of a neuronal network originate from the intrinsic properties and synaptic interactions of the constituent neurons. Our recent studies support this view, showing that the discharge of a single frog retina ganglion cell brings an elementary neuronal network of the tectum (tectum column) to a suprathreshold activity of two distinct levels that are related to the activation of the slow L-type calcium current in dendrites of the recurrent pear-shaped neurons (lower level) and the NMDA receptors in neurons (higher level) of the tectum column. We show in the present study that the dendritic slow L-type calcium current is necessary for the NMDA receptor activation in the tectum column. A small decrease of this current prevents the NMDA receptor activation and, hence, the transition of the network to the higher activity level, at which the efferent neuron of the network fires. So, the activity of the frog tectum column can be effectively controlled through the intrinsic properties of the recurrent pear-shaped neurons of the column.     

Developmental regulation of multiple nicotinic AChR channel subtypes in embryonic chick habenula neurons: contributions of both theα2 andα4 subunit genes

Habenula neurons from both early and late stage embryonic chickens express multiple subtypes of nicotinic acetylcholine receptor channels (nAChRs). The channel subtypes expressed by habenula neurons are similar in functional properties, but apparently distinct in subunit composition, from their peripheral counterparts in autonomic ganglia. Early in development, nicotine activates four classes of neuronal bungarotoxin (nBGT)-sensitive channels (approx. conductance=15, 30, 50, 60pS) that are intermingled on the surface of habenula neuronal somata. In neurons removed from older animals, nAChR channel activity has increased 4- to 40-fold and channel subtypes have become spatially segregated from one another. Analysis of the profile of nAChR subunit gene expression by polymerase chain reaction indicates that several of theα-type subunit genes, includingα2,3,4,5,7, andα8, as well as bothβ2 andβ4, are expressed. Treatment of the neurons with subunit specific antisense oligonucleotides reveals that theα2 andα4 (but notα3) subunits contribute to the functional profile of native nAChRs expressed by habenula neurons. Consideration of the functional properties and apparent subunit composition of autonomic ganglion nAChRs in the chick suggests that habenula neurons may utilize a very distinct set of subunit combinations to produce an array of nAChR channel subtypes similar in both conductance and pharmacological profile to those expressed by sympathetic neurons.     

Cooperative interaction among the various regulatory sites within the NMDA receptor-channel complex in modulating the evoked responses to noxious thermal stimuli of spinal dorsal horn neurons in the cat

Interactions among antagonists acting at different regulatory sites within the N-methyl-D-aspartate (NMDA) receptor-channel complex on the evoked responses to noxious thermal stimuli of wide dynamic range (WDR) neurons in spinal dorsal horn were studied on 21 adult anesthetized and spinalized cats. The responses of nociceptive spinal dorsal horn neurons to noxious heating (45–55°C) of the glabrous skin of the unilateral hind paw were reduced markedly by iontophoretically applied antagonists. The specific recognition site antagonist, DL-2-amino-5-phosphonovaleratic acid (APV), the strychnine-insensitive glycine site antagonist 7-chlorokynurenic acid (7CKA), the polyamine site antagonist ifenprodil (IFEN), and the phencyclidine (PCP) site antagonists ketamine (KET) and MK-801 (40–100 nA) significantly reduced (t-tests, P < 0.01) the noxious thermal stimulus-evoked responses in about 70% of the neurons by (mean ± SE) 54.1±5.8% (n=19), 80.8 ± 4.7% (n = 16), 51.1 ± 6.4% (n = 10), 77 ± 4.9% (n = 16) and 81.2 ± 8.1% (n = 5), respectively. APV and IFEN were less effective in blocking noxious thermal stimuli-evoked responses than 7CKA, KET and MK-801 (ANOVA, P < 0.05). The responses were completely inhibited in some neurons. After co-administration of the antagonists, APV + 7CKA, APV + IFEN, 7CKA + IFEN, APV + KET and APV + MK-801, all at the subthreshold ejection current, the responses were reduced markedly in 13 of 16, 7 of 10, 5 of 10, 3 of 6 and 3 of 5 neurons, respectively. The present study suggests that blockage of any component of the NMDA receptor-channel complex antagonizes the NMDA receptor-mediated response, and that there are the cooperative interactions among the various regulatory sites within the NMDA receptor-channel complex in the transmission or modulation of spinal nociceptive thermal information. Received: 18 March 1997 / Accepted: 20 October 1997