Interburst Interval Research Articles

Catestatin, a chromogranin A-derived peptide, is sympathoinhibitory and attenuates sympathetic barosensitivity and the chemoreflex in rat CVLM

Hypertension is a major cause of morbidity. The neuropeptide catestatin [human chromogranin A-(352-372)] is a peptide product of the vesicular protein chromogranin A. Studies in the periphery and in vitro studies show that catestatin blocks nicotine-stimulated catecholamine release and interacts with β-adrenoceptors and histamine receptors. Catestatin immunoreactivity is present in the rostral ventrolateral medulla (RVLM), a key site for blood pressure control in the brain stem. Recently, we reported that microinjection of catestatin into the RVLM is sympathoexcitatory and increases barosensitivity. Here, we report the effects of microinjection of catestatin (1 mM, 50 nl) into the caudal ventrolateral medulla (CVLM) in urethane-anesthetized, bilaterally vagotomized, artificially ventilated Sprague-Dawley rats (n = 8). We recorded resting arterial pressure, splanchnic sympathetic nerve activity, phrenic nerve activity, heart rate, and measured cardiovascular homeostatic reflexes. Homeostatic reflexes were evaluated by measuring cardiovascular responses to carotid baroreceptor and peripheral chemoreceptor activation. Catestatin decreased basal levels of arterial pressure (-23 ± 4 mmHg), sympathetic nerve activity (-26.6 ± 5.7%), heart rate (-19 ± 5 bpm), and phrenic nerve amplitude (-16.8 ± 3.3%). Catestatin caused a 15% decrease in phrenic inspiratory period (T(i)) and a 16% increase in phrenic expiratory period (T(e)) but had no net effect on the phrenic interburst interval (T(tot)). Catestatin decreased sympathetic barosensitivity by 63.6% and attenuated the peripheral chemoreflex (sympathetic nerve response to brief hypoxia; range decreased 39.9%; slope decreased 30.1%). The results suggest that catestatin plays an important role in central cardiorespiratory control.

Experimental analysis and computational modeling of interburst intervals in spontaneous activity of cortical neuronal culture

Rhythmic bursting is the most striking behavior of cultured cortical networks and may start in the second week after plating. In this study, we focus on the intervals between spontaneously occurring bursts, and compare experimentally recorded values with model simulations. In the models, we use standard neurons and synapses, with physiologically plausible parameters taken from literature. All networks had a random recurrent architecture with sparsely connected neurons. The number of neurons varied between 500 and 5,000. We find that network models with homogeneous synaptic strengths produce asynchronous spiking or stable regular bursts. The latter, however, are in a range not seen in recordings. By increasing the synaptic strength in a (randomly chosen) subset of neurons, our simulations show interburst intervals (IBIs) that agree better with in vitro experiments. In this regime, called weakly synchronized, the models produce irregular network bursts, which are initiated by neurons with relatively stronger synapses. In some noise-driven networks, a subthreshold, deterministic, input is applied to neurons with strong synapses, to mimic pacemaker network drive. We show that models with such "intrinsically active neurons" (pacemaker-driven models) tend to generate IBIs that are determined by the frequency of the fastest pacemaker and do not resemble experimental data. Alternatively, noise-driven models yield realistic IBIs. Generally, we found that large-scale noise-driven neuronal network models required synaptic strengths with a bimodal distribution to reproduce the experimentally observed IBI range. Our results imply that the results obtained from small network models cannot simply be extrapolated to models of more realistic size. Synaptic strengths in large-scale neuronal network simulations need readjustment to a bimodal distribution, whereas small networks do not require such changes.

Hippocampal networks on reliable patterned substrates

Toward the goal of reproducible live neuronal networks, we investigated the influence of substrate patterns on neuron compliance and network activity. We optimized process parameters of micro-contact printing for reproducible geometric patterns of 10 μm wide lines of polylysine with 4, 6, or 8 connections at a constant square array of nodes overlying the recording electrodes of a multielectrode array (MEA). We hypothesized that an increase in node connections would give the network more inputs resulting in higher neuronal outputs as network spike rates. We also chronically stimulated these networks during development and added astroglia to enhance network activity. Our results show that despite frequent localization of neuron somata over the electrodes, the number of spontaneously active electrodes was reduced 3-fold compared to random networks, independent of pattern complexity. Of the electrodes active, the overall spike rate was independent of pattern complexity, consistent with homeostasis of activity. Lower mean burst rates were seen with higher levels of pattern complexity; however, burst durations increased 1.6-fold with pattern complexity ( n = 6027 bursts, p < 0.001). Inter-burst interval and percentage of active electrodes displaying bursts also increased with pattern complexity. The extra-burst (non-burst or isolated) spike rate increased 4-fold with pattern complexity, but this relationship was reversed with either chronic stimulation or astroglia addition. These studies suggest for the first time that patterns which limit the distribution of branches and inputs are deleterious to activity in a hippocampal network, but that higher levels of pattern complexity promote non-burst activity and favor longer lasting, but fewer bursts.

Analyses of the facilitatory effect of orexin on eating and masticatory muscle activity in rats

The orexins (orexin-A and orexin-B) are neuropeptides that are secreted from neurons in the lateral hypothalamus and that participate in the regulation of feeding behavior. It remains to be determined, however, how the orexins exert their effects on feeding behavior, including masticatory movements. To this end, we analyzed food intake behavior and masticatory muscle activity using video analysis and electromyography (EMG) recording methods. The results showed that the cumulative food intake over 4 h was larger in rats intraventricularly injected with either orexin-A or orexin-B than in saline-injected control rats. The latency to eating and the feeding time for a fixed amount of pellets were shortened by injections of orexins in a dose-dependent manner, with a more potent effect by orexin-A than orexin-B. The shorter feeding time corresponded to a decreased number of chewing cycles. EMG recordings from both the digastric and masseter muscles showed two distinct patterns of bursts corresponding to the gnawing and chewing phases. After the injection of orexin-A, the magnitude of the bursts became larger in both phases in the masseter muscle, the burst duration became longer in the chewing phase in the masseter muscle, and the interburst interval became shortened in the gnawing phase in both muscles. Consequently, the burst frequency in the chewing phase was increased in the digastric muscle and, conversely, reduced in the masseter muscle. These results suggest that the orexin-A-induced facilitatory feeding behavior is characterized by a dynamic jaw-opener activity that opens the mouth rapidly and a powerful jaw-closer activity for crushing the increased amount of food taken into the mouth. The possible involvement of orexin-A in binge eating disorder is discussed.

Identification and Continuity of the Distributions of Burst-Length and Interspike Intervals in the Stochastic Morris-Lecar Neuron

Using the Morris-Lecar model neuron with a type II parameter set and K(+)-channel noise, we investigate the interspike interval distribution as increasing levels of applied current drive the model through a subcritical Hopf bifurcation. Our goal is to provide a quantitative description of the distributions associated with spiking as a function of applied current. The model generates bursty spiking behavior with sequences of random numbers of spikes (bursts) separated by interburst intervals of random length. This kind of spiking behavior is found in many places in the nervous system, most notably, perhaps, in stuttering inhibitory interneurons in cortex. Here we show several practical and inviting aspects of this model, combining analysis of the stochastic dynamics of the model with estimation based on simulations. We show that the parameter of the exponential tail of the interspike interval distribution is in fact continuous over the entire range of plausible applied current, regardless of the bifurcations in the phase portrait of the model. Further, we show that the spike sequence length, apparently studied for the first time here, has a geometric distribution whose associated parameter is continuous as a function of applied current over the entire input range. Hence, this model is applicable over a much wider range of applied current than has been thought.

On-line effects of quadripulse transcranial magnetic stimulation (QPS) on the contralateral hemisphere studied with somatosensory evoked potentials and near infrared spectroscopy

To evaluate on-line effects of quadripulse stimulation (QPS) over the primary motor cortex (M1) on cortical areas in the contralateral hemisphere. QPS consisted of 24 bursts of transcranial magnetic stimulation (TMS) pulses with an inter-burst interval of 5s for 2min (for on-line effect study) or 360 bursts for 30min (for after-effect study). Each burst consisted of four TMS pulses (i.e. QPS) separated by an interstimulus interval of 5 or 50ms (QPS-5 or QPS-50). QPSs were delivered over the left M1. Experiment 1 [on-line effect on somatosensory evoked potential (SEP)]: Left median nerve SEPs were recorded before, during and after QPS. Experiment 2 (after effect on SEP): After-effects of QPS were evaluated by following up SEPs after the QPS sessions. Experiment 3 (on-line effect on NIRS): Near infrared spectroscopy (NIRS) was also recorded at the right hemisphere during all QPS paradigms. Both QPS-5 and QPS-50 enlarged a cortical component of the contralateral SEP during stimulation. On the other hand, concerning the after effects, QPS-5 over M1 potentiated the contralateral SEP and QPS-50 tended to depress it. In NIRS study, both QPS-5 and QPS-50 induced a significant oxy-Hb decrease (deactivation pattern) at the right hemisphere during stimulation whereas sham stimulations unaffected them. We have shown the unidirectional on-line effects evoked by QPS-5 and QPS-50 on both SEP and NIRS, and bidirectional after effects on SEP at the contralateral hemisphere. The discrepancy between on-line effect and after effect may be explained by the differences in the underlying mechanisms between them. The former may be mainly explained by pure electrophysiological property changes in the membrane or synapses. The latter may be explained by synaptic efficacy changes which need some protein syntheses at least partly. Another discrepancy shown here is the direction of on-line effects. Electrophysiological (SEP) function was potentiated by both QPSs whereas hemodynamic (NIRS) function was depressed. This may be explained by which sensory areas contribute to NIRS or SEP generation.

Automatic burst detection for the EEG of the preterm infant

To aid with prognosis and stratification of clinical treatment for preterm infants, a method for automated detection of bursts, interburst-intervals (IBIs) and continuous patterns in the electroencephalogram (EEG) is developed. Results are evaluated for preterm infants with normal neurological follow-up at 2 years. The detection algorithm (MATLAB®) for burst, IBI and continuous pattern is based on selection by amplitude, time span, number of channels and numbers of active electrodes. Annotations of two neurophysiologists were used to determine threshold values. The training set consisted of EEG recordings of four preterm infants with postmenstrual age (PMA, gestational age + postnatal age) of 29–34 weeks. Optimal threshold values were based on overall highest sensitivity. For evaluation, both observers verified detections in an independent dataset of four EEG recordings with comparable PMA. Algorithm performance was assessed by calculation of sensitivity and positive predictive value. The results of algorithm evaluation are as follows: sensitivity values of 90% ± 6%, 80% ± 9% and 97% ± 5% for burst, IBI and continuous patterns, respectively. Corresponding positive predictive values were 88% ± 8%, 96% ± 3% and 85% ± 15%, respectively. In conclusion, the algorithm showed high sensitivity and positive predictive values for bursts, IBIs and continuous patterns in preterm EEG. Computer-assisted analysis of EEG may allow objective and reproducible analysis for clinical treatment.

Structure-Dependent Electrical and Concentration Processes in the Dendrites of Pyramidal Neurons of Superficial Neocortical Layers: Model Study

On mathematical models of pyramidal neurons localized in the neocortical layers 2/3, whose reconstructed dendritic arborization possessed passive linear or active nonlinear membrane properties, we studied the effect of morphology of the dendrites on their passive electrical transfer characteristics and also on the formation of patterns of spike discharges at the output of the cell under conditions of tonic activation via uniformly distributed excitatory synapses along the dendrites. For this purpose, we calculated morphometric characteristics of the size, complexity, metric asymmetry, and function of effectiveness of somatopetal transmission of the current (with estimation of the sensitivity of this efficacy to changes in the uniform membrane conductance) for the reconstructed dendritic arborization in general and also for its apical and basal subtrees. Spatial maps of the membrane potential and intracellular calcium concentration, which corresponded to certain temporal patterns of spike discharges generated by the neuron upon different intensities of synaptic activation, were superimposed on the 3D image and dendrograms of the neuron. These maps were considered “spatial autographs” of the above patterns. The main discharge pattern included periodic two-spike bursts (dublets) generated with relatively stable intraburst interspike intervals and interburst intervals decreasing with a rise in the intensity of activation. Under conditions of intense activation, the interburst intervals became close to the intraburst intervals, so the cell began to generate continuous trains of action potentials. Such a repertoire (consisting of two patterns of the activity, periodical dublets and continuous discharges) is considerably scantier than that described earlier in pyramidal neurons of the neocortical layer 5. Under analogous conditions of activation, we observed in the latter cells a variety of patterns of output discharges of different complexities, including stochastic ones. A relatively short length of the apical dendrite subtree of layer 2/3 neurons and, correspondingly, a smaller metric asymmetry (differences between the lengths of the apical and basal dendritic branches and paths), as compared with those in layer 5 pyramidal neurons, are morphological factors responsible for the predominance of periodic spike dublets. As a result, there were two combinations of different electrical states of the sites of dendritic arborization (“spatial autographs”). In the case of dublets, these were high depolarization of the apical dendrites vs. low depolarization of the basal dendrites and a reverse combination; only the latter (reverse) combination corresponded to the case of continuous discharges. The relative simplicity and uniformity of spike patterns in the cells, apparently, promotes the predominance of network interaction in the processes of formation of the activity of pyramidal neurons of layers 2/3 and, thereby, a higher efficiency of the processes of intracortical association.

Temporal correlation between resting tremor and voluntary movements in Parkinson disease, as revealed by Bereitschaftspotentials

To implement an automated analysis of EEG recordings from prematurely-born infants and thus provide objective, reproducible results.Bayesian probability theory is employed to compute the posterior probability for developmental features of interest in EEG recordings. Currently, these features include smooth delta waves (0.5–1.5 Hz, >100 μV), delta brushes (delta portion: 0.5–1.5 Hz, >100 μV; “brush” portion: 8–22 Hz, <75 μV), and interburst intervals (<10 μV), though the approach taken can be generalized to identify other EEG features of interest.When compared with experienced electroencephalographers, the algorithm had a true positive rate between 72% and 79% for the identification of delta waves (smooth or “brush”) and interburst intervals, which is comparable to the inter-rater reliability. When distinguishing between smooth delta waves and delta brushes, the algorithm’s true positive rate was between 53% and 88%, which is slightly less than the inter-rater reliability.Bayesian probability theory can be employed to consistently identify features of EEG recordings from premature infants.The identification of features in EEG recordings provides a first step towards the automated analysis of EEG recordings from premature infants.

Perceptual improvement following repetitive sensory stimulation depends monotonically on stimulation intensity

Electrical repetitive sensory stimulation (rSS) is a direct and effective means of inducing plasticity processes in human beings, and is increasingly being used as a therapeutic intervention. Suprathreshold intensities induce beneficial effects on tactile perception and sensorimotor abilities. However, it is not known whether there is an optimal range of stimulus intensity. We investigated the effect of varied intensities (low, 1.19 ± 0.07 mA; intermediate, 3.33 ± 0.27 mA; and high, 4.42 ± 0.56 mA) on the outcome of a 30-minute electrical rSS applied to the index finger (intermittent high-frequency stimulation, 20 Hz and interburst interval, 5 seconds) in three groups (n = 10 each) of participants. As a marker of perceptual changes, we measured tactile spatial two-point discrimination on the stimulated finger and on the heel of the hand before and after the rSS. rSS improved discrimination performance, with the gain being the highest in the high-intensity group and the lowest in the low-intensity group. Measurements on the heel of the hand revealed small improvements in the high-intensity group, indicative of recruitment processes. rSS of maximal intensity induced the strongest effects, indicative of a monotonic intensity-gain characteristic with no U-shaped dependency.

Network bursts in hippocampal microcultures are terminated by exhaustion of vesicle pools

Synchronized network activity is an essential attribute of the brain. Yet the cellular mechanisms that determine the duration of network bursts are not fully understood. In the present study, synchronized network bursts were evoked by triggering an action potential in a single neuron in otherwise silent microcultures consisting of 4-30 hippocampal neurons. The evoked burst duration, ∼2 s, depended on the recovery time after a previous burst. While interburst intervals of 35 s enabled full-length bursts, they were shortened by half at 5-s intervals. This reduction in burst duration could not be attributed to postsynaptic parameters such as glutamate receptor desensitization, accumulating afterhyperpolarization, inhibitory tone, or sodium channel inactivation. Reducing extracellular Ca(2+) concentration ([Ca(2+)](o)) relieved the effect of short intervals on burst duration, while depletion of synaptic vesicles with α-latrotoxin gradually eliminated network bursts. Finally, a transient exposure to high [K(+)](o) slowed down the recovery time following a burst discharge. We conclude that the limiting factor regulating burst duration is most likely the depletion of presynaptic resources.

Maternal dexamethasone and EEG hyperactivity in preterm fetal sheep

Maternal treatment with synthetic corticosteroids such as dexamethasone (DEX)significantly reduces neonatal morbidity and mortality, but its effects on the fetal brain remain unclear. In this study we evaluated the effects of DEX on EEG activity in preterm fetal sheep. Ewes at 103 days gestation received two intramuscular injections of DEX (12 mg, n = 8) or saline vehicle (n = 7) 24 h apart. Fetal EEG activity was recorded from 6 h before until 120 h after the first injection (DEX-1). DEX-1 was associated with a marked transient rise in total EEG power, maximal at 12 h (P < 0.001), with a relative increase in delta and reduced theta, alpha and beta activity, resolving by 24 h. Continuous EEG records showed a shift to larger but less frequent transient waveforms (P < 0.001). Unexpectedly, evolving epileptiform activity, consistent with electrographic and clinical seizures, developed from 178 ± 44 min after DEX-1.Similar but smaller changes were seen after the second injection. Following the injections, total power returned to control values, but the proportion of alpha activity progressively increased vs. controls (P < 0.001), with reduced interburst interval duration and number (P < 0.001). No histological neural injury or microglial activation was seen. In summary, exposure to maternal dexamethasone was associated with dramatic, evolving low-frequency hyperactivity on fetal cortical EEG recordings, followed by sustained changes consistent with maturation of fetal sleep architecture. We postulate that these effects may contribute to improved neonatal outcomes.

Airway inflammation and central respiratory control: Results from in vivo and in vitro neonatal rat

In infants, respiratory infection elicits tachypnea. To begin to evaluate the role of brainstem cytokine expression in modulation of breathing pattern changes, we compared the pattern generated after endotracheal instillation of lipopolysaccharide (LPS) in in vivo rat pups to local pro-inflammatory cytokine injection in the nucleus tractus solitarius (nTS) in an in vitro en bloc brainstem spinal cord preparation. We hypothesized that both challenges would elicit similar changes in patterning of respiration. In anesthetized, spontaneously breathing rat pups, lipopolysaccharide (LPS) or saline was instilled in the airway of urethane-anesthetized rats (postnatal days 10-11). We recorded diaphragm EMG over the subsequent 2h and saw a 20-30% decrease in interburst interval (Te) at 20-80min post-injection in LPS-instilled animals with no significant change in Ti. In contrast, IL-1β injections into the nTS of en bloc in vitro brainstem-spinal cord preparations from 0 to 5 day-old pups maintained Ti and caused an increase in Te as early as 20min later, decreasing frequency for 80-120min after injection. Our results suggest that the neonatal respiratory response to the cytokine IL-1β mediated inflammatory response depends on the site of the inflammatory stimulus and that the direct effect of IL-1β in the nTS is to slow rather than increase rate.

Neural mechanism of activity spread in the cat motor cortex and its relation to the intrinsic connectivity

Motor cortical points are linked by intrinsic horizontal connections having a recurrent network topology. However, it is not known whether neural activity can propagate over the area covered by these intrinsic connections and whether there are spatial anisotropies of synaptic strength, as opposed to synaptic density. Moreover, the mechanisms by which activity spreads have yet to be determined. To address these issues, an 8 × 8 microelectrode array was inserted in the forelimb area of the cat motor cortex (MCx). The centre of the array had a laser etched hole ∼500 μm in diameter. A microiontophoretic pipette, with a tip diameter of 2-3 μm, containing bicuculline methiodide (BIC) was inserted in the hole and driven to a depth of 1200-1400 μm from the cortical surface. BIC was ejected for ∼2min from the tip of the micropipette with positive direct current ranging between 20 and 40 nA in different experiments. This produced spontaneous nearly periodic bursts (0.2-1.0 Hz) of multi-unit activity in a radius of about 400 μm from the tip of the micropipette. The bursts of neural activity spread at a velocity of 0.11-0.24 ms⁻¹ (mean=0.14 mm ms⁻¹, SD=0.05)with decreasing amplitude.The area activated was on average 7.22 mm² (SD=0.91 mm²), or ∼92% of the area covered by the recording array. The mode of propagation was determined to occur by progressive recruitment of cortical territory, driven by a central locus of activity of some 400 μm in radius. Thus, activity did not propagate as a wave. Transection of the connections between the thalamus and MCx did not significantly alter the propagation velocity or the size of the recruited area, demonstrating that the bursts spread along the routes of intrinsic cortical connectivity. These experiments demonstrate that neural activity initiated within a small motor cortical locus (≤ 400 μm in radius) can recruit a relatively large neighbourhood in which a variety of muscles acting at several forelimb joints are represented. These results support the hypothesis that the MCx controls the forelimb musculature in an integrated and anticipatory manner based on a recurrent network topology

Population calcium imaging of spontaneous respiratory and novel motor activity in the facial nucleus and ventral brainstem in newborn mice

The brainstem contains rhythm and pattern forming circuits, which drive cranial and spinal motor pools to produce respiratory and other motor patterns. Here we used calcium imaging combined with nerve recordings in newborn mice to reveal spontaneous population activity in the ventral brainstem and in the facial nucleus. In Fluo-8AM loaded brainstem-spinal cord preparations, respiratory activity on cervical nerves was synchronized with calcium signals at the ventrolateral brainstem surface. Individual ventrolateral neurons at the level of the parafacial respiratory group showed perfect or partial synchrony with respiratory nerve bursts. In brainstem-spinal cord preparations, cut at the level of the mid-facial nucleus, calcium signals were recorded in the dorsal, lateral and medial facial subnuclei during respiratory activity. Strong activity initiated in the dorsal subnucleus, followed by activity in lateral and medial subnuclei. Whole-cell recordings from facial motoneurons showed weak respiratory drives, and electrical field potential recordings confirmed respiratory drive to particularly the dorsal and lateral subnuclei. Putative facial premotoneurons showed respiratory-related calcium signals, and were predominantly located dorsomedial to the facial nucleus. A novel motor activity on facial, cervical and thoracic nerves was synchronized with calcium signals at the ventromedial brainstem extending from the level of the facial nucleus to the medulla–spinal cord border. Cervical dorsal root stimulation induced similar ventromedial activity. The medial facial subnucleus showed calcium signals synchronized with this novel motor activity on cervical nerves, and cervical dorsal root stimulation induced similar medial facial subnucleus activity. In conclusion, the dorsal and lateral facial subnuclei are strongly respiratory-modulated, and the brainstem contains a novel pattern forming circuit that drives the medial facial subnucleus and cervical motor pools.

Basal ganglia dysfunction in OCD: subthalamic neuronal activity correlates with symptoms severity and predicts high-frequency stimulation efficacy

Functional and connectivity changes in corticostriatal systems have been reported in the brains of patients with obsessive–compulsive disorder (OCD); however, the relationship between basal ganglia activity and OCD severity has never been adequately established. We recently showed that deep brain stimulation of the subthalamic nucleus (STN), a central basal ganglia nucleus, improves OCD. Here, single-unit subthalamic neuronal activity was analysed in 12 OCD patients, in relation to the severity of obsessions and compulsions and response to STN stimulation, and compared with that obtained in 12 patients with Parkinson's disease (PD). STN neurons in OCD patients had lower discharge frequency than those in PD patients, with a similar proportion of burst-type activity (69 vs 67%). Oscillatory activity was present in 46 and 68% of neurons in OCD and PD patients, respectively, predominantly in the low-frequency band (1–8 Hz). In OCD patients, the bursty and oscillatory subthalamic neuronal activity was mainly located in the associative–limbic part. Both OCD severity and clinical improvement following STN stimulation were related to the STN neuronal activity. In patients with the most severe OCD, STN neurons exhibited bursts with shorter duration and interburst interval, but higher intraburst frequency, and more oscillations in the low-frequency bands. In patients with best clinical outcome with STN stimulation, STN neurons displayed higher mean discharge, burst and intraburst frequencies, and lower interburst interval. These findings are consistent with the hypothesis of a dysfunction in the associative–limbic subdivision of the basal ganglia circuitry in OCD's pathophysiology.

Carbon Dioxide and Glucose Affect Electrocortical Background in Extremely Preterm Infants

To investigate if Paco(2) and plasma glucose levels affect electrocortical activity. Ours was an observational study of 32 infants with a gestational age of 22 to 27 weeks. We performed simultaneous single-channel electroencephalogram (EEG) and repeated blood gas/plasma glucose analyses during the first 3 days (n = 247 blood samples with corresponding EEG). Interburst intervals (IBIs) and EEG power were averaged at the time of each blood sample. There was a linear relationship between Paco(2) and IBI; increasing Paco(2) was associated with longer IBIs. One day after birth, a 1-kPa increase in Paco(2) was associated with a 16% increase in IBI in infants who survived the first week without severe brain injury. EEG power was highest at a Paco(2) value of 5.1 kPa and was attenuated both at higher and lower Paco(2) values. Corrected for carbon dioxide effects, plasma glucose was also associated with IBI. Lowest IBI appeared at a plasma glucose level of 4.0 mmol/L, and there was a U-shaped relationship between plasma glucose level and EEG with increasing discontinuity at glucose concentrations above and below 4.0 mmol/L. Both carbon dioxide and plasma glucose level influenced EEG activity in extremely preterm infants, and values considered to be within normal physiologic ranges were associated with the best EEG background. Increasing EEG discontinuity occurred at carbon dioxide levels frequently applied in lung-protection strategies; in addition, moderate hyperglycemia was associated with measurable EEG changes. The long-term effects of changes in carbon dioxide and glucose on brain function are not known.

Zinc Effects on NMDA Receptor Gating Kinetics

Zinc accumulates in the synaptic vesicles of certain glutamatergic forebrain neurons and modulates neuronal excitability and synaptic plasticity by multiple poorly understood mechanisms. Zinc directly inhibits NMDA-sensitive glutamate-gated channels by two separate mechanisms: high-affinity binding to N-terminal domains of GluN2A subunits reduces channel open probability, and low-affinity voltage-dependent binding to pore-lining residues blocks the channel. Insight into the high-affinity allosteric effect has been hampered by the receptor's complex gating; multiple, sometimes coupled, modulatory mechanisms; and practical difficulties in avoiding transient block by residual Mg 2+. To sidestep these challenges, we examined how nanomolar zinc concentrations changed the gating kinetics of individual block-resistant receptors. We found that block-insensitive channels had lower intrinsic open probabilities but retained high sensitivity to zinc inhibition. Binding of zinc to these receptors resulted in longer closures and shorter openings within bursts of activity but had no effect on interburst intervals. Based on kinetic modeling of these data, we conclude that zinc-bound receptors have higher energy barriers to opening and less stable open states. We tested this model for its ability to predict zinc-dependent changes in macroscopic responses and to infer the impact of nanomolar zinc concentrations on synaptic currents mediated by 2A-type NMDA receptors.

PHASE RESETTING ANALYSIS OF HIGH POTASSIUM EPILEPTIFORM ACTIVITY IN CA3 REGION OF THE RAT HIPPOCAMPUS

The theory of phase resetting can reveal important information about the dynamic behavior of a periodic system when a single brief stimulus is applied to that system at the appropriate time. Phase resetting studies have revealed the existence in some biological systems of a vulnerable stimulus window generating desynchronization and suppression of the activity. The objective of this study was to test the hypothesis that a "singular" stimulus could annihilate this activity. Perfusion with the high-K solution produced synchronous, quasi-periodic population bursts with inter-burst interval of ~0.8-1.5 seconds. A single 0.1 ms duration anodic pulse of programmable delay and magnitude was applied to the somatic layer of the CA3 pyramidal cells. Three types of phase-resetting behavior were observed: (1) Weak resetting with little or no effect on the timing of the subsequent burst, (2) Strong resetting where the applied current pulse delayed the next event by one time period, (3) Singular behavior where the applied pulse partially or completely suppressed the subsequent bursting. The singular stimulus parameter window, however, was very narrow making it difficult to generate the singular behavior reliably. Nevertheless, the results indicate that singularities exist for high potassium neural activity and that a well timed pulse applied with the right amplitude can suppress this activity. This study suggests that phase resetting of a population of neurons is possible for quasi-periodic interictal activity and similar techniques could be applied to the control of epileptic seizures.

Strange Nonchaotic Bursting in a Quasiperiodically-forced Hindmarsh-Rose Neuron

We study the transition from a silent state to a bursting state by varying the dc stimulus in the Hindmarsh-Rose neuron under quasiperiodic stimulation. For this quasiperiodically-forced case, a new type of strange nonchaotic (SN) bursting state is found to occur between the silent state and the chaotic bursting state. This is in contrast to the periodically-forced case where the silent state transforms directly to a chaotic bursting state. Using a rational approximation to the quasiperiodic forcing, we investigate the mechanism for the appearance of such an SN bursting state. Thus, a smooth torus (corresponding to a silent state) is found to transform to an SN bursting attractor through a phase-dependent subcritical period-doubling bifurcation. These SN bursting states, together with chaotic bursting states, are characterized in terms of the interburst interval, the bursting length, and the number of spikes in each burst. Both bursting states are found to be aperiodic complex ones. Consequently, aperiodic complex burstings may result from two dynamically different states with strange geometry (one is chaotic and the other is nonchaotic). Thus, in addition to chaotic burstings, SN burstings may become a dynamical origin for the complex physiological rhythms that are ubiquitous in organisms.