Antidromic and orthodromic activation of epileptic neurons in neocortex of awake monkey

One hundred forty normal and epileptic precentral neurons recorded from two awake monkeys with chronic experimental (alumina gel) epileptic foci were orthodromically and antidromically activated by thalamic and pyramidal tract stimulation. The response of normal neurons to single stimuli from either site was a single action potential, whereas epileptic neurons responded with a burst. Epileptic neurons firing in long-first-interval bursts responded antidromically to pyramidal tract stimulation with a long-first-interval burst, and orthodromically to thalamic stimulation with a burst whose timing coincided with the afterburst of the long-first-interval burst. Repetitive thalamic stimulation at critical frequencies of 4–5 Hz were particularly effective in evoking synchronized burst activity.     

Operantly conditioned firing patterns of epileptic neurons in the monkey motor cortex

In an awake rhesus monkey we operantly conditioned the activity of single precentral pyramidal tract cells near a chronic alumina-induced epileptic focus. Units chosen for conditioning fired predominantly in stereotyped high-frequency long-first-interval bursts. Most units also exhibited brief periods of tonic regular firing, typical of normal precentral cells. The proportion of spikes occurring as long-first-interval bursts was determined on the basis of interspike intervals and defined as the epileptic index. Operantly reinforcing transient increases in unit activity with applesauce produced increases in average rates in all nine cells, with no consistent change in the mean epileptic index. Reinforcing transient decreases in firing rate produced a clear decrease in average rate for two cells, no sustained rate changes in six, and an increase in one; the average epileptic index did not change consistently, although transient pauses in cell activity were invariably preceded and followed by long-first-interval bursts. Reinforcing decreases in the epileptic index produced a sustained drop in the number of long-first-interval bursts/min and a concomitant increase in both regular firing and total rate. Reinforcing an increase in epileptic index produced no consistent changes. These results suggest that firing patterns of epileptic cells may be synaptically modified in awake animals. Analysis of reinforced responses suggest that transient increases in synaptic drive generating higher rates may also decrease the proportion of long-first-interval bursts.     

Epileptic neurons during sleep and wakefulness

Forty normal and 17 abnormal neurons were recorded from alumina gel-induced chronic neocortical epileptic foci during transitions between sleep and wakefulness. During sleep, normal neurons did not alter their firing patterns from what would be expected from previous reports, i.e., they behaved as normal neurons, althouth they were studied from epileptic cortex. The abnormal neurons (epileptic neurons) were divided into two groups (as defined from a previous report): group-1 neurons (grossly epileptic during wakefulness) did not change firing patterns significantly except for increased number of spikes per burst, whereas group-2 neurons (mildly epileptic during wakefulness) changed drastically, becoming indistinguishable from group-1 neurons in burst structure. Group-1 neurons differed from group-2 neurons in that their burst frequency did not appear to be highly influenced by surface EEG events, whereas group-2 neurons' burst rhythm appeared to be influenced by such events as spindles and K complexes.     

Progressive, potassium-sensitive epileptiform activity in hippocampal area CA3 of pilocarpine-treated rats with recurrent seizures

Rat hippocampal area CA3 pyramidal cells synchronously discharge in rhythmic bursts of action potentials after acute disinhibition or convulsant treatment in vitro. These burst discharges resemble epileptiform activity, and are of interest because they may shed light on mechanisms underlying limbic seizures. However, few studies have examined CA3 burst discharges in an animal model of epilepsy, because a period of prolonged, severe seizures (status epilepticus) is often used to induce the epileptic state, which can lead to extensive neuronal loss in CA3. Therefore, the severity of pilocarpine-induced status epilepticus was decreased with anticonvulsant treatment to reduce damage. Rhythmic burst discharges were recorded in the majority of slices from these animals, between two weeks and nine months after status epilepticus. The incidence and amplitude of bursts progressively increased with time after status, even after spontaneous behavioral seizures had begun. The results suggest that modifying the pilocarpine models of temporal lobe epilepsy to reduce neuronal loss leads to robust network synchronization in area CA3. The finding that these bursts increase long after spontaneous behavioral seizures begin supports previous arguments that temporal lobe epilepsy exhibits progressive pathophysiology.     

Multiple firings by cat cerebellar Purkinje cells in sleep and waking

Purkinje cells can be identified in extracellular microelectrode recordings by the presence of complex spikes known to be the result of activation by climbing fibers. It has been assumed that effective synaptic contact with each Purkinje cell is made by one and only one set of climbing fiber endings. As a corollary, it has also been assumed that contact by other (secondary) climbing fibers was not sufficiently strong to generate the supramaximal discharge of the complex spike. Among 200 cerebellar neurons, most of which were probably Purkinje cells, we have found two whose simple spikes occurred in bursts of four. One of these, which also discharged as a complex spike and was therefore certainly a Purkinje cell, was studied in detail. The rate of occurrence of bursts, the number of spikes in a burst, and the interval properties of the burst all suggested that the burst was a modified climbing fiber response. The possibility is thus raised that Purkinje cells are rarely excited by secondary climbing fibers.     

Epileptic and normal neurons in monkey neocortex: A quantitative study of degree of operant control

The object of this study was to quantify and compare the degree of control monkeys may assert over firing patterns of normal and epileptic neurons. Thirty-seven epileptic and 70 normal neurons were studied in detail. The operant task was for the monkey to generate specified consecutive interspike intervals (ISI). The monkeys demonstrated far greater accuracy in controlling consecutive ISIs of normal neurons and were only able to control the intervals between bursts from epileptic neurons. The data implies that high frequency bursts of action potentials from epileptic neurons are all-or-nothing events initiated by synaptic mechanisms. In addition, some data are from a monkey with epilepsia partialis continua; in comparison to less active foci, this focus was comprised of a higher percentage of 'pacemaker' epileptic neurons.     

Structurally stable burst and synchronized firing in human amygdala neurons: auto- and cross-correlation analyses in temporal lobe epilepsy

Burst structure and synchronized firing of bursts were studied, in the interictal period, using auto- and cross-correlation analyses in human amygdala neurons in temporal lobe epilepsy patients diagnosed as having a unilateral limbic seizure focus in anterior hippocampus and/or amygdala. Satisfactory single unit recordings were obtained from chronically implanted microelectrodes in 51 amygdala neurons, and auto-correlation analysis identified 27 of 51 neurons where burst firings recurred with regular interspike interval structures (structurally stable burst: S-burst). This structural stability was characteristic only for a short burst, or at the beginning of a series of repetitive firings, involving 2-5 action potentials. In 'non-epileptic' amygdala neurons located contralateral to the seizure focus, the average duration of S-burst was 15 msec and the number of action potentials (spikes) in the S-burst was inversely related to the interspike intervals in the S-burst, suggesting that endogenous membrane characteristics of non-epileptic amygdala neurons determine the patterns of S-burst. In contrast, in the seizure focus amygdala ('epileptic'), the duration of the S-burst was prolonged among epileptic neurons, not because of the occurrence of more action potentials within the S-burst, but because of a prolonged interspike interval within the S-burst. Furthermore, there was no relationship between the interspike interval and the number of action potentials in the S-burst, suggesting that synaptic inputs and/or extracellular environmental factors may affect an intrinsic mechanism for generating stable S-burst in epileptic neurons. Cross-correlation analysis identified synchronized firings in epileptic neurons: when two epileptic neurons both exhibited S-bursts, when either epileptic neuron exhibited S-burst, but never when neither exhibited S-bursts. Conversely, non-epileptic neurons rarely fired synchronously; even though they showed S-bursts. The difference in the pattern of S-bursts between epileptic and non-epileptic amygdala neurons seems to be the degree of firing synchrony. Our results provide, for the first time, direct evidence that human epileptogenic amygdala neurons recorded in vivo have unique burst firing patterns and significant synchronous excitatory interactions, different from a burst pattern found in non-epileptogenic amygdala neurons during the interictal period.     

Double-pulse stimulation dissociates intrathalamic and cortical high-frequency (>400Hz) SEP components in man

Human somatosensory evoked potentials (SEP) contain high-frequency (600 Hz) wavelet bursts possibly reflecting repetitive population spikes in thalamocortical axons and/or postsynaptic responses. To dissociate thalamic and cortical burst components the recovery of intrathalamic SEP (derived from electrodes implanted for movement disorder therapy in seven patients) was compared with scalp SEP in six age-matched Parkinsonian patients and six healthy younger subjects. Upon electric median nerve double-pulse stimulation conditioned scalp bursts were found attenuated in both groups, more for 10ms than 20ms interstimulus intervals; moreover, intraburst frequencies decreased from 690Hz to 590Hz. By contrast, intrathalamic burst amplitudes and frequencies (around 1 kHz) remained largely stable. These dissociations indicate functionally distinct generator mechanisms for scalp and intrathalamic high-frequency SEP bursts.     

Spontaneous EEG spikes in the normal hippocampus. II. Relations to synchronous burst discharges

Spontaneous EEG spikes (SPKs) were recorded from the CA1 region of the dorsal hippocampus in normal rats during awake immobility and slow wave sleep. These SPKs were accompanied by synchronous burst discharges in the pyramidal cell layer. These discharges are called 'population bursts (PBs)' in that they seem to require a population of synchronously bursting neurons. PBs were classified into 2 forms on the basis of their morphologies. One form (mixed burst or MB) consisted of a mixture or superimposition of action potential bursts from a relatively small number of neurons. The other form (ripple) was a series of 3-13 (typically 5-8) high frequency (125-250 Hz) waves, usually waxing and waning. Unit action potentials were superimposed mainly on negative portions of these high frequency waves. The ripple was considered to represent summed activity of highly synchronized complex spike bursts from a relatively large number of pyramidal cells. The similarity in wave structure between these non-pathological ripples and multipeaked, epileptiform (interictal) field potentials recorded from the penicillin-treated hippocampus suggests that they may share some common underlying mechanisms.     

Recognition Impairment Correlated with Short Bisynchronous Epileptic Discharges

The occurrence of transitory cognitive impairment during diffuse subclinical electroencephalographic (EEG) discharges has been widely documented but the role of the parameters influencing the cognitive performance and the involvement of motor or verbal response in the tasks used is still under debate. Fifteen patients suffering from primary generalized epilepsy with frequent bisynchronous EEG epileptic bursts underwent a shape recognition task during EEG monitoring. The test sequence was as follows: memorandum, pause, and multiple choice set. After pressing the response button, the patient was asked to confirm the choice verbally. The following parameters were considered: geometrical complexity of the shape, chronological position of the burst occurring during the single test, and the duration of discharge ranging from 1 to 3 s. Results showed a significant increase in incorrect responses during the test when discharges occurred, with more errors occurring for difficult than for easy shapes. Neither the discharge position nor the duration of the epileptic burst influenced the performance. Diffuse epileptic activity of short duration produced selective effects on the cognitive process regardless of the motor component of the response.     

Low concentrations of penicillin reveal rhythmic, synchronous synaptic potentials in hippocampal slice

Field and intracellular recordings were used to examine the effects of varying concentrations of penicillin on synchronous CA3 activity in guinea pig hippocampal slices. In addition to the high-amplitude bursts, extracellular recordings in the distal apical dendrites (700-1200 microns from the soma) revealed biphasic mini field potentials (MFPs) which were not evident at the soma in 2000 IU/ml. A long-lasting (76 ms) field potential (A potential) with a waveform similar to the positive component of the MFP initiated the bursts. The cellular correlate of the positive component of the MFP and of the A potential appeared to be an EPSP and that of the negative component of the MFP and IPSP. Reductions of penicillin concentration below 2000 IU/ml (3.4 mM) decreased the burst rate and amplitude and increased burst threshold. At concentrations below 250 IU/ml the bursts were blocked and the MFPs increased in amplitude and occurred rhythmically at a mean frequency of 2.6 Hz. At intermediate concentrations the bursts arose from the rhythmic background. This activity more closely resembles that recorded with electroencephalography in human epileptic foci than does the high-dose penicillin preparation and may provide a better model of epileptiform discharge.     

Video/EEG aspects of early-infantile epileptic encephalopathy with suppression-bursts (Ohtahara syndrome).

Early-infantile epileptic encephalopathy (EIEE) with suppression-bursts is a severe neonatal epileptic encephalopathy. The etiology is multiple, with cerebral malformations as the more frequent. We review the clinical and video/EEG aspects of eight infants with EIEE. These infants, aged between 4 and 70 days at the time of video/EEG recordings, were studied in relation to their clinical and video/EEG characteristics, evolution, persistence of suppression-burst pattern and etiology. Seven of the eight infants showed an ictal clinical sign correlated to the burst of the suppression-burst pattern, four of whom died within 11 months of age. The other three are alive. One, now aged 4 years, underwent surgery for hemimegalencephaly and is seizure-free, with good neurological outcome. One, now aged 9 months, was pyridoxine-dependent and she is seizure-free, and with normal neurological evolution under pyridoxine therapy. One, now aged 3 years and 9 months, is seizure-free, but with severe neurological and cognitive impairment. The only child who did not show a clinical ictal correlation of burst is also alive, now aged 3 years and 9 months, with drug-resistant epilepsy, and severe neurological and cognitive deficits. With regard to the etiology, three showed structural abnormalities, two more showed some signs of prenatal origin of neurological disease, and three had metabolic etiology. Our study confirms that EIEE is a severe age-dependent early epileptic encephalopathy. The etiology is mostly malformative. The prognosis is poor regarding motor and cognitive development, seizures, as well as life expectancies. The presence of an ictal burst of the suppression-burst pattern usually correlates with a negative outcome.     

Effects of perfusion pressure on the bursting neurons in the intact or segmented cardiac ganglion of the lobster, Panulirus japonicus

Impulse activity of the bursting neurones in the intact or segmented cardiac ganglion could be recorded in the isolated and freely beating hearts of lobsters. In the segmented ganglion, the four large cells (LCs), the medium cell (MC), and the four small cells (SCs) generated phasic, short tonic, and long tonic bursts of impulses with different rhythms, respectively. The periodic bursts of the LCs, the MC, and the SCs in the intact and the segmented ganglia were perturbed by a change of heart tonus which reflected a change of perfusion pressure in the heart. When correlation between period and duration of the perturbed bursts was plotted, the LCs, the MC, and the SCs in the segments were different from one another in distribution of the plots. Further, the correlation plots for the bursts of the MC in the intact ganglia were compared to those of the LCs, the MC, and the SCs in the segmented ganglia. The burst period and duration of the MC in the intact ganglion were altered markedly by a change of the burst period of the LCs and the burst duration of the SCs, as well as by change of heart tonus.     

Fz theta/alpha bursts: a transient EEG pattern in healthy newborns

We named transient activity recorded from midline frontal area 'Fz theta/alpha bursts' and investigated their characteristics and clinical significance. Polygraphic examinations were carried out on a total of 155 infants from 35 to 46 weeks of postconceptional age. Fz theta/alpha bursts were recorded in 40 (36%) of 111 infants without neurological problems. Especially these bursts were found in 33 (55%) of 60 infants at 38-42 weeks of postconceptional age. They occurred in pre-term as well as in full-term newborns. Three hundred and sixty-two Fz theta/alpha bursts were recorded from 40 infants without neurological problems. Ninety-one percent of them were found in quiet sleep, and others in indeterminate sleep. None of them were recorded in active sleep. Fz theta/alpha bursts did not occur synchronously with frontal or temporal sharp transients. The incidence of Fz theta/alpha bursts in infants with abnormal neurological signs was lower than in control infants (4/44 vs. 37/73; P less than 0.01). The bursts were not detected in EEGs with moderately or more severely depressed background. One hundred and thirty-five infants were followed up for more than 12 months. Fz theta/alpha bursts were recorded in 38 (35%) of 109 infants with normal outcome, and in only 1 (4%) of 26 infants with abnormal outcome. Our results indicated that Fz theta/alpha bursts were of normal EEG components without pathological significance.     

Deterministic and stochastic neuronal contributions to distinct synchronous CA3 network bursts

Computational studies have suggested that stochastic, deterministic, and mixed processes all could be possible determinants of spontaneous, synchronous network bursts. In the present study, using multicellular calcium imaging coupled with fast confocal microscopy, we describe neuronal behavior underlying spontaneous network bursts in developing rat and mouse hippocampal area CA3 networks. Two primary burst types were studied: giant depolarizing potentials (GDPs) and spontaneous interictal bursts recorded in bicuculline, a GABA(A) receptor antagonist. Analysis of the simultaneous behavior of multiple CA3 neurons during synchronous GDPs revealed a repeatable activation order from burst to burst. This was validated using several statistical methods, including high Kendall's coefficient of concordance values for firing order during GDPs, high Pearson's correlations of cellular activation times between burst pairs, and latent class analysis, which revealed a population of 5-6% of CA3 neurons reliably firing very early during GDPs. In contrast, neuronal firing order during interictal bursts appeared homogeneous, with no particular cells repeatedly leading or lagging during these synchronous events. We conclude that GDPs activate via a deterministic mechanism, with distinct, repeatable roles for subsets of neurons during burst generation, while interictal bursts appear to be stochastic events with cells assuming interchangeable roles in the generation of these events.     

Effects of changes in cortical excitability upon the epileptic bursts in generalized penicillin epilepsy of the cat.

Previous studies had suggested that the epileptic bursts of feline generalized penicillin epilepsy represent the response of hyperexcitable cortex to thalamocortical volleys normally evoking spindles. If this were the case, it should be possible to convert the epileptic bursts of generalized penicillin epilepsy into spindles by decreasing the excitability of cortical neurons. In cats exhibiting the EEG signs of feline generalized penicillin epilepsy cortical excitability was decreased by hypoxia, by the topical application to the cortex of KCl (inducing spreading depression), barbiturates, GABA, AMP or noradrenaline. During generalized penicillin epilepsy, hypoxia and KCl-induced spreading depression abolished epileptic bursts which were replaced by spindles. When spindles and epileptic complexes occurring in the same animal were compared, a direct correlation between the frequencies of these two rhythms could be demonstrated, that of the epileptic complexes being about half that of the spindle waves. These observations support the hypothesis that the epileptic bursts of feline generalized penicillin epilepsy are induced by thalamocortical volleys normally involved in spindle genesis. Topical cortical applications of barbiturates, GABA, AMP and noradrenaline reduced or inverted the negative spikes of the spike and wave complexes, while augmenting the negative slow waves, or revealing them clearly in instances in which they had been poorly developed. This effect is interpreted as being due to a selective inactivation of the superficial cortical layers. That topical cortical application of barbiturates, GABA, AMP and noradrenaline was capable of transforming into typical spike and wave complex epileptic bursts, which had not previously conformed to this pattern, indicates that the intracortical electrophysiological events of typical and atypical epileptic bursts in feline generalized penicillin epilepsy are fundamentally the same and reflect an alternation between excitatory and inhibitory sequences.     

High frequency discharges in sensory nerves following ischemia

The effects of ischemia and recovery from ischemia on afferent discharges recorded from dorsal root filaments were assessed in anesthesized cats. During ischemia produced by cross-clamping the lumbar aorta, some of the hindlimb afferents originating in muscle spindles exhibited a sustained high frequency discharge of 120--160 Hz, the so-called "explosion." During recovery from ischemia, nerve discharges appeared in previously inactive dorsal root afferent nerve fibers not of muscle spindle origin. The post-ischemic high frequency discharges appeared in bursts of action potentials at frequencies of 200--500 per second, with 6--32 spikes per burst; the bursts recurred at intervals of 120--600 msec. The nerve fibers exhibiting post-ischemic bursts could not be activated by muscle stretch, muscle tension, palpation, or tactile skin stimulation prior to or during the ischemia. No post-ischemic burst discharges could be detected in analogous experiments with the sural nerve. Intermediate size fibers from normal cutaneous and muscle mechanoreceptors were eliminated as possible origins of the post-ischemia activity. Possible sources include dorsal root ganglion cells or fibers whose sensory endings lie in deep structures such as the walls of the larger blood vessels.     

Daily number and lengths of activity bursts in rabbit jaw muscles

Muscle activity has predominantly been studied for specific motor tasks not necessarily representative of normal daily behaviour. The few studies that have examined daily muscle use have quantified this by duty time, merging all levels of muscle activity. Muscle activity can also be characterized by the number, duration and level of bursts. The purpose of this study was to characterize, for various levels of muscle activity, the daily masseter and digastric actions in the rabbit. Characterization was realized by quantification of duty time (summed length of all bursts as a percentage of total time), number of bursts and distribution of burst lengths. A telemetric device was implanted in the two muscles of six rabbits, ensuring the recording of their jaw muscle activities while they moved freely. The continuously transmitted signals over 1 day were analysed. The results showed that (i) more than 100,000 bursts per day exceeded the 2% level of the maximum muscle activity in both muscles, whereas fewer than 100 bursts per day exceeded the 90% level; and (ii) the digastric muscle exhibited a significantly higher duty time than the masseter (respectively, 23% and 14% for activities exceeding the 2% level), which was mainly caused by the on average longer burst lengths at the lowest levels. The characterization of muscle activity in daily burst number and distribution of burst lengths exceeding various activity levels provides valuable information on motor control and enables further investigation of the adaptive capacity of muscles.     

Ocular microtremor in patients with idiopathic Parkinson's disease

Abnormalities in the oculomotor control mechanism of patients with idiopathic Parkinson's disease are well recognised. In this study the effect of Parkinson's disease on tonic output from oculomotor nuclei was studied by using oculomicrotremor as an index of such output. Oculomicrotremor readings were taken from 22 parkinsonian patients and 22 normal healthy volunteers using the piezoelectric strain gauge technique. There was a slower overall tremor frequency, baseline, and burst frequency in the parkinsonian group. There was also a significant increase in the duration of baseline, with a decrease in the number of bursts a second and a decrease in average duration of bursts in the patient group compared with the normal group. One patient, whose medication was withdrawn, showed a marked decrease in mean frequency and baseline frequency with a decrease in number of bursts and increase in baseline duration compared with readings taken when treatment recommenced. These results suggest that variables measured in oculomicrotremor are altered compared with normal subjects, reflecting altered tonic output from oculomotor nuclei in patients with idiopathic Parkinson's disease.     

Bursts and the efficacy of selective serotonin reuptake inhibitors

We present a new hypothesis for the efficacy of selective serotonin reuptake inhibitors (SSRIs). We propose that SSRIs bring the response to the phasic firing of raphe nucleus cells back to normal, even though the average extracellular 5HT concentration remains low. We discuss burst firing in the raphe nuclei and use mathematical models to argue that tonic firing and phasic firing may be decoupled and may come from different mechanisms. We use a mathematical model for serotonin synthesis, release, and reuptake in terminals to illustrate the responses in terminal regions to bursts in a normal individual and in an individual with low vesicular serotonin. We then show that acute doses of SSRIs do not bring the response to bursts back to normal, but that chronic doses do return the response to normal. These model results need to be confirmed by new electrophysiological and pharmacological experiments.