Anatomical, Physiological, and Theoretical Basis for the Antiepileptic Effect of Vagus Nerve Stimulation

Summary: The vagus is a mixed nerve carrying somatic and visceral afferents and efferents. The majority of vagal nerve fibers are visceral afferents and have a wide distribution throughout the central nervous system (CNS) either monosynaptically or via the nucleus of the solitary tract. Besides activation of well-defined reflexes, vagal stimulation produces evoked potentials recorded from the cerebral cortex, the hippocampus, the thalamus, and the cerebellum. Activation of vagal afferents can depress monosynaptic reflexes, decrease the activity of spinothalamic neurons, and increase pain threshold. Depending on the stimulation parameters, vagal afferent stimulation in experimental animals can produce electroencephalo-graphic (EEG) synchronization or desynchronization and has been shown to affect sleep states. The desynchronization of the EEG appears to depend on activation of afferent fibers that have conduction velocities of ≤ 15 m/s. Vagal afferent stimulation can also influence the activity of interictal cortical spikes produced by topical strychnine application, and either attenuate or stop seizures produced by pentylenetetrazol, 3-mercaptoproprionic acid, maximal electroshock, and topical alumina gel. The mechanisms for the antiepileptic effects of vagal stimulation are not fully understood but probably relate to effects on the reticular activating system. The vagus provides an easily accessible, peripheral route to modulate CNS function.     

Anatomical,Physiological, and Theoretical Basis for the Antiepileptic Effect of Vagus Nerve Stimulation

Summary: The vagus is a mixed nerve carrying somatic and visceral afferents and efferents. The majority of vagal nerve fibers are visceral afferents and have a wide distribution throughout the central nervous system (CNS) either monosynaptically or via the nucleus of the solitary tract. Besides activation of well-defined reflexes, vagal stimulation produces evoked potentials recorded from the cerebral cortex, the hippocampus, the thalamus, and the cerebellum. Activation of vagal afferents can depress monosynaptic reflexes, decrease the activity of spinothalamic neurons, and increase pain threshold. Depending on the stimulation parameters, vagal afferent stimulation in experimental animals can produce electroencephalo-graphic (EEG) synchronization or desynchronization and has been shown to affect sleep states. The desynchronization of the EEG appears to depend on activation of afferent fibers that have conduction velocities of ≤ 15 m/s. Vagal afferent stimulation can also influence the activity of interictal cortical spikes produced by topical strychnine application, and either attenuate or stop seizures produced by pentylenetetrazol, 3-mercaptoproprionic acid, maximal electroshock, and topical alumina gel. The mechanisms for the antiepileptic effects of vagal stimulation are not fully understood but probably relate to effects on the reticular activating system. The vagus provides an easily accessible, peripheral route to modulate CNS function.     

Influence of sympathetic autonomic arousal on cortical arousal: implications for a therapeutic behavioural intervention in epilepsy

Negative amplitude shifts of cortical potential are related to seizure activity in epilepsy. Regulation of the cortical potential with biofeedback has been successfully used to reduce the frequency of some patients' seizures. Although such behavioural treatments are increasingly popular as an alternative to pharmacotherapy, there has been no investigation of the mechanisms that might bridge the behavioural index of peripheral autonomic activity and the central regulation of arousal. Galvanic Skin Response (GSR) is a sensitive measurement of autonomic arousal and physiological state which reflects one's behaviour. Thus we investigated the effect of peripheral autonomic modulation on cortical arousal with the future intention of using GSR biofeedback as a therapeutic treatment for epilepsy. The cortical negative potential was induced using the paradigm called Contingent Negative Variation (CNV) and measured in different physiological states. A high skin resistance state (reflecting a state of relaxation) and a low skin resistance state (reflecting a state of arousal), were engendered by two opposing procedures of GSR biofeedback. The CNV negative potential, acting as an index of cortical excitation, was significantly greater in amplitude at high levels of skin resistance (relaxed state) than at low levels of skin resistance (aroused state). Our results suggest an inverse relationship between a peripheral measure of autonomic arousal and an index of cortical arousal, the CNV. Moreover, we demonstrate modulation of this arousal-related potential by a behavioural intervention, indicating a potential therapeutic use of arousal biofeedback using GSR in the management of treatment-resistant epilepsy.     

In vitro analog of operant conditioning in aplysia. I. Contingent reinforcement modifies the functional dynamics of an identified neuron.

Previously, an analog of operant conditioning in Aplysia was developed using the rhythmic motor activity in the isolated buccal ganglia. This analog expressed a key feature of operant conditioning, namely a selective enhancement in the occurrence of a designated motor pattern by contingent reinforcement. Different motor patterns generated by the buccal central pattern generator were induced by monotonic stimulation of a peripheral nerve (i.e., n.2,3). Phasic stimulation of the esophageal nerve (E n.) was used as an analog of reinforcement. The present study investigated the neuronal mechanisms associated with the genesis of different motor patterns and their modifications by contingent reinforcement. The genesis of different motor patterns was related to changes in the functional states of the pre-motor neuron B51. During rhythmic activity, B51 dynamically switched between inactive and active states. Bursting activity in B51 was associated with, and predicted, characteristic features of a specific motor pattern (i.e., pattern I). Contingent reinforcement of pattern I modified the dynamical properties of B51 by decreasing its resting conductance and threshold for eliciting plateau potentials and thus increased the occurrences of pattern I-related activity in B51. These modifications were not observed in preparations that received either noncontingent reinforcement (i.e., yoke control) or no reinforcement (i.e., control). These results suggest that a contingent reinforcement paradigm can regulate the dynamics of neuronal activity that is centrally programmed by the intrinsic cellular properties of neurons.     

Left vagus nerve stimulation suppresses experimentally induced pain

OBJECTIVE: To test whether electric stimulation of the vagus nerve has an antinociceptive effect in humans. BACKGROUND: In a variety of animal studies, vagus nerve stimulation was shown to inhibit nociceptive behavior as well as electric responses of spinal nociceptive neurons. In humans, chronic left vagus nerve stimulation is used to treat pharmacologically refractory epilepsy. METHODS: The authors investigated experimental pain in 10 patients with seizures before and twice after implantation of a vagus nerve stimulator by using different controlled stimuli, including noxious heat, tonic pressure, and short impact. Pain was quantified on a visual analogue scale. Twelve nonepileptic age- and gender-matched individuals served as control subjects. RESULTS: Vagus nerve stimulation reduced increasing pain associated with trains of five consecutive stimuli at 1.5-second intervals ("wind-up"; p < 0.001). In a similar manner, pain on tonic pressure was reduced by vagus nerve stimulation (p < 0.03). Pain associated with single-impact stimuli as well as heat pain thresholds were unaltered under vagus nerve stimulation. Thus, vagus nerve stimulation led to pain relief predominantly in experimental procedures in which pain magnitude was amplified by central processing. The antinociceptive effect was independent of the acute on-off cycles of vagus nerve stimulation. CONCLUSIONS: Vagus nerve stimulation is effective in reducing pain in humans. In humans, the antinociceptive effect might rely on central inhibition rather than alterations of peripheral nociceptive mechanisms. These results indicate a promising, potential future role of vagus nerve stimulation in pain treatment.     

Suppression of Interictal Spikes and Seizures by Stimulation of the Vagus Nerve

The effects of electrical stimulation of the vagus nerve, a proposed treatment for patients with intractable epilepsy, on focal interictal spikes produced by penicillin and EEG secondarily generalized seizures induced by pentylenetetrazol were assessed in rats. Interictal spike frequency was reduced by 33% during 20 s of stimulation (p < 0.001) and remained low for ≤3 min. Amplitude of residual spikes was also decreased. Cardiac and respiratory rates were suppressed. Cooling the nerve proximal to the point of stimulation abolished the EEG and respiratory effects. A similar reduction in spike frequency of 39% was obtained by heating the animals' tail (p < 0.01). Vagal stimulation at onset of seizures reduced mean seizure duration from 30.2 ± 15.7 s without stimulation to 5.0 ± 1.8 s (p < 0.01). Only the EEG equivalent of the clonic phase of the seizure was affected. These findings suggest that vagus nerve stimulation can be a potent but nonspecific method to reduce cortical epileptiform activity, probably through an indirect effect mediated by the reticular activating system.     

Modulation of sensory responsiveness of single somatosensory cortical cells during movement and arousal behaviors

This study tested the hypothesis that the transmission of cutaneous sensory information to single somatosensory (SI) cortical neurons may be modulated or gated during movement or “arousal” behaviors. The results showed that movement by itself was associated with a powerful suppression of the sensory input to SI cortical cells from their cutaneous receptive fields. Control experiments showed that this sensory suppression during movement could not be due to either(i) an obscuring of the sensory responses by the large increases in the spontaneous discharge rates of these cells generally found during movement, (ii) an occlusion of the sensory response to the test stimuli by the increased activity in parallel sensory channels caused by repetitive foot contact during locomotion, (iii) distraction of the animal's attention or, (iv) differences in the motivational or arousal states associated with various movement states, because sensory suppression was found in both grooming and treadmill locomotion. It was also found that, in the absence of movement, strong arousal was associated with a slight increase in sensory responsiveness and a decrease in spontaneous discharge rate. The finding that movement rather than arousal or attentiveness caused the most potent modulation of the sensory responsiveness and firing rates of SI cortical cells suggests that this cortical area may be closely integrated with central nervous system motor functions.     

Influence of sympathetic autonomic arousal on tics: Implications for a therapeutic behavioral intervention for Tourette syndrome

ObjectivesThe pharmacological treatment of Tourette syndrome (TS) has improved due to the application of new medications and combinations of medications, coupled to greater phenomenological and neurobiological understanding of the condition. Nevertheless, for many individuals with TS, potentially troublesome tics persist despite optimized drug treatment. Anecdotally, a relationship is frequently described between tic frequency and states of bodily arousal and/or focused attention. The galvanic skin response (GSR) is an accessible and sensitive index of sympathetic nervous activity, reflecting centrally induced changes in peripheral autonomic arousal. Sympathetic nervous arousal, measured using GSR, has been shown to have an inverse relationship with an electroencephalographic index of cortical excitability (slow cortical potential), and GSR arousal biofeedback shows promise as an adjunctive therapy in management of treatment-resistant epilepsy.MethodWe examined how changes in sympathetic arousal, induced using GSR biofeedback, impact on tic frequency in individuals with TS. Two different physiological states (sympathetic arousal and relaxation) were induced using GSR biofeedback in 15 individuals with a diagnosis of TS. During both biofeedback sessions, participants were videotaped to monitor the occurrence of tics.ResultsWe observed significantly lower tics during relaxation biofeedback compared to arousal biofeedback, with tic frequency positively correlating with sympathetic arousal during the arousal session.ConclusionThese findings indicate that the conjunction of focused attention to task and reduced peripheral sympathetic tone inhibits tic expression and suggests a potential therapeutic role of biofeedback relaxation training for tic management in patients with TS.     

Set related and premovement related activity of primate primary somatosensory cortical neurons depends upon stimulus modality and subsequent movement

The activity of primate primary somatosensory (SI) cortical neurons was examined in monkeys trained to perform wrist movements in response to visual or vibratory cues using single-unit, extracellular recording techniques. Neuronal discharge rates associated with peripheral stimulus onset often differed depending upon the modality of the stimulus and whether the animals were instructed to make wrist movements or withhold them. Premovement activity changes that led muscle activation commonly were of different magnitude depending on the modality of the triggering stimulus. This was true both for neurons that responded to vibratory stimuli and those that exhibited no vibratory response. These observations suggest that the activity of SI neurons may be influenced by central modulatory as well as peripheral inputs during task behavior.     

Effects of hypoxia on cardiac vagal efferent activity and on the action of the vagus nerve at the heart in the dog

The discharge of cardiac efferent fibres in the central end of the transected vagus nerve was studied in single or few-fibre preparations in anaesthetized dogs. At the same time standard electrical stimuli were delivered to the cardiac end of the vagus nerve. During progressive asphyxic hypoxia induced by tracheal occlusion cardiac vagal activity increased and vagal action on the heart was potentiated.     

Influence of sympathetic autonomic arousal on tics: Implications for a therapeutic behavioral intervention for Tourette syndrome

Objectives

The pharmacological treatment of Tourette syndrome (TS) has improved due to the application of new medications and combinations of medications, coupled to greater phenomenological and neurobiological understanding of the condition. Nevertheless, for many individuals with TS, potentially troublesome tics persist despite optimized drug treatment. Anecdotally, a relationship is frequently described between tic frequency and states of bodily arousal and/or focused attention. The galvanic skin response (GSR) is an accessible and sensitive index of sympathetic nervous activity, reflecting centrally induced changes in peripheral autonomic arousal. Sympathetic nervous arousal, measured using GSR, has been shown to have an inverse relationship with an electroencephalographic index of cortical excitability (slow cortical potential), and GSR arousal biofeedback shows promise as an adjunctive therapy in management of treatment-resistant epilepsy.

Method

We examined how changes in sympathetic arousal, induced using GSR biofeedback, impact on tic frequency in individuals with TS. Two different physiological states (sympathetic arousal and relaxation) were induced using GSR biofeedback in 15 individuals with a diagnosis of TS. During both biofeedback sessions, participants were videotaped to monitor the occurrence of tics.

Results

We observed significantly lower tics during relaxation biofeedback compared to arousal biofeedback, with tic frequency positively correlating with sympathetic arousal during the arousal session.

Conclusion

These findings indicate that the conjunction of focused attention to task and reduced peripheral sympathetic tone inhibits tic expression and suggests a potential therapeutic role of biofeedback relaxation training for tic management in patients with TS.     

A pseudo-equilibrium thermodynamic model of information processing in nonlinear brain dynamics

Computational models of brain dynamics fall short of performance in speed and robustness of pattern recognition in detecting minute but highly significant pattern fragments. A novel model employs the properties of thermodynamic systems operating far from equilibrium, which is analyzed by linearization near adaptive operating points using root locus techniques. Such systems construct order by dissipating energy. Reinforcement learning of conditioned stimuli creates a landscape of attractors and their basins in each sensory cortex by forming nerve cell assemblies in cortical connectivity. Retrieval of a selected category of stored knowledge is by a phase transition that is induced by a conditioned stimulus, and that leads to pattern self-organization. Near self-regulated criticality the cortical background activity displays aperiodic null spikes at which analytic amplitude nears zero, and which constitute a form of Rayleigh noise. Phase transitions in recognition and recall are initiated at null spikes in the presence of an input signal, owing to the high signal-to-noise ratio that facilitates capture of cortex by an attractor, even by very weak activity that is typically evoked by a conditioned stimulus.     

Analysis of the generators of epileptic activity in early-onset childhood benign occipital lobe epilepsy.

OBJECTIVE: The Panayiotopoulos type of idiopathic occipital epilepsy has peculiar and easily recognizable ictal symptoms, which are associated with complex and variable spike activity over the posterior scalp areas. These characteristics of spikes have prevented localization of the particular brain regions originating clinical manifestations. We studied spike activity in this epilepsy to determine their brain generators. METHODS: The EEG of 5 patients (ages 7-9) was recorded, spikes were submitted to blind decomposition in independent components (ICs) and those to source analysis (sLORETA), revealing the spike generators. Coherence analysis evaluated the dynamics of the components. RESULTS: Several ICs were recovered for posterior spikes in contrast to central spikes which originated a single one. Coherence analysis supports a model with epileptic activity originating near lateral occipital area and spreading to cortical temporal or parietal areas. CONCLUSIONS: Posterior spikes demonstrate rapid spread of epileptic activity to nearby lobes, starting in the lateral occipital area. In contrast, central spikes remain localized in the rolandic fissure. SIGNIFICANCE: Rapid spread of posterior epileptic activity in the Panayitopoulos type of occipital lobe epilepsy is responsible for the variable and poorly localized spike EEG. The lateral occipital cortex is the primary generator of the epileptic activity.     

Hormonal and genetic influences on arousal--sexual and otherwise.

Genetic influences on lordosis, a mammalian social behavior, are amenable for study because of the relative simplicity of both stimuli and response. The neural circuit for lordosis involves a supraspinal loop, which is controlled by an estrogen- and progesterone-dependent signal from the medial hypothalamus and results in heightened sexual motivation. In turn, this involves elevated states of arousal, defined by increased sensory alertness, motor activity and emotional reactivity. Mice in which the gene encoding the alpha form of the estrogen receptor (ERalpha) has been knocked out show that ERalpha is crucial for lordosis behavior. Comparing ERalpha-, ERbeta- and double knockouts reveals that different patterns of sexual behaviors in mice require different patterns of ER activity. Understanding how hormonal and genetic effects on deep motivational and arousal processes contribute to their effects on specific sexual and aggressive behaviors pose significant challenges for mouse functional genomics.     

Activity of suprachiasmatic and hypothalamic neurons during sleep and wakefulness in the rat

Single unit activity was recorded from the suprachiasmatic nucleus (SCN) and preoptic/anterior hypothalamus (POAH) of unrestrained Wistar rats during sleep and wakefulness. Regularly firing cells, which are abundant in in vitro SCN preparations and have been considered the basis of a central neuronal oscillator, were conspicuously absent in this preparation and in other in vivo studies. Most of the 55 cells recorded in the SCN and POAH were characterized by spontaneous firing rates below 12 Hz and with heterogeneous patterns of changes in frequency with arousal states. In vivo neurophysiological studies of the SCN in which the anesthetic agent urethane is used should consider the effect of different levels of arousal, as indicated by the cortical EEG, in evaluating the relationship between sensory stimulation and single unit activity.     

Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation

CNI-1493 is a potent anti-inflammatory agent, which deactivates macrophages and inhibits the synthesis of proinflammatory mediators. The objective of the present study was to identify the role of the central nervous system (CNS) and efferent vagus nerve signaling in CNI-1493-mediated modulation of acute inflammation in the periphery. CNI-1493 was administered either intracerebroventricularly (i.c.v., 0.1-1,000 ng/kg) or intravenously (i.v., 5 mg/kg) in anesthetized rats subjected to a standard model of acute inflammation (subcutaneous (s.c.) injection of carrageenan). I.c.v. CNI-1493 significantly suppressed carrageenan-induced paw edema, even in doses at least 6-logs lower than those required for a systemic effect. Bilateral cervical vagotomy or atropine blockade (1 mg/kg/h) abrogated the anti-inflammatory effects of CNI-1493 (1 microg/kg, i.c.v. or 5 mg/kg, i.v.), indicating that the intact vagus nerve is required for CNI-1493 activity. Recording of the efferent vagus nerve activity revealed an increase in discharge rate starting at 3-4 min after CNI-1493 administration (5 mg/kg, i.v.) and lasting for 10-14 min (control activity=87+/-5.4 impulses/s versus CNI-1493-induced activity= 229+/-6.7 impulses/s). Modulation of efferent vagus nerve activity by electrical stimulation (5 V, 2 ms, 1 Hz) of the transected peripheral vagus nerve for 20 min (10 min before carrageenan administration and 10 min after) also prevented the development of acute inflammation. Local administration of the vagus nerve neurotransmitter, acetylcholine (4 microg/kg, s.c.), or cholinergic agonists into the site of carrageenan-injection also inhibited acute inflammation. These results now identify a previously unrecognized role of efferent vagus nerve activity in mediating the central action of an anti-inflammatory agent.     

Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway

The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the "cholinergic anti-inflammatory pathway," defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (alpha7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to alpha7nAChR knockout mice failed to suppress TNF levels, indicating that the alpha7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and alpha7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage.     

Cardiac arrest/cardiopulmonary resuscitation increases anxiety-like behavior and decreases social interaction.

Advances in medical technology have increased the number of individuals who survive cardiac arrest/cardiopulmonary resuscitation (CPR). This increased incidence of survival has created a population of patients with behavioral and physiologic impairments. We used temperature manipulations to characterize the contribution of central nervous system damage to behavioral deficits elicited by 8 minutes of cardiac arrest/CPR in a mouse model. Once sensorimotor deficits were resolved, we examined anxiety-like behavior with the elevated plus maze and social interaction with an ovariectomized female. We hypothesized that anxiety-like behavior would increase and social interaction would decrease in mice subjected to cardiac arrest/CPR and that these changes would be attributable to central nervous system damage rather than damage to peripheral organs or changes orchestrated by the administration of epinephrine. Mice that were subjected to cardiac arrest/CPR while the peripheral organs, but not the brain, were protected by hypothermia exhibited increased anxiety-like behavior and decreased social interaction, whereas mice with hypothermic brains and peripheral organs during cardiac arrest/CPR did not exhibit behavioral impairments. The present study demonstrates that central nervous system damage from cardiac arrest/CPR results in increased anxiety and decreased social interaction and that these behavioral changes are not attributed to underlying sensorimotor deficits, dynamics of arrest and CPR, or peripheral organ damage.     

Discriminatory Effect of Cyclic Alternating Pattern in Focal Lesional and Benign Rolandic Interictal Spikes During Sleep

Twenty epileptic patients (10 male and 10 female) were polygraphically recorded during nocturnal sleep. Ten subjects, with a wide age range, were affected by focal lesional epilepsy, and 10 were children affected by benign epilepsy with rolandic spikes (BERS). In five cases a bihemispheric expression of the focal lesional bursts emerged occasionally during the night recordings. The behavior of interictal electroencephalographic (EEG) paroxysms were analyzed with respect to the two arousal states of non-rapid-eye-movement (REM) sleep: (a) the cyclic alternating pattern (CAP), expressed by biphasic EEG periodic activities and related to long-lasting fluctuations between greater (phase A) and lesser (phase B) arousal levels; and (b) the non-CAP (NCAP), manifested by EEG stationarities that reflect a sustained relative stability of arousal. The CAP/NCAP modality affected the spiking activity and distribution of the focal lesional EEG paroxysms, which appeared enhanced during CAP and which were mostly collected in phase A. The even more powerful influence of CAP and especially phase A on the secondary bisynchronous bursts suggests a crucial integration among thalamocortical circuits, arousal modulation, and epileptic generalization mechanisms. Conversely, in the BERS recordings no significant differences emerged throughout CAP and NCAP. The intense activity of the rolandic foci induced by sleep as such could be explained on the basis of the greater dependence of these functional cortical EEG abnormalities on the degree of synchronization during sleep.     

The Functional Organization of the Interictal Spike Complex in Benign Rolandic Epilepsy

Summary: Purpose : We studied the functional organization of the interictal epileptic spike complex in patients with benign rolandic epilepsy of childhood (BREC).
Methods : We recorded interictal epileptiform spikes and somatosensory evoked potentials after median nerve stimulation, providing a biologic marker for the location of the central sulcus in 12 patients with BREC. We used multiple dipole modeling to assess the number, the three-dimensional intracerebral location, and the time activity of the underlying neuronal sources.
Results : Although the interictal spike complex could be modeled by a single tangential dipolar source in seven patients (group 1), in the remaining five patients, two sources—a radial and a tangential dipole—were necessary adequately to explain the interictal spikes (group 2). The tangential source was located deeper than the radial source and was characterized by a frontal positivity and a centroparietal negativity with a phase reversal across the central sulcus, suggesting that the interictal spikes originated in the anterior wall of the central sulcus. The radial source showed a single electronegativity over the ipsilateral central region, which would be compatible with involvement of the top of either the pre- or postcentral gyrus. Both sources showed biphasic time patterns with an average latency difference of 30 ms.
Conclusions : Our results indicate that in some patients with typical BREC, the interictal epileptiform spike complex is generated by multiple, simultaneously active neuronal populations within the central region and that epileptiform activity is propagated between these two adjacent cortical areas.