Cellular-synaptic generation of EEG activity
György Buzsáki1, Roger D. Traub2 and Timothy Pedley3
1Center
for Molecular and Behavioral Neuroscience, Rutgers,
The State University of New Jersey, 197 University Avenue,
Newark, NJ 07102
2
Department of Physiology, Neuroscience Unit
Medical School, University of Birmingham
Birmingham B15 2TT, U.K.
and
3Department
of Neurology
Columbia University, New York, NY 10032
Correspondence:
György Buzsáki
Center for Molecular and Behavioral
Neuroscience, Rutgers University
197 University Avenue
Newark, NJ 07102
Tel: (973) 353-1080 ext. 3131
Fax: (973) 353-1588
E-mail: buzsaki@axon.rutgers.edu
Key words: EEG, cellular activity, synchrony, extracellular currents, intrinsic
oscillations, synaptic activity, current-source density analysis
Supported by NIH (NS34994, MH54671) and the Wellcome Trust.
1
Introduction
To date, three methods can provide high temporal resolution of neuronal interactions at
the network level: electric field recording (EEG), magnetoencephalogram (MEG; 51, 70)
and optical imaging (32, 86). Each of these have their advantages and shortcomings.
MEG is not practical for experimental work on freely moving subjects due to the large
size of magnetic sensors. A major obstacle of the optical imaging method is that its
"view" is confined to surface events. Since most of the network interactions occur in the
depth of the brain at the level of the synapses, a search for alternative methods is
warranted. In addition, research in both MEG and optical imaging fields face the same
fundamental questions as those arose decades ago in connection with scalp-recorded
EEG: the "reverse engineering" problem of signal interpretation (cf. 10, 31, 63).
Membrane currents generated by neurons pass through the extracellular space. These
currents can be measured by electrodes placed outside the neurons. The field potential
(i. e., local mean field), recorded at any given site, reflects the linear sum of numerous
overlapping fields generated by current sources (current from the intracellular space to
the extracellular space) and sinks (current from the extracellular space to the
intracellular space) distributed along multiple cells. This macroscopic state variable can
be recorded with electrodes as a field potential or electroencephalogram (EEG) or with
magnetosensors (SQUIDs) as a magnetoencephalogram (MEG). These local field
patterns, therefore, provide experimental access to the spatio-temporal activity of
afferent, associational and local operations in a given structure. To date, field potential
measurements provide the best experimental and clinical tool for assessing cooperative
neuronal activity at high temporal resolution. However, without a mechanistic
description of the underlying neuronal processes, the scalp or depth EEG simply
remains a gross correlate of brain activity rather than a predictive descriptor of the
specific functional/anatomic events. The essential experimental tools for the exploration
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of EEG generation have yet to come. In this chapter we provide a basic description of
field potential generation in the mammalian archicortex and neocortex and summarize
recent progress and future directions.
A straightforward approach to deconvolve the surface (scalp) recorded event is to
simultaneously study electrical activity on the surface and at the sites of the
extracellular current generation. Electrical recording from deep brain structures using
wire electrodes is one of the oldest methods in neuroscience. Local field potential
measurements or "micro-EEG" (66) combined with recording of neuronal discharges is
the best experimental tool available to study the influence of cytoarchitectural
properties, such as cortical lamination, distribution, size and network connectivity of
neural elements on electrogenesis. However, large number of observation points
combined with decreased distance between the recording sites are required for high
spatial resolution and for making interpretation of the underlying cellular events
possible. Progress in this field is expected to be accelerated by the availability of
micromachined silicon-based probes with numerous recording sites (60). The
information obtained from the depth of the brain will then help interpret the surfacerecorded events. Clearly, such a task requires collaborative work among neuroscience,
silicon nanotechnology, micromachinery, electric engineering, mathematics and
computer science. The stake is high, since interpretation of macrosignals such as those
obtained with EEG, MEG, fast MRI, PET or optical imaging methods will still require
network (submillimeter) level interpretation of the cellular- synapic interactions.
In principle, every event associated with membrane potential changes of individual
cells (neurons and glia) should contribute to the perpetual voltage variability of the
extracellular space. Until recently, synaptic activity has been viewed as the exclusive
source of extracellular current flow or EEG. As will be discussed below, however,
synaptic activity is only one of the several membrane voltage changes that contributes
to the measured field potential. Progress during the past decade revealed numerous
3
sources of relatively slow membrane potential fluctuations, not directly associated with
synaptic activity. Such non-synaptic events may contribute also significantly to the
generation of local field potentials. These include calcium spikes, voltage-dependent
oscillations and spike afterpotentials observed in various neurons.
Sources of extracellular current flow
1. Fast (Na+) action potentials
The largest amplitude intracellular event is the sodium-potassium spike, referred to as
the fast (Na+) action potential intracellularly and as unit activity extracellularly.
Individual fast action potentials are usually not considered to contribute significantly to
the scalp recorded EEG, mainly because of their short duration (<2 msec). An additional
factor is the high-pass frequency filtering (capacitive) property of the extracellular
medium, which attenuates spatial summation of high frequency events. As a result, the
amplitude of extracellular unit activity decreases much more rapidly with distance
between the cell membrane and the recording site than is the case for slower membrane
events. However, when a microelectode is placed close to the cell body layer of cortical
structures the recorded field potentials contain both extracellular units and summed
synaptic potentials. Furthermore, when action potentials from a large number of
neighboring neurons occur within a short time window, e. g., in response to electrical
stimulation of afferents, during epileptic activity or even during synchronous
physiological patterns, these "population spikes" can be recorded with relatively large
size electrodes and in a larger volume (Fig. 1; refs. 4, 9, 25).
2. Synaptic activity
In most physiological situations, synaptic activity is clearly the most significant source
of extracellular current flow or EEG. The notion that synaptic potentials contribute to
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the generation of EEG stems from the recognition that for the summation of
extracellular currents from numerous individual compartments, the events must be
relatively slow (39). The dendrites and soma of a neuron form a tree made of an
electrically conducting interior surrounded by a relatively insulating membrane with
tens of thousands of synapses on it. Each synapse acts as a small battery to drive
current, always in a closed loop. Depending on the chemical nature of the
neurotransmitter released in the synaptic cleft, the postsynaptic membrane is
depolarized (EPSP) or hyperpolarized (IPSP). Excitatory currents, involving Na+ or
Ca2+ ions, flow inwardly at an excitatory synapse (i. e., from the activated postsynaptic
site to the other parts of the cell) and outwardly away from it. Such an outward current
is referred to as a passive return current from the intracellular milieu to the extracellular
space. Inhibitory loop currents, involving Cl- or K+ ions, flow in the opposite direction.
The current flowing across the external resistance of the cortex sums with the loop
currents of neighboring neurons to constitute a local mean field (Fig. 1). Viewed from
the perspective of the extracellular space, membrane areas where current flows into or
out of the cells are termed sinks or sources, respectively. The active or passive nature of
the sinks and sources are ambiguous, unless the location and types of synapses,
involved in the current generation, are identified. Supplementary information may
come from simultaneous intracellular recording from neurons dominantly involved in
the current generation. Alternatively, extracellular recording of the action potentials
and their cross-correlation with the laminar distribution of the field event can provide
the necessary clues for the identification of an sink as opposed to a passive return
(inward) current of an active inhibitory source (outward). Cross-correlation of the
interneuronal discharges with the field potential in question may further decrease the
ambiguity regarding the passive versus active nature of the sink-source dipole (16).
Identification of synaptic currents in the archicortex
5
Figure 1 illustrates the necessary steps in the identification of network mechanisms of
evoked and spontaneous field events. The example is taken from the hippocampus,
because it is a simple, three-layered structure consisting of orderly arranged principal
cells (pyramidal and granule cells) and interneurons. Therefore, the synaptic
interpretation of the extracellular current is much simpler than in multilayered
structures. The termination zones of the excitatory paths and the inhibitory connections
are also well studied in the hippocampus (10, 84). Activation of the excitatory
associational input by indirect, trisynaptic electrical stimulation will depolarize the midapical and basal dendrites of pyramidal cells (shown in blue in Fig. 1). The passive
return current will flow out of the cells at the level of the neuronal bodies and distal
apical dendrites (shown in red in Fig. 1). This change in voltage is reflected by the
characteristic distribution of field potentials in different depths. The extracellular
voltage is negative close to the excitatory synapse and positive in the cell body layer.
The reason for this is the large depolarization of the dendrite and the gradual decrease
of intracellular depolarization towards to soma. This synaptic activity-induced
intracellular voltage difference between the dendrites and soma (a "dipole") will result
in a current flow across the membrane (arrows in Fig. 1F). Simultaneous events in many
neighboring pyramidal cells will linearly summate and produce an extracellular voltage
fluctuation which can be measured with closely-spaced electrodes. After determining
the impedance characteristics of the extracellular space, the voltage change can be
converted into current change (28).
Increased afferent discharge also activates interneurons, some of which terminate on the
cell bodies of the pyramidal cells. The discharging basket cells release GABA and
activate Cl- channels with resulting hyperpolarization of the pyramidal cell somata.
Somatic hyperpolarization, in turn, creates a voltage gradient between the soma and
dendrites (inhibitory dipole). The created intracellular voltage difference is the driving
force of charges across the cell membrane and the consequent spatially distributed
current flow in the surrounding extracellular fluid (Fig. 1). Note that the direction of
6
current flow is the same as in the case when the driving force is apical dendritic
depolarization (active sink). Since the direction of current flow is identical for dendritic
excitation and somatic inhibition, the excitatory and inhibitory currents will sum in the
extracellular space, resulting in large amplitude field potentials.
The contribution of GABAa-mediated inhibitory currents, however, is believed to be
small, because the Cl- equilibrium potential is close to the resting membrane potential.
Thus, the change of the transmembrane voltage is limited. However, in actively spiking
neurons, when the cell body is depolarized, the transmembrane potential, mediated by
GABAa synapses can be large. Another cautionary note is that inhibition may operate
also on the dendrites, causing current flow opposite to the direction of excitatory
currents. For the identification of excitatory and inhibitory components, represented by
the extracellular current flow, a precise knowledge about the anatomical network is
essential. Physiological experiments, including recordings from interneurons and
pyramidal cells as well as differential pharmacological blockage of the excitatory and
inhibitory synapses, can then provide the necessary knowledge for the proper
interpretation of the observed sinks and sources. When all this knowledge is in place,
the extracellular events can be interpreted unambiguously.
Provided that dendritic excitation is strong enough to override somatic inhibition, the
cells may discharge. In the simplest case, a Na+ spike will be generated in the initial
segment of several pyramidal neurons. The large inward current associated with the
spike is reflected by a negative change of the extracellular voltage at the level of the
axon initial segment/cell body accompanied by a smaller amplitude, extracellular
positive deflection out in the dendritic regions for the same reasons as described above
for the EPSPs. However, since the spatial location of this event is opposite to the
afferent excitation of dendrites, the direction of the extracellular current flow will also
be opposite. The contribution of fast spikes to the extracellular mean field is due to the
hypersynchronous discharge of many pyramidal neurons (population spike) as a result
7
of artificial stimulation of an afferent bundle. Interpretation of the extracellular events
after the population spike is not straightforward, however, due to complex feedback
effects of the network and other non-synaptic events (see below).
Once a circuitry, such as shown in Fig. 1, has been "calibrated" by electrically evoked
potentials, one can move to the next step: network level description of the generation of
spontaneous EEG events. The tutorial example is an intermittently occurring, large
amplitude hippocampal sharp wave (SPW). SPWs are present during immobility,
consummatory behaviors and slow wave sleep. It is important that the events to be
analyzed are clearly separable from other waveforms. After extracting the invariable
features of this EEG pattern by averaging or other pattern recognition methods, the
simultaneous voltage measurements are converted into a current-source density map
(Fig. 1D and E). Note that the distribution of the sinks and sources of SPW is strikingly
similar to the potentials elicited by stimulation of the associational/commissural inputs
to the pyramidal cells. Indeed, experimental work revealed that SPW in the
hippocampus arise from the quasi-synchronous discharge of CA3 pyramidal neurons,
the source of associational and commissural afferents to the CA1 region (9, 13).
Temporally overlapping activation of converging activity on single CA1 pyramidal cells
results in a large depolarization of the dendrites, similar to the depolarization of these
cell when the associational pathways are electrically activated. These extra- and
intracellular events therefore provide circumstantial evidence that the same neuronal
machinery is activated during spontaneously occurring SPWs as during electrical
stimulation of the associational afferents.
Identification of synaptic currents in the neocortex
The strategy described above is, in principle, applicable to any other a priori identified
rhythmic or sparse EEG event. Complications arise when several dipoles are involved
8
in the generation of the same EEG patterns, especially when these dipoles are phaseshifted, as is the case in the generation of numerous neocortical patterns (11, 80, 81).
Of the neocortical EEG patterns, two conspicuous low-frequency (<15 Hz) rhythms, the
physiological sleep spindles and spike-and-wave discharges, associated with petit mal
epilepsy, have been studied most extensively (11, 14, 44, 55, 77, 80). It is widely accepted
that the source of rhythm generation for both patterns is the interplay between the
GABAergic reticular nucleus and corticopetal nuclei of the thalamus (11, 14, 79, 80). It is
less clear, however, whether synaptic currents of the thalamocortical afferents can fully
account for these rhythms or whether intracortical circuitries are significantly involved
in their generation (40). Initially, the "recruiting" response, evoked by repetitive
stimulation of intralaminar thalamic nuclei, was thought to be the evoked equivalent of
spontaneous spindle waves and spike-and-wave patterns (19, 24, 41, 59, 67). Subsequent
studies, however, have suggested that spindle waves are more similar to the
"augmenting" response; a pattern evoked by repetitive simulation of sensorimotor
thalamic nuclei (58, 75, 76). From the point of EEG generation, this distinction is
important since recruiting and augmenting responses have different voltage-versusdepth profiles in the cortex. Thus, a critical issue is the identity of synapses and neurons
involved in the generation of these rhythmic patterns. If the thalamocortical synapses
are the major source of the extracellular synaptic current then the major sinks are
expected to correspond to the anatomical targets of the corticopetal thalamic fibers.
Using the approach described above for the hippocampus helped clarify these issues
(Fig. 2; 44). The most striking aspects of the experiment shown is Fig. 2 is the general
similarity of the spontaneous and evoked field events, independent of the initiating
conditions. The spatial position of the major current sinks are sources are similar,
independent which thalamic nucleus is being stimulated or which hemisphere. The
differences are expressed mainly in the latencies of the large sink-source pairs.
Therefore, the similar spatio-temporal distribution of the main sinks and sources
9
suggest that the major current flow derives from the activity of the intracortical
circuitry. The neocortex, in essence, functions as a powerful amplifier during these
oscillatory events. Because the thalamocortical network is in a metastable state during
reduced activities of the brainstem and basal forebrain (55; 77), a weak thalamic or
callosal input is capable of recruiting a large population of intracortical neurons. The
triggering input may even remain undetectable in the field and the spread of activity
reflects primarily the connectivity and excitability of the cortical circuitry rather than
the nature of the initiating input (16, 17).
The CSD map and the associated multiple-site unit analysis also revealed that at least
three dipoles were involved in the generation of the rhythmic field events (Fig. 3; 44).
The most consistent dipole was characterized by a major sink in layer IV (dipole 2).
When a surface-positive field component was present, it was associated with a major
sink in layers V-VI and a source in layers II-III (dipole 1). The third, delayed dipole was
represented by a surface-negative spike component and a corresponding sink in layers
II-III (dipole 3). The relative strength of these respective sinks varied within single
episodes of HVS (Fig. 3). Although the numerous cell types and the complexity of the
intracortical circuitry makes identification of the cellular-synaptic origin of neocortical
EEG less accessible, these recent findings indicate that the use of simultaneous
recording of field and unit activity is a proper method for the revelation of the synapticcellular mechanisms of extracellular current flow in the neocortex.
3. Calcium spikes
Beside the fast Na+ spike, an important non-synaptic event in neurons is a wide Ca2+mediated action potential. These Ca2+ spikes are generated in the dendrites and do not
propagate to the soma (89). Their major role is believed to boost synaptic inputs and
assist plastic modification of synapses (42, 53, 54, 91). Ca2+ spikes represent an inward
dendritic current and are large in amplitude (20 to 50 mV). They can occur
10
synchronously with dendritic EPSPs and for this reason they cannot be simply revealed
or separated from EPSPs with extracellular recordings. Because Ca2+ spikes are
activated by a voltage-dependent mechanism, intradendritic depolarization can trigger
them.
Figure 4 illustrates in vivo recording from a distal dendrite of a hippocampal CA1
pyramidal neuron during theta oscillation (43). As the dendrite is progressively
depolarized by intracellular current injection, the rhythmic synaptic potentials are
superimposed by large amplitude Ca2+ events. Are such Ca2+ spikes triggered by
physiological stimuli? Recent evidence indicates that it may well be the case. Patterned
stimulation of the visual system evoked putative Ca2+ events in layer V pyramidal
neurons of area 17 (37). Furthermore, intradendritic recordings during spontaneous
SPW bursts revealed that the amount of depolarization, brought about by the
converging active presynaptic afferents to CA1 pyramidal cells, is sufficient to trigger
voltage-dependent Ca2+ spikes (42). This new information, of course, indicates the need
for the reinterpretation of the extracellular events illustrated in Fig. 1. Provided that
Ca2+ spikes occur simultaneously in several neurons near the recording electrodes, these
large inward currents can significantly contribute to the field sinks observed in the
dendritic layers.
To date, the quantitative contribution of dendritic Ca2+ spikes to the field EEG has not
been determined. They may be quite important in highly synchronous events, such as
epilepsy, because synchronous Ca2+ spikes in neighboring neurons may be reflected in
the field as large sinks. A complicating factor is that, in contrast to EPSPs, Ca2+ spikes
can actively propagate and therefore large dendritic segments and dendritic locations
distant from the initiating site, may be also involved.
4. Voltage-dependent intrinsic oscillations
11
Experiments similar to that shown in Fig. 4 revealed that when intradendritic
depolarization is sufficiently strong, the resonant property of the membrane may give
way to a self-sustained oscillation of the voltage in the theta frequency range, even in
the absence of network-driven theta activity. Intrinsic, voltage-dependent slow
oscillations and theta frequency resonance have been observed also in somatic
recordings of hippocampal pyramidal cells (49), thalamocortical neurons (63), stellate
cells of the entorhinal cortex (2) and layer V-VI pyramidal cells of the neocortex (73). In
stellate cells, the main driving force of the oscillation is a persistent Na+ current (2),
whereas another depolarizing current, (Ih) in conjunction with the low threshold Ca2+
current (IT), is responsible for the maintenance of the cellular rhythm in thalamic
neurons (6).
Voltage-dependent oscillatory activation of ionic channels has been shown also in the
gamma frequency range. The membrane potential of sparsely spiny inhibitory
interneurons in cortical layer IV can sustain a 40 Hz oscillation by sequential activation
of a persistent sodium current followed by a slowly inactivating K+ conductance (50,
51). Similar intrinsic oscillatory properties have been shown in the intralaminar
thalamocortical and GABAergic neurons of the n. reticularis neurons in vivo (80) and in
the dendrites of hippocampal pyramidal cells (Penttonen et al., 1988).
In most neurons, the voltage-dependent oscillation is subthreshold to trigger action
potentials. However, when action potentials do occur, they are phase-locked to the
depolarizing portion of the oscillatory cycle. Because these intrinsic, oscillatory
membrane fluctuations can occur simultaneously in a number of nearby neurons, their
contribution to the extracellular EEG may be substantial. This is perhaps best illustrated
in the “low- Ca2+, high Mg2+ “ model of epilepsy, when all synaptic activity is
completely blocked and the large rhythmic extracellular field potentials are exclusively
due to the voltage-dependent fluctuation of pyramidal cells, coordinated by ephaptic
(non-synaptic) transmembrane effects (34).
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5. Intrinsic spike afterhyperpolarizations: their contribution to cortical delta waves
In addition to voltage changes, perturbation of the intracellular concentration of one ion
species may trigger influx of other ions by activation of ligand-gated channels. The
large Ca2+ influx, in association with a dendritic Ca2+ spike, is followed by the
suppression of fast spikes and hyperpolarization of the membrane due to activation of
Ca2+-mediated increase of K+ conductance (38, 72). These burst-induced
afterhyperpolarizations (AHP) are frequently larger in amplitude and of longer
duration than synaptic events. A logical progress of thought is to conclude that they
should also be considered as an important source of the extracellularly recorded EEG
potential.
Large amplitude, slow delta waves (1-4 Hz) are among the most frequently studied
neocortical EEG patterns. These irregular, semi-rhythmic or rhythmic patterns are most
frequently observed during stage 4 sleep in the normal brain. The rhythmicity of the
cortical delta waves is explained by the triggering effect of the periodic quasisynchronous thalamocortical inputs (22, 78). The thalamus can maintain a rhythmic
oscillation in the delta range due to the intrinsic properties of thalamocortical neurons
and their network connectivity with the GABAergic reticular nucleus (22, 78). In short,
the "rhythm generator" of delta waves is the thalamus whereas the "voltage generator"
is the neocortex, similar to sleep spindles and spike-and-wave patterns, discussed
above.
Delta waves occur with largest amplitude in deep (layer V) cortical layers and they are
recorded as negative waves on the neocortical surface or the scalp. Depth profile
measurements in the neocortex of the cat (15, 40, 71), rabbit (68) and rat (11, 87) revealed
that surface negative - deep positive delta waves during slow wave sleep correlate with
13
the suppression or cessation of discharges of layer V pyramidal neurons. Intracellularly,
the deep positive waves are correlated with hyperpolarization of pyramidal cells (21).
The depth profile of the slow delta waves and the associated unit activity are
compatible with the hypothesis that the extracellularly recorded delta waves reflect
inhibition of pyramidal cells mediated by GABAergic interneurons (3, 69, 74). GABA
released at the somata of layer V pyramidal cells would open the Cl-channels and
produce an active outward current whose extracellular spatial summation corresponds
to deep positivity. A simultaneously occurring passive inward current at the distal
dendrites would set up extracellular (surface) negativity. Indeed, with their
widespread action GABAergic interneurons may play an important role in affecting
large numbers of pyramidal cells, as discussed earlier. Because subcortical inputs
terminate also on GABAergic interneurons (29, 30), the subcortical afferents may
globally affect the whole neocortical mantle.
A major problem with this `classic` model of delta wave generation is the lack of direct
supportive evidence. An explicit prediction of the GABA-interneuron-pyramidal cell
model of slow wave generation is that GABAergic cells should fire during the deeppositive delta waves. However, experiments directly addressing this issue failed to find
such a correlation in the rat neocortex (11). All putative, physiologically identified,
neocortical interneurons decreased their firing rates during the deep-positive slow
waves. Although the duration of the GABA effect may outlast the action potentials by
tens of msec (23), the effect may be too short for the postulated delta wave-associated
GABA-mediated somatic hyperpolarization. GABAB-receptor mediated IPSPs may be a
possible candidate.
An alternative non-synaptic explanation of the origin of delta wave generation is based
on the summation of long-lasting AHPs of layer V pyramidal neurons (11, 77). During
sleep, pyramidal cells of the neocortex often fire bursts in response to rhythmic thalamic
14
volleys (22, 78), and these bursts, in turn, can trigger Ca2+-mediated K+-conductance
changes. The long-lasting nature of AHP favors the summation of outward somatic
currents of individual pyramidal cells resulting in a local positive field in deep layers.
Such extracellularly summated currents were hypothesized to form the basis of slow
delta EEG waves recorded during sleep (10). The reason why delta waves occur only
during slow wave sleep is because subcortical neurotransmitters, such as basal
forebrain and brainstem cholinergic neurons, locus coeruleus cells, neurons of the raphe
nuclei and hypothalamic histaminergic neurons (1, 5, 11, 33; 77) neurotransmitters are
released mostly in the awake brain and the common property of these neurons is to
reduce the calcium-mediated potassium conductance (20, 34, 52). These actions of
subcortical neurotransmitters at the cellular level therefore result in the blockade of
delta waves. Using whole-cell recordings in vivo, Metherate and Ashe (57) could
differentiate between IPSPs and AHPs in cortical neurons of the intact brain. First, they
showed, by intracellular injection of cesium, that a large part of the delta EEG result
from a K+ current. Second, stimulation of the cholinergic nucleus basalis mimicked the
cesium effect. Third, cesium injection blocked the nucleus basalis stimulation effect.
These findings directly support the suggestion that delta wave-concurrent
hyperpolarizations result from the calcium-activated K+ current, rather than by GABAmediated IPSPs. Overall, these examples illustrate that knowledge of the intrinsic
properties of the neurons is as important for the identification of sources of the
extracellular ion flow as knowledge of synaptic potentials and anatomical circuitry.
6. Other non-synaptic neuronal effects
Synchronous discharge of large neuronal populations are often associated with large
amplitude extracellular potentials (mV to tens of mV) and steep voltage versus depth
gradients. These large field currents, in turn, can influence the activity of nearby
neurons by changing their transmembrane voltage (ephaptic effects). Measurement of
transmembrane potential changes (as opposed to potentials relative to a distant ground)
15
indicated that such extracellular current loops can depolarize neurons to spike
threshold under certain conditions (34, 83). Computer simulations of multiple neurons,
embedded in a conductive medium, show that such a mechanism is plausible with
observed estimates of extracellular resistivity (85). Importantly, the voltage gradient
across pyramidal cell bodies during physiological SPWs and especially during epileptic
or interictal spikes is larger than experimentally induced voltage gradients that are
known to affect cellular excitability. Although direct experimental support is not
available yet, one might expect that ephaptic effects could recruit neurons to fire that
are otherwise not or not sufficiently activated by synaptic inputs alone (9, 34).
7. Neuron-glia communication
The glial syncytium (astrocytes) is connected through gap junctions, which allow the
direct spread of current and the diffusion or transport of small molecules. Although the
role of concerted changes in membrane potentials of glia in the generation of
extracellular current under physiological conditions has not been studied extensively,
recent work on neuron-glia interactions indicate that the glial syncytium my contribute
to the slow field patterns in an important way. Intercellular coupling through gap
junctions is required for both propagating Ca2+ waves and spreading depression (62).
The traveling Ca2+ waves, in turn, can trigger calcium influx into neurons (61, 62). The
glia-neuron dialogue in vivo may be responsible for postictal depression (8, 26, 35, 36,
48, 82). The increased [K+]o, resulting from intensive neuronal activity during epileptic
afterdischarge, may trigger propagating waves in the astrocytic network reflected by
the slowly spreading sustained potentials. In turn, astrocytes at the front of the
propagating depolarization wave release more K+ (47, 56), resulting in a large
depolarization of neurons. The ensuing depolarization block of spike generation
contributes to the termination of the afterdischarge and is regarded as the cause of the
consequent "postictal depression" of the EEG (8, 82).
16
DC currents or ultraslow change of the extracellular voltage cannot be recorded with
conventional EEG devices with high pass-filtered inputs. Nevertheless, the relatively
quick changes in the DC level, such as epilepsy associated spreading depression (8),
could be identified mistakenly as slow delta or faster “waves“, due to the differential
effect of the high pass-filters.
Neuron-glia communication may contribute also to physiological EEG patterns. Sensory
evoked responses in scalp recordings with DC amplifiers and non-polarizing electrodes
often contain reliable and relatively long-lasting DC changes, usually referred to as
Bereitschaftpotenzial (46) or contingent negative variation (88). It remains to be revealed
whether and to what extent glial depolarization contributes to these evoked patterns.
Ultrafast cortical rhythms
SPW-associated depolarization of hippocampal CA1 neurons sets into motion a shortlived, dynamic interaction between interneurons and pyramidal cells. The product of
this interaction is an oscillatory field potential (ripple) within stratum pyramidale and a
phase-locked discharge of the CA1 network at 200 Hz in the rat (12). SPW-related
ripples are also present in higher mammals, including humans (7). The specific synaptic
currents, mediating the high-frequency oscillation, are largely mediated by rhythmic,
synchronized IPSPs near the soma of CA1 neurons. The mechanism by which highly
coherent discharge of pyramidal cells is brought about over the entire dorsal
hippocampus during the ripple is not understood (18). Three different hypotheses have
been advanced for the explanation of the spatial coherence of fast ripples. The first
assumes that the CA3 output produces a voltage-dependent fast discharge in the
interneurons and that synchronization of the interneurons is mediated by gap junctions
(45). A second explanation is based on the reciprocal connections between the
interneuronal and pyramidal cell populations. Fast oscillatory discharges in
interneurons would, again, be brought about by the ramp-like depolarizing CA3
17
output. Chance discharge of just a few CA1 pyramidal cells within ~1 ms is
hypothesized to reset ongoing oscillatory spiking in the target interneurons and
generate a short-lived coherent discharge (90). According to the third hypothesis, zerotime lag synchronization of pyramidal neurons is brought about by assumed gap
junctions between their axons (25).
Fast field oscillations (300-500 Hz) are also present in the neocortex, in particular in
association with sleep spindles and spike-and-wave patterns (Fig. 5; 44). The maximum
amplitude of the field oscillation occurs in layer V and the ripple waves reverse in
phase in the upper part of layer V. The discharge of pyramidal cells are phase-locked to
the ripples. The physiological significance of the fast “ripples“ has yet to be clarified. It
may be suggested that the fast oscillation of interneurons during a strong network drive
provides a dissipative mechanism to decelerate and limit population synchrony of
pyramidal cells and to prevent the "all-or-none" discharge of the activated pyramidal
cells by protracting the recruitment process and limiting the number of participating
neurons.
Because conventional EEG devices are limited in their frequency response, these fast
events are often impossible to discern reliably from human scalp recordings (see
ENA98). In addition, volume conduction of these fast events is quite limited due to the
low-pass filtering properties of lipid membranes, as discussed above. Nevertheless,
their detection may be of clinical importance because fast oscillatory events may herald
the spread and/or termination of epileptic activity (8, 27).
18
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Figure legends:
Fig. 1. Generation of extracellular field potentials. A. Simultaneously recorded evoked
field responses in the CA1-dentate gyrus axis of the rat hippocampus in response to
stimulation of the entorhinal input (stim). * Indicate population discharge of the
monosynaptically activated granule cells. Their discharge, in turn, activates CA3
pyramidal cells (no shown) whose associational collaterals will depolarize CA1
pyramidal cells and interneurons. This trisynaptic actication of CA1 pyramidal cells
is reflected as a late field event (vertical dashed line). B. Spontaneously occurring
sharp wave recorded during immobility. The traces are averages of 40 individual
events. C. A frontal section of the hippocampus indicating the contact sites of the
recording silicon probe (small squares). o, stratum oriens; p, pyramidal layer; r,
stratum radiatum; hf, hippocampal fissure; g, granule cell layer; h, hilar region. D
and E. Current-source density (CSD) maps of evoked field responses to perforant
path stimulatin (D) and of the spontaneous SPW pattern. Sinks (s, inward currents)
and sources (so, outward currents) are indicated by cold and warm colors,
respectively. iso, zero current flow. The time scale in A and D, B and E are the same.
F. Interpretation of the current sinks and sources on the basis of anatomical
connectivity. Recorded layers are shown on the right of the pyramidal cell (above)
and granule cell (below). Putative active currents are indicated on the right, passive
return (re) currents on the left of the pyramidal neuron. Note identical current sinksource distribution of the evoked and spontaneous events in the CA1 region
(compare D and E). Sinks in stratum radiatum and oriens reflect excitation of the
apical and basal dendrites of CA1 pyramidal cells, respectively by the associational
(Schaffer) collaterals of the CA3 region. The large source in the pyramidal layer is a
combination of active outward current due to hyperpolarization of the soma by the
simultaneously activated basket cells (not shown) and passive return currents from
the sinks generated in the basal and apical dendrites. The source in the distal apical
dendrites (re) is assumed to represent a passive return current due to the active sink
in the middle of stratum radiatum. In addition to EPSPs, dendritic Ca2+ spikes may
also contribute to the sinks in strata oriens and radiatum (see Fig. 4). (Reprinted
with permission from Buzsaki and Traub, 1996).
Fig. 2. Voltage versus depth profiles superimposed onto CSD maps of high voltage
spike-and-wave patterns (HVS) and thalamic evoked responses under Ketamine
anesthesia and in the awake rat. The 16-site recording probe was located in the
31
somatosensory area. The approximate position of the different layers are indicated
left of the CSD maps. Note the overall similarity of the major sinks and sources of
the averaged HVS and evoked responses. Major sinks are numbered (1 to 4 in
HVS). Vertical dashed lines help identify the earliest sinks/sources. VPLi, primary
response; VL and VPLc, augmenting responses 200 msec after the primary response
(not shown). In VL, weak early sinks can be indentified in layer VI and layer V,
followed by major sinks at similar locations as in the other CSD maps. Stimulating
sites are shown in the histological section. The tip of the ipsilateral VPL (VPLi) was
two sections (120 µm) posterior to the VL site. An electrolytic lesion was produced
at the contralateral VPL (VPLc) stimulating site. Voltage and current calibrations
are identical in all panels. iso, baseline isopotential. (Reprinted with permission
from Kandel and Buzsaki, 1997).
Fig.3. Variations in the voltage-versus-depth profiles and CSD maps of HVSs in the
awake rat. A. CSD map of a single HVS episode (3 sec sweep). The superimposed
field traces were recorded from layers II, IV and VI, respectively. Note the
consistent presence of the layer IV sink but large variability of sinks and sources at
other depth locations. B. Selected averages of HVS traces and corresponding CSD
maps. All: averages of 200 successive events. ppHVS, average HVS with prominent
surface-positive spike component; pHVS, average HVS with less pronounced
surface-positive component; nnHVS, average HVS with dominant surface-negative
spike component and large sink in layers II-III; nHVS, average HVS with negative
spike component in layer IV; DS, average HVS with double spike components at
short interspike intervals. Note a prominent delayed sink in layers II-III in ppHVS
and nnHVS. Averages from 40 to 50 traces selected from a 5-min recording session.
Representative single events of the averages are indicated by vertical lines in A. iso,
baseline isopotential. (Reprinted with permission from Kandel and Buzsaki, 1997).
Fig. 4. Voltage-dependence of theta-frequency oscillation in a hippocampal pyramidal
cell dendrite. Continuous recording of extracellular (extra) and intradendritic (intra)
activity in a CA1 pyramidal cell. Holding potential was manually shifted to
progressively more depolarized levels by intradendritic current injection (0 to 0.8
nA). The marked epochs (horizontal bars) are shown at faster speed in the bottom
records. The recording electrode also contained QX-314 to block Na+ spikes (20
mM). Note large increase of intradendritic theta oscillation amplitude upon
depolarization. The relationship of the putative high threshold calcium spikes to the
32
phase of extracellular theta in the CA1 pyramidal layer is indicated by dotted lines.
(Reprinted with permission from Kamondi et al., 1998).
Fig. 5. HVS-induced fast field oscillation (400-500 Hz ripple). A. Averaged HVS and
asssociated unit firing histograms from layers IV to VI. B. Wide-band (a and a'; 1
Hz-5 kHz), filtered field (b and b'; 200-800 Hz) and filtered unit (c and c'; 0.5-5 kHz)
traces from layer IV and layer V. C. Averaged fast waves and corresponding unit
histograms. The field ripples are filtered (200-800 Hz) derivatives of the wide-band
signals recorded from 16 sites. Note sudden phase-reversal of the oscillatory waves
(arrow) and phase locked discharges of units in all cortical layers (dashed line).
(Reprinted with permission from Kandel and Buzsaki, 1997).
33
Summary
Field potential measurements provide an excellent tool for the exploration of network
activity in the intact brain. The various rhythms and intermittent EEG potentials can be
regarded as time reference points to relate neuronal discharges of single cells. These
field potentials (local or global EEG) emerge as a result of synchronous (i. e.,
simultaneous) changes of the membrane potential of neighboring neurons.
Synchronous membrane potential changes can be brought about by synaptic activity
(EPSPs and IPSPs), Ca spikes or emerge as a result of intrinsic neuronal patterns
(oscillations, burst-induced afterpotentials). The isolated cortical tissue maintains burst
discharges of pyramidal cells followed by long-lasting afterhyperpolarization. The
synchronous hyperpolarizations in neighboring pyramidal cells can be measured as
slow waves in the extracellular space ("synchronization"). In addition, these subcortical
neurotransmitters induce a gamma frequency oscillation ("desynchronized" pattern) by
activating networks of inhibitory interneurons.
34