Glissandi: transient fast electrocorticographic oscillations of steadily increasing frequency, explained by temporally increasing gap junction conductance

Abstract

Purpose: We describe a form of very fast oscillation (VFO) in patient electrocorticography (ECoG) recordings, that can occur prior to ictal events, in which the frequency increases steadily from ≈ 30-40 to >120 Hz, over a period of seconds. We dub these events "glissandi" and describe a possible model for them.

Methods: Four patients with epilepsy had presurgical evaluations (with ECoG obtained in two of them), and excised tissue was studied in vitro, from three of the patients. Glissandi were seen spontaneously in vitro, associated with ictal events-using acute slices of rat neocortex-and they were simulated using a network model of 15,000 detailed layer V pyramidal neurons, coupled by gap junctions.

Key findings: Glissandi were observed to arise from human temporal neocortex. In vitro, they lasted 0.2-4.1 s, prior to ictal onset. Similar events were observed in the rat in vitro in layer V of frontal neocortex when alkaline solution was pressure-ejected; glissandi persisted when γ-aminobutyric acid A (GABA(A)), GABA(B), and N-methyl-d-aspartate (NMDA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were blocked. Nonalkaline conditions prevented glissando generation. In network simulations it was found that steadily increasing gap junction conductance would lead to the observed steady increase in VFO field frequency. This occurred because increasing gap junction conductance shortened the time required for an action potential to cross from cell to cell.

Significance: The in vitro and modeling data are consistent with the hypothesis that glissandi arise when pyramidal cell gap junction conductances rise over time, possibly as a result of an alkaline fluctuation in brain pH.

Figure 1. Glissando activity in pre-seizure ECoG recording (subdural grid), from a patient with seizures originating in temporal neocortex

The patient is the same as described as patient B in Roopun et al. (2009). A. Example trace showing transition from normal ECoG activity to ictal event (upper). Note the appearance of large slow baseline fluctuations prior to full ictal discharge onset. A glissando discharge is revealed by removal of the slow baseline fluctuation with a higher pass band filter (lower trace). Scale bars 100 μV, 5s, upper trace; 15μV, 0.8s, lower trace. B. Sliding window spectrogram (100 ms window width, offset 5 ms) illustrates the glissando occurring from 1 – 5 s into the lower trace shown in A. Example epochs of ECoG data are shown at the beginning (1) and end (2) of the event. Scale bars 15 μV, 100 ms.

Figure 2. Association of multiple forms of glissando discharges in epileptic human neocortex with ictal behavior

A. Epileptic human temporal cortex slices obtained from patient 2 maintained in normal aCSF. Consecutive 60 s traces illustrate the onset of an ictal event (iii) preceded by slow DC potentials (i, ii) in vitro. Individual glissandi are indicated by numbered arrows. Scale bars 10 s, 1 mV B. Individual glissandi show a variety of temporal features. Expanded trace of each individual event highlighted in ‘B’ and the corresponding spectrogram shown to the right of the trace. Scale bars 0.2 s, 1 mV. C. 60 s trace of interictal sharp wave activity preceding the consecutive traces illustrates in ‘A i–iii’. Scale bars 10 s, 1 mV. Note the increase in the occurrence of glissandi (ii) directly preceding the onset of the ictal discharge (iii).

Figure 3. Experimental model of glissando discharges in normal rat neocortex: implication of pH

A. Rat frontal cortex maintained in normal ACSF. Transient alkalinization was induced by pressure ejection of 30–70 nl ACSF containing 200 mM NaOH (asterisk). This induced a gradual increase in low amplitude spontaneous activity with an increasing peak frequency until onset of ictal event lasting >30s. Scale bars 1 s, 2 mV. B. Comparison of glissando discharges evoked in normal conditions and conditions with the main chemical synaptic components blocked (gabazine, CGP55845, NBQX and D-AP5). The left trace is expanded from ‘A’ and the corresponding spectrogram shown below. The right trace shows response to the same alkalinizing ACSF pulse in the cocktail described above. Note: no ictaform events were seen with the chemical synaptic blockers present; and there is an absence of accompanying slower frequencies as the glissando progresses during blockade of chemical synapses. Scale bars 0.1 mV, 100 ms.

Figure 4. The latency for a spike to cross from axon to axon is predicted to decrease as gap junction conductance increases

Simulations of a single layer V pyramidal neuron, with a standardized prejunctional axonal spike coupled to an axonal compartment, through a conductance set at 1, 2, 3, …, 10 nS. A: the superimposed traces of axonal potential, with the onset of the prejunctional spike at the time marked by the vertical arrow. B: details of the axonal potential. The threshold gap junction conductance for spike transmission was between 2 and 3 nS. With conductances above 3 nS, the latency for axonal spiking decreases, although with “diminishing returns”. The largest decrease occurs between 3 and 4 nS.

Figure 5. Parameter dependence of network frequency in model

A. Phase plot of field oscillation frequency, as a function of M-conductance (g_K(M)) and axonal gap junction conductance, based on simulations of a network of 15,000 model layer V pyramidal neurons coupled by axonal gap junctions. The model predicts that a “glissando” will occur if g_K(M) is large enough, and gap junction conductance rises progressively. Network behavior is more complicated when g_K(M) is small, with beta2 (~25 Hz) oscillations predicted to occur at small gap junction conductances (Roopun et al., 2006), with a rapid ‘switch’ to VFO with small increases in this parameter. B. Field and intracellular behavior, 400 ms epochs, at two values of gap junction conductance and fixed large g_K(M) (scaling factor 2.7, corresponding to points 1 and 2 in Figure 5A). Note the increase in both field frequency and spikelet frequency, as gap junction conductance rises, for large enough M-conductance. Scale bars 100 ms, 50 mV (units for the fields are arbitrary, but the relative amplitudes are correct).

Figure 6. Glissando simulated by steadily rising gap junction conductance, in a network without chemical synapses

The network of Figure 5 was used (g_K(M) scaling factor 2.7, as in Figure 5B); but axonal gap junction conductance rose progressively from 2.0 nS to 12.0 nS over a time interval of 2 seconds. Field amplitude is arbitrary, and field time scale is identical to the scale in the spectrogram below. Note the similarity to Figures 1B and 3B.