Time evolution of interhemispheric coupling in a model of focal neocortical epilepsy in mice

Epilepsy is characterized by substantial network rearrangements leading to spontaneous seizures and little is known on how an epileptogenic focus impacts on neural activity in the contralateral hemisphere. Here, we used a model of unilateral epilepsy induced by injection of the synaptic blocker tetanus neurotoxin (TeNT) in the mouse primary visual cortex (V1). Local field potential (LFP) signals were simultaneously recorded from both hemispheres of each mouse in acute phase (peak of toxin action) and chronic condition (completion of TeNT effects). To characterize the neural electrical activities the corresponding LFP signals were analyzed with several methods of time series analysis. For the epileptic mice, the spectral analysis showed that TeNT determines a power redistribution among the different neurophysiological bands in both acute and chronic phases. Using linear and nonlinear interdependence measures in both time and frequency domains, it was found in the acute phase that TeNT injection promotes a reduction of the interhemispheric coupling for high frequencies ($12\text{–}30$ Hz) and small time lag ($<20$ ms), whereas an increase of the coupling is present for low frequencies ($0.5\text{–}4$ Hz) and long time lag ($>40$ ms). On the other hand, the chronic period is characterized by a partial or complete recovery of the interhemispheric interdependence level. Granger causality test and symbolic transfer entropy indicate a greater driving influence of the TeNT-injected side on activity in the contralateral hemisphere in the chronic phase. Lastly, based on experimental observations, we built a computational model of LFPs to investigate the role of the ipsilateral inhibition and exicitatory interhemispheric connections in the dampening of the interhemispheric coupling. The time evolution of the interhemispheric coupling in such a relevant model of epilepsy has been addressed here.

Figure 1

(a) Schematic representation of the protocol used for LFP recordings. We performed the TeNT/RSA injection in one hemisphere (the ipsilateral) and we placed two bipolar electrodes in both V1 of epileptic and vehicle mice. (b),(c),(d),(e) Examples of LFP traces in TeNT mice. LFPs were registered in both acute (b),(c) and chronic phase (d),(e), 10 and 45 days after TeNT injection, respectively. In particular, (b) and (c) display LFP traces obtained from the ipsilateral hemisphere, whereas (d) and (e) are example of LFPs recorded from the contralateral hemisphere.

Figure 2

Ipsilateral spectra of vehicle and epileptic mice. For all panels, the shaded area display the $95\%$ interval of confidence for each experimental group. (a) Comparison between the ipsilateral spectra of vehicle (black) and acute epileptic animals (red). (b) Comparison between the ipsilateral spectra of vehicle (black) and chronic epileptic animals (blue). In both panels, an increase of the $\delta$ band $\left(0.5\text{–}4\right)\mathrm{Hz}$ is followed by a reduction of the $\beta$ band $\left(12\text{–}30\right)\mathrm{Hz}$. Precise values of the power bands are reported in Table 1.

Figure 3

Contralateral spectra of vehicle and epileptic mice. For all panels, the shaded area display the $95\%$ interval of confidence for each experimental group. (a) Comparison between the contralateral spectra of vehicle (black) and acute epileptic animals (red). (b) Comparison between the contralateral spectra of vehicle (black) and chronic epileptic animals (blue). As for the case of the ipsilateral hemisphere, we observed an increase of slow waves $\delta$ band $\left(0.5\text{–}4\right)\mathrm{Hz}$ followed by a dampening of fast activities $\beta$ band $\left(12\text{–}30\right)\mathrm{Hz}$. Precise values of the power bands are reported in Table 2.

Figure 4

Coherence of vehicle and epileptic mice. For all panels, the shaded area display the $95\%$ interval of confidence for each experimental group. (a) Coherence in vehicle (black) and acute epileptic animals (red). Slow waves $\delta$ band $\left(0.5\text{–}4\right)\mathrm{Hz}$ are more coupled than fast activities $\beta$ band $\left(12\text{–}30\right)\mathrm{Hz}$. (b) Coherence in vehicle (black) and chronic epileptic mice (blue). The CHR phase is characterized by a partial return to control condition. Precise values of the coherence measure on frequency bands are reported in Table 3.

Figure 5

Imaginary part of cross spectrum of vehicle and epileptic mice. For all panels, the shaded area display the $95\%$ interval of confidence for each experimental group. (a) Imaginary part of cross spectrum in vehicle (black) and acute epileptic animals (red). (b) Imaginary part of cross spectrum in vehicle (black) and chronic epileptic mice (blue). The results are in keeping with the coherence measure and exclude possible effect of volume conduction in our LFP recordings. Precise values of the imaginary part of cross spectrum on frequency bands are reported in Table 4.

Figure 6

Cross correlation for vehicle and epileptic mice. For all panels, the shaded area display the $95\%$ interval of confidence for each experimental group. (a) Curves of cross correlation for vehicle (black) and acute epileptic animals (red). The AC phase is characterized by a delayed interhemispheric coupling manifested by a shift toward positive values of the maximum of the cross correlation for acute animals. Moreover, a reduction of the cross correlation is observed for small lag $N<2$ with a partial increase for long lag $N>4$. (b) Curves of cross correlation for vehicle (black) and chronic epileptic mice (blue). A partial return to control condition is observed in the CHR phase. Precise values of the cross correlation averaged over different lags are reported in Table 5.

Figure 7

Mutual information in vehicle and epileptic animals. For all panels, the shaded area display the $95\%$ interval of confidence for each experimental group. Mutual information in vehicle (black), acute (red), and chronic epileptic animals (blue). (a) Comparison between vehicle and acute epileptic animals. (b) Comparison between vehicle and chronic epileptic mice. The results are in keeping with the cross correlation, i.e., a delayed interhemispheric coupling in AC phase with decrease (increase) of the interhemispheric coupling for small (long) lag and a partial recovery of the control condition in the CHR phase. Precise values of mutual information averaged over different lags are reported in Table 5.

Figure 8

Mean values and standard errors of the level of $G$-causality ratio $R_G$ for TeNT and vehicle mice. Black histograms refer to vehicles, while red and blue histograms represents TeNT mice for AC and CHR phases, respectively. The green line corresponds to the value of the $R_G$ equal to one, that distinguishes between the contra $>$ ipsi and ipsi $>$ contra coupling directionality. No significant differences were found between TeNT and vehicle mice; however, a slight reduction of the $G$-causality ratio $R_G$ can be observed ($p=0.159$ for the AC phase; $p=0.124$ for the CHR phase).

Figure 9

Mean values and standard errors of the symbolic transfer entropy ratio $R_{\mathrm{STE}}$ measure for TeNT and vehicle mice. Black histograms refer to vehicles, while red and blue histograms represent TeNT mice for AC and CHR phases, respectively. The green line corresponds to the value of the $R_{\mathrm{STE}}$ ratio equal to one, that distinguishes between the contra $>$ ipsi and ipsi $>$ contra coupling directionality. We found a decrease of the value of $R_{\mathrm{STE}}$ ratio in the CHR phase between TeNT and vehicle mice $p<0.05$. The AC phase did not present significant differences of the TeNT mice with respect to vehicle condition.

Figure 10

Cross correlation coefficient ${\rho }^{\mathrm{fast}}$ calculated on LFPs generated by the computational model. (a) ${\rho }^{\mathrm{fast}}$ vs ${\mathrm{\Delta }}_{\mathrm{syn}}^{\mathrm{e}\text{−}\mathrm{ipsi},\mathrm{e}\text{−}\mathrm{contra}}\equiv g_{\mathrm{syn}}^{\mathrm{e}\text{−}\mathrm{contra},\mathrm{e}\text{−}\mathrm{ipsi}}-g_{\mathrm{syn}}^{\mathrm{e}\text{−}\mathrm{ipsi},\mathrm{e}\text{−}\mathrm{contra}}$. A monotonic decrease of the interhemispheric coupling is achieved by increasing the influence of the ipsilateral hemisphere on the contralateral one $\left({\mathrm{\Delta }}_{\mathrm{syn}}^{\mathrm{e}\text{−}\mathrm{ipsi},\mathrm{e}\text{−}\mathrm{contra}}>0\right)$. (b) In this simulation, we decrease both the contra-ipsi and ipsi-contra synaptic coupling keeping a condition of perfect symmetry (i.e., $g_{\mathrm{syn}}^{\mathrm{e}\text{−}\mathrm{contra},\mathrm{e}\text{−}\mathrm{ipsi}}=g_{\mathrm{syn}}^{\mathrm{e}\text{−}\mathrm{ipsi},\mathrm{e}\text{−}\mathrm{contra}}$). Also in this case we found a reduction of the ${\rho }^{\mathrm{fast}}$ coefficient. (c) Reduction of the interhemispheric cross-talk through the dampening of the total ipsilateral inhibitory tone $g_{\mathrm{ipsilateral}}^{\mathrm{inhibitory}}=(g_{\mathrm{syn}}^{\mathrm{e}\text{−}\mathrm{ipsi},\mathrm{i}\text{−}\mathrm{ipsi}},g_{\mathrm{syn}}^{\mathrm{i}\text{−}\mathrm{ipsi},\mathrm{i}\text{−}\mathrm{ipsi}})$.