On the Yin and Yang of spike and waves

The spike-and-wave discharge (SWD) is the archetypical EEG feature of various types of epilepsy and trains of SWDs are typical for the absence epilepsies. The two key elements of the discharge, the spike and the wave, occur as an ensemble – the spike is preceded and followed by the wave and they are intertwined, one does not exist without the other, they are Yin and Yang. The neurophysiological underpinning of spike-wave discharges is caused by collective firing of numerous neurons phase-locked to the spike as recorded in the field potential, followed by neuronal inhibitions, and silence of the cells. This observation is classical and has been established in numerous studies, in various brain systems, in vitro and in vivo and in various species, such as cats, monkeys and rodents, and in various seizure and epilepsy models, including GAERS and WAG/Rij rats, two well-described and validated genetic rat models of generalized genetic absence epilepsy. The Yin and Yang in the form of massive synchronized firing (excitation) followed by silence (inhibition) of cortical and thalamic neurons phase-locked to the field potentials has also been demonstrated in female rats of the WAG/Rij strain, genetically endowed with age-dependent spontaneous occurring spike-wave discharges (Inoue et al. 1993). In this issue of The Journal of Physiology, Terlau et al. (2020) (and many references therein) confirmed the Yin and Yang of SWDs in the GAERS model as recorded with silicon probes by showing increased multi-unit activity during the spike of the spike-wave complex at the site of origin, the facial area of the somatosensory cortex (S1), followed by neuronal silence. Moreover, they identified both cortical layer specific sinks during the spike and sources during the wave, illustrating that interlaminar processes in all cortical layers play a role in the occurrence of SWDs. However, Yin was experimentally separated from Yang: pharmacological inactivation of the central medial nucleus (CM) of the thalamus, known to be involved in attention and arousal processes and being part of the classical ascending reticular activating system, diminished the amplitude of the spike in the motor cortex (M2) field recording, while the amplitude and the frequency of the wave remained unaltered. Importantly, the waves in M2 remained synchronized with the SWDs in S1. Control inactivation of the ventral basal part of the primary SWD generating circuit diminished the amplitudes of the spike and the wave equally in both S1 and M2. The detailed and precise analyses of the sources and sinks showed nicely that the diminution of the amplitude of the spike in the motor cortex is associated with the disappearance of the associated sinks and a reduction in phase related multiple unit activity. This results as described by Terlau et al. (2020) are important and interesting for several reasons. The fact that the wave remained untouched and that the spike vanished shows an obvious dissociation between the spike and the wave, and this has never been so clearly experimentally demonstrated. A second reason is that, as was proposed by the authors, the circuit by which the spike is transferred from one site in the cortex to another might be different from that for the wave. The route that the spike takes goes via the CM, while the wave does not use the CM. This result fits with the theory of Guillery and Sherman (2002): these authors proposed that much of the communication between different parts of the cortex goes via higher order thalamic nuclei. The present results show that this is indeed the case for the spike, while the wave seems to use a cortico-cortical pathway. A direct measure of the changes in functional cortical connectivity between the somatosensory and motor cortex before and after the inhibition of the CM at specifically higher (beta and gamma) frequencies supports a selective role for the (mainly) higher frequencies in the CM governing cortico-cortical communication. This finding of a separation between the < 15 and > 15 Hz oscillations in the usage of pathways is a clear extension of Sherman and Guillery’s theory and might have important consequences beyond concepts of how seizures generalize. The results are also interesting because Terlau et al.’s analyses of sources and sinks described the temporal order of neural generators responsible for the occurrence of spike and waves, and their results showed that an ordered temporal sequence of interlaminar within column processes is occurring and is necessary for the expression of spikes and waves in the cortex, few reports of which have been seen in the recent literature. The authors propose a mechanism for SWD occurrence in which cortico-cortical oscillatory 5–9 Hz waves provide a time window for the integration of thalamo-cortical inputs and feedback responses from other layers. The results are also important in showing that the CM is not the thalamic initiation site for the occurrence of SWDs, as was previously supposed based on the outcomes of the classical electrical stimulation studies in the last century. Pharmacological inhibition of the CM did not stop the occurrence of SWDs; this was most prominently observed for more lateral thalamic inhibition, which reduced the amplitude of both spikes and waves equally. Moreover, inactivation of the CM did not have an effect on the morphology of the SWDs, recorded at S1. This study raises many questions and comments. It challenges the idea that spike and waves travel and spread together over the cortex, as is suggested by the visual picture of a multichannel EEG record of a SWD and the very short, less than 7 ms delays, in the appearance of the spike at the motor cortex after being seen in its focal region (Meeren et al. 2002). A combined cortical mapping and CM inactivation study might answer this question. It is worth noting that the decoupling of the spike and the wave described by Terlau et al. is not uniquely induced by inactivation of the CM. It is also illustrated by the authors in their Fig. 1, which shows the presence of slow waves only in layer 6 of the M2 in intact GAERS (Fig. 1, Terlau et al. 2020). Another example comes from topographical