Investigating the role of fast-spiking interneurons in neocortical dynamics

PhD ThesisFast-spiking interneurons are the largest interneuronal population in neocortex. It is well documented that this population is crucial in many functions of the neocortex by subserving all aspects of neural computation, like gain control, and by enabling dynamic phenomena, like the generation of high frequency oscillations. Fast-spiking interneurons, which represent mainly the parvalbumin-expressing, soma-targeting basket cells, are also implicated in pathological dynamics, like the propagation of seizures or the impaired coordination of activity in schizophrenia. In the present thesis, I investigate the role of fast-spiking interneurons in such dynamic phenomena by using computational and experimental techniques. First, I introduce a neural mass model of the neocortical microcircuit featuring divisive inhibition, a gain control mechanism, which is thought to be delivered mainly by the soma-targeting interneurons. Its dynamics were analysed at the onset of chaos and during the phenomena of entrainment and long-range synchronization. It is demonstrated that the mechanism of divisive inhibition reduces the sensitivity of the network to parameter changes and enhances the stability and exibility of oscillations. Next, in vitro electrophysiology was used to investigate the propagation of activity in the network of electrically coupled fast-spiking interneurons. Experimental evidence suggests that these interneurons and their gap junctions are involved in the propagation of seizures. Using multi-electrode array recordings and optogenetics, I investigated the possibility of such propagating activity under the conditions of raised extracellular K+ concentration which applies during seizures. Propagated activity was recorded and the involvement of gap junctions was con rmed by pharmacological manipulations. Finally, the interaction between two oscillations was investigated. Two oscillations with di erent frequencies were induced in cortical slices by directly activating the pyramidal cells using optogenetics. Their interaction suggested the possibility of a coincidence detection mechanism at the circuit level. Pharmacological manipulations were used to explore the role of the inhibitory interneurons during this phenomenon. The results, however, showed that the observed phenomenon was not a result of synaptic activity. Nevertheless, the experiments provided some insights about the excitability of the tissue through scattered light while using optogenetics. This investigation provides new insights into the role of fast-spiking interneurons in the neocortex. In particular, it is suggested that the gain control mechanism is important for the physiological oscillatory dynamics of the network and that the gap junctions between these interneurons can potentially contribute to the inhibitory restraint during a seizure.Wellcome Trust

Normative brain mapping of interictal intracranial EEG to localize epileptogenic tissue

The identification of abnormal electrographic activity is important in a wide range of neurological disorders, including epilepsy for localising epileptogenic tissue. However, this identification may be challenging during non-seizure (interictal) periods, especially if abnormalities are subtle compared to the repertoire of possible healthy brain dynamics. Here, we investigate if such interictal abnormalities become more salient by quantitatively accounting for the range of healthy brain dynamics in a location-specific manner. To this end, we constructed a normative map of brain dynamics, in terms of relative band power, from interictal intracranial recordings from 234 subjects (21,598 electrode contacts). We then compared interictal recordings from 62 patients with epilepsy to the normative map to identify abnormal regions. We hypothesised that if the most abnormal regions were spared by surgery, then patients would be more likely to experience continued seizures post-operatively. We first confirmed that the spatial variations of band power in the normative map across brain regions were consistent with healthy variations reported in the literature. Second, when accounting for the normative variations, regions which were spared by surgery were more abnormal than those resected only in patients with persistent post-operative seizures (t=-3.6, p = 0.0003), confirming our hypothesis. Third, we found that this effect discriminated patient outcomes (AUC = 0.75 p = 0.0003). Normative mapping is a well-established practice in neuroscientific research. Our study suggests that this approach is feasible to detect interictal abnormalities in intracranial EEG, and of potential clinical value to identify pathological tissue in epilepsy. Finally, we make our normative intracranial map publicly available to facilitate future investigations in epilepsy and beyon

Computational modelling of the long-term effects of brain stimulation on the local and global structural connectivity of epileptic patients.

Computational studies of the influence of different network parameters on the dynamic and topological network effects of brain stimulation can enhance our understanding of different outcomes between individuals. In this study, a brain stimulation session along with the subsequent post-stimulation brain activity is simulated for a period of one day using a network of modified Wilson-Cowan oscillators coupled according to diffusion imaging based structural connectivity. We use this computational model to examine how differences in the inter-region connectivity and the excitability of stimulated regions at the time of stimulation can affect post-stimulation behaviours. Our findings indicate that the initial inter-region connectivity can heavily affect the changes that stimulation induces in the connectivity of the network. Moreover, differences in the excitability of the stimulated regions seem to lead to different post-stimulation connectivity changes across the model network, including on the internal connectivity of non-stimulated regions