Epilepsy as a Network Disorder (2): What can we learn from other network disorders such as dementia and schizophrenia, and what are the implications for translational research?

Abstract

There is common agreement that many disorders of the central nervous system are 'complex', that is, there are many potential factors that influence the development of the disease, underlying mechanisms, and successful treatment. Most of these disorders, unfortunately, have no cure at the present time, and therapeutic strategies often have debilitating side effects. Interestingly, some of the 'complexities' of one disorder are found in another, and the similarities are often network defects. It seems likely that more discussions of these commonalities could advance our understanding and, therefore, have clinical implications or translational impact. With this in mind, the Fourth International Halifax Epilepsy Conference and Retreat was held as described in the prior paper, and this companion paper focuses on the second half of the meeting. Leaders in various subspecialties of epilepsy research were asked to address aging and dementia or psychosis in people with epilepsy (PWE). Commonalities between autism, depression, aging and dementia, psychosis, and epilepsy were the focus of the presentations and discussion. In the last session, additional experts commented on new conceptualization of translational epilepsy research efforts. Here, the presentations are reviewed, and salient points are highlighted.

Keywords: Alzheimer's disease; Circuit; Neurology; Neuroscience; Preclinical; Psychosis; Seizure; Systems.

Figure 1

DA neuron activity states are regulated by distinct afferent circuits. In the baseline condition, approximately half of the DA neurons are firing spontaneously; the rest are held in a hyperpolarized, inactive state by strong inhibitory input from the ventral pallidum. The ventral pallidum in turn is controlled by a circuit originating in the ventral hippocampus. In contrast, the burst firing pattern is controlled by a glutamatergic input activated by salient stimuli. Therefore, when an animal is exposed to a behaviorally salient event, DA neurons are driven to fire in a rapid, phasic burst firing state. However, to burst fire, a DA neuron must be spontaneously active. Whether it is active or not is controlled by the hippocampus-ventral striatum-ventral pallidum circuit. Therefore, in environmental contexts where rapid responses are required, the hippocampus drives the DA system into a highly responsive state via activation of silent neurons. However, if the hippocampus is pathologically hyperactive, the DA system is rendered hyper-responsive to stimuli, leading to overactivation by stimuli and overinterpretation of events, which is proposed to be the basis for psychosis.

Figure 2

Neural Coordination. Example illustrating the need for coordination in a system where information is distributed across multiple (here only 4) potentially independent elements. Although each cube only reports a particular subset of information, the message “EXPERIENCE” is only encoded when the synchronous display of all four cube faces is accomplished. Here analogous to neural coordination, coordinating mechanisms are crucial for keeping the four cubes synchronous in space and time.