Future Trends in Neuronal Networks—Selective and Combined Targeting of Network Hubs

Abstract Future trends in neuronal network research will involve improvements in our understanding of the operating mechanisms of networks that mediate important functions of the central nervous system (CNS). We also need to improve our rudimentary understanding of how these networks interact with each other under normal conditions and how this changes in CNS disorders. Resting on the shoulders of the ambitious network approach described in this book, we now outline a forward-looking organized framework for investigating and treating CNS disorders. We propose that this network-based approach should lead to the ability to develop selective therapies for CNS disorders by intelligent combinations of stimulation paradigms with selective drug therapies to target critical network hubs. This process should begin with neuroimaging the normal network function in humans and evaluating the changes in these networks in patients with specific CNS disorders. This should ideally be followed by assessment of changes in neuroimaging induced by effective or partially effective stimulation or drug therapies. The identification of appropriate animal models using behavioral and neuroimaging approaches in unanesthetized animals would be a useful next step. This should be followed by evaluation of changes in the model induced by therapies that are clinically effective. Differentiation of the requisite versus ancillary network sites that are activated but not required in the model to produce the behaviors is an important next step, which involves focal inactivation of each identified network site and observing changes in the signs of the disorder in the model. This is a critical distinction, since identification of requisite sites is crucial for selective targeting of future therapies. Neuronal recording from the requisite sites during episodes of the disorder will identify targets for therapy. These data are critical for developing effective and selective future therapies by identifying the abnormal neuronal firing patterns that therapeutic measures can potentially correct. The actions of clinically effective stimulation paradigms and therapeutic doses of drugs on these neuronal firing abnormalities in the model should allow identification of the emergent properties in each requisite network hub that are potential therapeutic targets. The effects on these neuronal firing abnormalities of new potential therapies and repurposed drugs that are effective in the model should also be evaluated. Since current therapies for CNS disorders are, in most cases, only partially effective, combined stimulation and drug therapies should be considered. Many CNS disorders, including Alzheimer's disease, epilepsy, stroke, cognitive disorders, chronic pain, and major depression, all have the potential to be improved by combined drug and stimulation therapies that are intelligently targeted at specific network sites. Examples of potential drug therapies are agents that affect neuronal responsiveness in specific brain sites, including agents that block GABA-mediated inhibition or that increase cholinergic stimulation. Combining these types of drugs with stimulation paradigms that have been shown to selectively affect requisite network hubs for specific CNS disorders should improve therapy. These targeted therapies are expected to correct the specific pathophysiological mechanisms that occur in network nuclei of these CNS disorders and provide improved relief for many serious, painful, and debilitating conditions.