The Development of Inhibitory Networks Regulating Sustained Attention

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Project Summary/Abstract Deficits in sustained attention are common in the general population, and even more common in patients with underlying neuropsychiatric diseases. The diagnosis is complicated by the lack of an objective biomarker, and the most effective treatments are stimulants, which are controlled substances with the potential for abuse or diversion. The focus of this proposal is to explore the use of brain oscillations in the electroencephalogram (EEG) as a translational tool to evaluate the relationship between fast and slow frequencies as an underlying mechanism for attention. This unique EEG signal, known as phase-amplitude coupling (PAC), has the potential to integrate the brain processes involved with focusing attention on a task. The central hypothesis of this proposal is that PAC in the posterior parietal region of the brain in mice coordinates normal attention processes, and this PAC is impaired in mice with attention deficits. Two genetic mouse models of epilepsy have abnormal PAC, one genetic model has the same type of epilepsy but normal PAC, and a fourth genetic model has no epilepsy but abnormal PAC. Testing of these models with simultaneous EEG and behavioral testing, however, has not previously been done. In addition, these models provide mechanistic insight to the disease on a cellular and network level. Using behavioral experiments with simultaneous video-EEG monitoring in mice, the specific aims of this project are to: (1) Demonstrate the relationship between PAC and attention in normal mice; (2) evaluate normal and aberrant PAC throughout development; and (3) determine the relationship between genetic and environmental influences on the development of PAC and sustained attention. This proposal uniquely approaches these aims by merging computational analysis of EEG, behavioral studies, and pharmacological/genetic manipulations over the course of neurodevelopment. In the short term, the work from this proposal will elucidate the developmental mechanisms underlying sustained attention on a network level. In the long term, this work may validate the use of PAC as a translational biomarker for drug discovery in rodents as well as aid in the diagnosis, prognosis, and treatment of patients with deficits in attention. Ultimately, the completion of this research will shed new light on the relationship between brain oscillations, behavior and therapy, and can directly lead to improvements in drug development, neurofeedback, and patient care.