We perform sequences of tasks every day, such as making a cup of coffee. These `abstract' sequences can be distinguished from motor sequences along a variety of dimensions. In contrast to a specific order of muscle activations (e.g. playing piano) found in typical motor sequences, abstract sequences consist of sub- goals that might be achieved by any of a number of actions. Patients with frontal lobe damage have deficits in completing every day task sequences, even when they perform normally on non-sequential tests of executive function. Despite the importance of abstract sequences for understanding human behavior in health and for treating disease, relatively little is known about their neural mechanisms. Systematically answering this question is the defining goal of our research program. Our previous work using a sequential decision making task revealed a novel and necessary dynamic where activity in the rostrolateral prefrontal cortex (RLPFC) increased from the beginning to the end of each abstract sequence (?ramped?) using fMRI and TMS in humans. We hypothesized this ramp represented the resolution of accumulating positional uncertainty through the sequence. However, also inherent to all of these tasks requiring complex decision making is monitoring, and placing in order, multiple variables. The goal of this project is to test the prediction that RLPFC and its associated network support sequence monitoring modulated by uncertainty; and, simultaneously, develop an animal model of this human cognitive process that can be used for future cross-species hypothesis testing. The experiments in Aim 1 with utilize human fMRI in two separate but complimentary experiments to investigate how the dynamics in the rostral frontal previously found to be necessary for sequential task performance are modulated during sequence monitoring and uncertainty.
Aim 2 will utilize nonhuman primate fMRI and the same behavioral paradigm as in humans to establish an animal model of abstract sequence monitoring and directly test functional homology with humans. This study will be the first comparison of performance of a sequential task of this kind across both species.
In Aim 3 we will determine the necessity of the signals revealed in Aims 1 and 2, with direct manipulation of the circuits using TMS in humans and neurotransmitter agonists in monkeys. Together, the proposed experiments will compose a unique, cross-species investigation of the neural basis of abstract sequence performance. Such investigation is necessary to understand the complex yet ubiquitous sequences of tasks that make up daily life, and that patients with frontal lobe damage and Parkinson's Disease often struggle with. This understanding could contribute to novel treatments and therapies for such disorders.
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