Hierarchical Interactions Supporting Cognitive Control

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Cognitive control refers to the ability to guide behavior in an intentional and goal-directed manner amidst competing demands. This hallmark of human cognition is supported by the prefrontal (PFC) and posterior parietal cortices (PPC), areas that have undergone extensive evolutionary expansion. The PFC and PPC are central to integrating the present context with plans for the future in order to guide intentional behavior. Accordingly, dysfunction of these regions leads to a wide-variety of deficits including inflexibility, inattention, impulsivity, and disorganization. Such cognitive deficits are evident in numerous psychiatric and neurological disorders such as schizophrenia, attention-deficit hyperactivity disorder, substance addiction, mood disorders, Parkinson’s disease, Huntington’s disease, stroke, and traumatic brain injury. However, impairments in cognitive control are particularly challenging to treat in part due to insufficient mechanistic understanding of the PFC, PPC, and their interactions. To understand and treat disorders of higher-level cognition we need to detail the directed interactions of the PFC and PPC, elucidating functional chains among brain regions and behavior. However, elucidating directed interactions in humans is challenging given limitations of available techniques. Animal models may not translate to the PFC and PPC-mediated abilities that are exceptional in humans. As a result, how the directed interactions of the PFC/PPC mediate higher-level cognition and how they can be manipulated to model dysfunction and move towards rehabilitation remains unclear. This proposal aims to fill this gap using a combination of techniques. Functional magnetic resonance imaging (fMRI) will be coupled with computational techniques to model how directed PFC/PPC interactions support cognitive control. Chief among the interests of this proposal are identification of putative hierarchical organizations with the PFC and PPC that are symbolized by asymmetries of directed influence. Areas at the apex of such hierarchies are predicted to exert widespread influence over other brain areas and cognition. Such apical areas would therefore serve as important biomarkers to monitor for disorder progression, and targets for treatment. Modeled apical roles will be causally validated using interleaved transcranial magnetic stimulation (TMS) and fMRI by examining the impact of focal stimulation on downstream brain areas and behavior. Both continuous theta-burst TMS (cTBS) and intermittent theta-burst TMS (iTBS) will be employed with putative inhibitory and excitatory effects, respectively. It is predicted that cTBS will impair behavior, serving as a model of dysfunction, while iTBS will enhance behavior, serving as a road towards treatment. Aim 1 will estimate hierarchical models in the PFC, validate these models using cTBS, and start the path towards treatment using iTBS. Aim 2 will apply a similar logic to the PPC and contrast the relative efficacy of PFC vs. PPC TMS. Collectively, these aims will provide directed models of PFC/PPC interactions supporting cognitive control, and causal data regarding how targeted manipulation of these networks can hinder or improve control.