A whole new world: embracing the systems-level to understand the indirect impact of pathology in neurodegenerative disorders.

The direct link between neuropathology and the symptoms that emerge from damage to the brain is often difficult to discern. In this perspective, we argue that a satisfying account of neurodegenerative symptoms most naturally emerges from the consideration of the brain from the systems-level. Specifically, we will highlight the role of the neuromodulatory arousal system, which is uniquely positioned to coordinate the brain's ability to flexibly integrate the otherwise segregated structures required to support higher cognitive functions. Importantly, the neuromodulatory arousal system is highly heterogeneous, encompassing structures that are common sites of neurodegeneration across Alzheimer's and Parkinson's disease. We will review studies that implicate the dysfunctional interactions amongst distributed brain regions as a side-effect of pathological involvement of the neuromodulatory arousal system in these neurodegenerative disorders. From this perspective, we will argue that future work in clinical neuroscience should attempt to consider the inherent complexity in the brain and employ analytic techniques that do not solely focus on regional functional impairments, but rather captures the brain as an inherently dynamic, distributed, multi-scale system. Through this lens, we hope that we will devise new and improved diagnostic markers and interventional approaches to aid in the treatment of neurodegenerative disorders.