The direct link between neuropathology and the symptoms that emerge from damage to the brain is often difficult to discern. In this perspective, the authors of this new publication argue that a satisfying account of neurodegenerative symptoms most naturally emerges from the consideration of the brain from the systems-level.
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Specifically, the authors 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.
Neuromodulatory systems, including the noradrenergic, serotonergic, dopaminergic, and cholinergic systems, track environmental signals, such as risks, rewards, novelty, effort, and social cooperation. These systems provide a foundation for cognitive function in higher organisms; attention, emotion, goal-directed behavior, and decision-making derive from the interaction between the neuromodulatory systems and brain areas, such as the amygdala, frontal cortex, hippocampus, and sensory cortices.
The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation.
Important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell—cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process.
Given their strong influence on behavior and cognition, these systems also play a key role in disease states and are the primary target of many current treatment strategies. The fact that these systems interact with each other either directly or indirectly, however, makes it difficult to understand how a failure in one or more systems can lead to a particular symptom or pathology.
Importantly, the neuromodulatory arousal system is highly heterogeneous, encompassing structures that are common sites of neurodegeneration across Alzheimer's and Parkinson's disease.
The scientists here 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, the authors 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, the authors hope that the authors will devise new and improved diagnostic markers and interventional approaches to aid in the treatment of neurodegenerative disorders.