Neuroregeneration Institute, McLean Hospital / Harvard Medical School, Belmont, MA 02478, USA.
Neuroregeneration Institute, McLean Hospital / Harvard Medical School, Belmont, MA 02478, USA; Department of Neurology and Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
Prog Neurobiol. 2024 Nov;242:102673. doi: 10.1016/j.pneurobio.2024.102673. Epub 2024 Oct 9.
Synaptic networks determine brain function. Highly complex interconnected brain synaptic networks provide output even under fluctuating or pathological conditions. Relevant to the treatment of brain disorders, understanding the limitations of such functional networks becomes paramount. Here we use the example of Parkinson's Disease (PD) as a system disorder, with PD symptomatology emerging only when the functional reserves of neurons, and their interconnected networks, are unable to facilitate effective compensatory mechanisms. We have denoted this the "threshold theory" to account for how PD symptoms develop in sequence. In this perspective, threshold functions are delineated in a quantitative, synaptic, and cellular network context. This provides a framework to discuss the development of specific symptoms. PD includes dysfunction and degeneration in many organ systems and both peripheral and central nervous system involvement. The threshold theory accounts for and explains the reasons why parallel gradually emerging pathologies in brain and peripheral systems generate specific symptoms only when functional thresholds are crossed, like tipping points. New and mounting evidence demonstrate that PD and related neurodegenerative diseases are multisystem disorders, which transcends the traditional brain-centric paradigm. We believe that representation of threshold functions will be helpful to develop new medicines and interventions that are specific for both pre- and post-symptomatic periods of neurodegenerative disorders.
突触网络决定大脑功能。高度复杂的相互连接的大脑突触网络即使在波动或病理条件下也能提供输出。与大脑疾病的治疗相关，了解这些功能网络的局限性变得至关重要。在这里，我们以帕金森病 (PD) 为例，将其视为一种系统紊乱，只有当神经元及其相互连接的网络的功能储备无法促进有效的代偿机制时，才会出现 PD 症状。我们将其称为“阈值理论”，以解释 PD 症状如何按顺序发展。在这种观点中，阈值功能在定量、突触和细胞网络背景下进行了描述。这为讨论特定症状的发展提供了一个框架。PD 包括许多器官系统的功能障碍和退化，以及外周和中枢神经系统的参与。阈值理论解释了为什么大脑和外周系统中平行逐渐出现的病理学只有在功能阈值被跨越时，才会产生特定的症状，就像临界点一样。越来越多的新证据表明，PD 和相关的神经退行性疾病是多系统疾病，这超越了传统的以大脑为中心的范式。我们相信，阈值函数的表示将有助于开发针对神经退行性疾病的前症状和后症状期的特异性新药和干预措施。
