Neuroanatomical characteristics of the human pre-Bötzinger complex and its involvement in neurodegenerative brainstem diseases.

Abstract

The pre-Bötzinger complex has been identified as an essential part of the medullary respiratory network in mammals. Although well described in experimental animals, its localization in the human brain has remained elusive. Using serially sectioned brainstems from 19 normal individuals and patients suffering from neurodegenerative diseases (multiple system atrophy, n = 10; spinocerebellar ataxia type 3, n = 8), we have identified a circumscribed area of the ventrolateral medulla that represents the human homologue of the pre-Bötzinger complex and have mapped its longitudinal and horizontal extents. The presumed human pre-Bötzinger complex is characterized by an aggregation of loosely scattered, small and lipofuscin-rich neurons, which contain neurokinin 1 receptor as well as somatostatin, but are negative for markers of monoaminergic neurons and of motoneurons. In brains of patients suffering from multiple systems atrophy (with central respiratory deficits but without swallowing problems), pre-Bötzinger complex neurons were reduced, whereas pharyngeal motoneurons of the ambigual nucleus were not affected. In contrast, in brains of patients with spinocerebellar ataxia 3 (no reported central respiratory deficits but with dysphagia), pre-Bötzinger complex neurons were preserved, whereas ambigual motoneurons, which control swallowing, were diminished. These pathoanatomical findings support the view, that affection of the central respiratory network, including the pre-Bötzinger complex, contributes to breathing disorders in multiple system atrophy, whereas damage to ambigual motoneurons is important for pathogenesis of breathing disturbances and dysphagia in patients with spinocerebellar ataxia type 3. On the basis of these findings, the putative human homologue of the pre-Bötzinger complex can now be reliably delineated on pigment-Nissl-stained sections, making neuropathological investigations of central respiratory disturbances feasible.