Reduced brainstem functional connectivity in patients with peripheral autonomic failure

Autonomic homeostasis is dependent upon several brainstem nuclei, as well as several cortical and subcortical structures. Together, these sites make up, in part, the central autonomic network. Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic failure that occurs due to a failure to increase sympathetic efferent activity in response to postural changes. Therefore, the purpose of the current study was to investigate brainstem functional connectivity in NOH patients with peripheral autonomic lesions resulting in autonomic failure. Fifteen controls (63 ± 13 years) and fifteen Neurogenic Orthostatic Hypotension patients (67 ± 6 years; p = .2) with peripheral autonomic dysfunction completed 5-min of rest and three Valsalva maneuvers during a functional brain scan. Functional connectivity from the brainstem to cortical and subcortical structures were contrasted between patients and controls. At rest controls had significantly greater brainstem connectivity to the anterior cingulate cortex (T-value: 4.29), left anterior insula (T-value:3.31), left putamen (T-value:3.31) and bilateral thalamus (T(RIGHT)-value: 3.83; T(LEFT)-value:4.25) (p-FDR < 0.005). During Valsalva, controls showed significantly more connectivity between the brainstem and both the left anterior (cerebellum 4/5) and bilateral posterior cerebellum (cerebellar 9 and left cerebellar 6). Other cerebellar regions included brainstem-to-vermis. Other brainstem-to-cortical and subcortical regions included: bilateral putamen, posterior cingulate cortex (PCC), amygdala and medial prefrontal cortex. There was a significant negative correlation between the brainstem-cerebellar connectivity and severity of autonomic dysfunction (p < .01). During recovery phase of the Valsalva, controls had greater brainstem connectivity to the left thalamus (T-value:4.17); PCC (T-value:3.32); right putamen (T-value:3.28); right paracingulate gyrus (T-value:3.25) and left posterior cerebellum (C9) (T-value:3.21) (p-FDR < 0.05). The effect sizes for each brainstem connectivity during Valsalva and recovery ranged from moderate to strong. Patients with autonomic failure show reduced coupling between the brainstem and regions of the central autonomic network, including the cerebellum, insula, thalamus and cingulate cortices. Connectivity was associated with autonomic impairment. These findings may suggest impaired brainstem connectivity in patients with autonomic failure.