Brainstem-cortical dynamics of Parkinson's disease autonomic failure

In Parkinsons disease (PD), failure to regulate blood pressure is a common comorbidity that is hard to treat, worsens quality-of-life and often precedes diagnosis. It is caused by -synuclein-mediated damage to the autonomic nervous system (ANS) that precedes overt symptoms, and while central dysfunction is a key component it remains uncharacterised in-vivo due to various imaging challenges. Here, we characterised the function of a brainstem-cortical ANS network in relation to cardiovascular autonomic failure. 81 individuals with early-PD and 65 aged-matched healthy controls (HC) performed resting-state 3T fMRI, neurological assessments and a 3-minute standing test: lied down for 5-minutes, had blood-pressure measured, then stood-up and had blood-pressure measured every minute for 3-minutes. We used Dynamic Causal Modelling to investigate how drops in blood pressure linked to effective connectivity in medullary and relay nuclei, hypothalamus, and cortical autonomic regions. Steep drops in blood-pressure in PD were associated with an overall inhibitory pattern departing from the rostro-ventrolateral medulla, a region responsible for sympathetic-mediated increase in blood pressure, as well as increased self-inhibition of this region. Additionally, the patient model was dominated by bottom-up connectivity from medullary regions to relay and cortical ones, potentially pertaining to state-signalling to higher-order regions, given the decreased ability of medullary regions to regulate blood pressure. Conversely, in HC, we observed widespread and unspecific weakening of connectivity. Our findings elucidate for the first time how a baseline dysfunction originating from the medulla, may cause poor central ANS reactivity to orthostatic stimuli and predispose those with PD to drops in blood pressure upon standing. These findings are compatible with known pathophysiology literature, pave the way to more in-depth characterisations of central autonomic dysfunction in-vivo, and may result in functional signatures useful to track disease progression or outcomes in clinical trials.