Sleep-like bistability, loss of causality and complexity in the cerebral cortex of unresponsive wakefulness syndrome patients

Abstract

Unresponsiveness Wakefulness Syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and responsive to sensory stimuli. In most of these patients, Transcranial Magnetic Stimulation combined with electroencephalography (TMS/EEG) shows that structurally preserved cortical areas react to TMS, but fail to engage complex patterns of effective interactions, as assessed by the perturbational complexity index (PCI). Another condition during which thalamocortical circuits are intact, active and reactive, yet unable to generate complex responses, is non-rapid eye movement (NREM) sleep, in which cortical neurons become bistable and tend to fall into a silent state (OFF-period) upon receiving an input. Here we tested whether a pathological form of bistability may be responsible for the loss of cortical complexity in UWS patients. In eyes-open UWS patients (n=16) TMS evoked a slow wave-like EEG response that was associated with a suppression of high-frequency (above 20Hz) oscillations suggesting the occurrence of OFF-periods similar to the ones observed in healthy subjects (n=8) during NREM sleep. Crucially, this phenomenon was never detected in healthy awake subjects (n=20). In all targeted cortical areas (Brodmann areas 6 and 7, bilaterally) of UWS patients, pathological OFF-periods significantly impaired local causal interactions (as measured by the phase-locking factor) and prevented the build-up of global complexity (as measured by PCI). Our results draw a first link between neuronal events (OFF-periods) and global brain dynamics (complexity) in UWS patients. Detecting the presence of sleep-like bistability and tracking its evolution over time, may offer a valuable read-out to devise, guide and titrate therapeutic strategies aimed at restoring consciousness.