Recovery of cortical effective connectivity and recovery of consciousness in vegetative patients

TLDR

Severe brain injury survivors can regain consciousness even without motor or communicative abilities, and electrophysiological and neuroimaging methods using sensory stimuli have detected higher‑order processing, while theory suggests consciousness requires rapid effective connectivity among specialized cortical areas. The study aims to develop methods for detecting consciousness recovery that do not rely on intact sensory pathways or the subject’s comprehension or motor execution. We use bedside transcranial magnetic stimulation with high‑density EEG to assess effective connectivity in non‑communicating severe brain‑injured patients, bypassing subcortical pathways and requiring no active participation or language comprehension, thereby enabling detection and tracking of consciousness recovery. TMS‑EEG revealed that vegetative patients exhibit only local responses, whereas minimally conscious patients show widespread activations, and longitudinal data show effective connectivity changes precede overt communication or EEG alterations, indicating this method can detect and track consciousness recovery.

Abstract

Patients surviving severe brain injury may regain consciousness without recovering their ability to understand, move and communicate. Recently, electrophysiological and neuroimaging approaches, employing simple sensory stimulations or verbal commands, have proven useful in detecting higher order processing and, in some cases, in establishing some degree of communication in brain-injured subjects with severe impairment of motor function. To complement these approaches, it would be useful to develop methods to detect recovery of consciousness in ways that do not depend on the integrity of sensory pathways or on the subject's ability to comprehend or carry out instructions. As suggested by theoretical and experimental work, a key requirement for consciousness is that multiple, specialized cortical areas can engage in rapid causal interactions (effective connectivity). Here, we employ transcranial magnetic stimulation together with high-density electroencephalography to evaluate effective connectivity at the bedside of severely brain injured, non-communicating subjects. In patients in a vegetative state, who were open-eyed, behaviourally awake but unresponsive, transcranial magnetic stimulation triggered a simple, local response indicating a breakdown of effective connectivity, similar to the one previously observed in unconscious sleeping or anaesthetized subjects. In contrast, in minimally conscious patients, who showed fluctuating signs of non-reflexive behaviour, transcranial magnetic stimulation invariably triggered complex activations that sequentially involved distant cortical areas ipsi- and contralateral to the site of stimulation, similar to activations we recorded in locked-in, conscious patients. Longitudinal measurements performed in patients who gradually recovered consciousness revealed that this clear-cut change in effective connectivity could occur at an early stage, before reliable communication was established with the subject and before the spontaneous electroencephalogram showed significant modifications. Measurements of effective connectivity by means of transcranial magnetic stimulation combined with electroencephalography can be performed at the bedside while by-passing subcortical afferent and efferent pathways, and without requiring active participation of subjects or language comprehension; hence, they offer an effective way to detect and track recovery of consciousness in brain-injured patients who are unable to exchange information with the external environment.