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

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.

Functional neuroanatomy of disorders of consciousness

“…In contrast, in patients with MCS, TMS triggered complex EEG activations which sequentially involved distant cortical areas, similar to activations recorded in locked-in patients, in healthy awake subjects, and during vivid dreams [53,54,56]. Interestingly, a patient with MCS assessed during a period of no responsiveness still showed complex and widespread brain responses to TMS, even though no conscious behavior could be observed at the bedside [53].…”

“…This technique allows noninvasive stimulation of a subset of cortical neurons, measuring the effects of the perturbation across the cortex [51]. Stimulation of a superficial region of the cerebral cortex of patients with VS/UWS with TMS has been shown to either induce no response or trigger a simple, local EEG response, indicating a breakdown of effective connectivity [52,53], similar to that observed in deep sleep and anesthesia [54,55]. In contrast, in patients with MCS, TMS triggered complex EEG activations which sequentially involved distant cortical areas, similar to activations recorded in locked-in patients, in healthy awake subjects, and during vivid dreams [53,54,56].…”

“…Stimulation of a superficial region of the cerebral cortex of patients with VS/UWS with TMS has been shown to either induce no response or trigger a simple, local EEG response, indicating a breakdown of effective connectivity [52,53], similar to that observed in deep sleep and anesthesia [54,55]. In contrast, in patients with MCS, TMS triggered complex EEG activations which sequentially involved distant cortical areas, similar to activations recorded in locked-in patients, in healthy awake subjects, and during vivid dreams [53,54,56]. Interestingly, a patient with MCS assessed during a period of no responsiveness still showed complex and widespread brain responses to TMS, even though no conscious behavior could be observed at the bedside [53].…”

What Is Lost During Dreamless Sleep: The Relationship Between Neural Connectivity Patterns and Consciousness

“…This further supports the prediction that interactions between cortical areas are necessary for the generation of conscious experience. Similar results to those seen in NREM sleep were obtained in some disorders of consciousness (Rosanova et al, 2012; discussed below) and in general anaesthesia ; this has led to the suggestion that a breakdown of effective connectivity is characteristic of states of reduced consciousness in general . Additional support for this idea comes from the finding that the activity of cortical neurons appears to be highly synchronised in the anaesthetised brain, similar to the state they are in during SWS (Supp, Siegel, Hipp, & Engel, 2011).…”

Consciousness supporting networks

“…Only MCS and not VS/UWS patients showed such long-range connectivity changes. This technique also permitted to longitudinally follow connectivity changes in patients who recovered (or failed to recover) from VS/UWS [29 ]. These early functional connectivity studies highlight the importance of connectivity measurements in the emergence of human conscious awareness.…”