Patients lying in a vegetative state present severe impairments of consciousness [] caused by lesions in the cortex, the brainstem, the thalamus and the white matter []. There is agreement that this condition may involve disconnections in long-range cortico–cortical and thalamo-cortical pathways []. Hence, in the vegetative state cortical activity is ‘deafferented’ from subcortical modulation and/or principally disrupted between fronto-parietal regions. Some patients in a vegetative state recover while others persistently remain in such a state. The neural signature of spontaneous recovery is linked to increased thalamo-cortical activity and improved fronto-parietal functional connectivity []. The likelihood of consciousness recovery depends on the extent of brain damage and patients’ etiology, but after one year of unresponsive behavior, chances become low []. There is thus a need to explore novel ways of repairing lost consciousness. Here we report beneficial effects of vagus nerve stimulation on consciousness level of a single patient in a vegetative state, including improved behavioral responsiveness and enhanced brain connectivity patterns.

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4 Schiff N.D.

Giacino J.T.

Kalmar K.

Victor J.D.

Baker K.

Gerber M.

Fritz B.

Eisenberg B.

O’Connor J.

Kobylarz E.J.

et al. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. 5 Rutecki P. Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation. 5 Rutecki P. Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation. 6 Henry T.R.

Votaw J.R.

Pennell P.B.

Epstein C.M.

Bakay R.A.

Faber T.L.

Grafton S.T.

Hoffman J.M. Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy. 7 Dorr A.E. Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission. Consistent with an important role of the thalamic-cortical axis for awareness, one study has demonstrated an increased behavioral responsiveness after deep thalamic stimulation limited to the stimulation period []. Here we propose to activate the thalamo-cortical network based on vagus nerve stimulation. The vagus nerve carries somatic and visceral efferents and afferents distributed throughout the central nervous system, either monosynaptically or via the nucleus of the solitary tract (NTS) []. The vagus directly modulates activity in the brainstem and via the NTS it reaches the dorsal raphe nuclei, the thalamus, the amygdala, and the hippocampus []. In humans, vagus nerve stimulation increases metabolism in the forebrain, thalamus and reticular formation []. It also enhances neuronal firing in the locus coeruleus which leads to massive release of norepinephrine in the thalamus and hippocampus, a noradrenergic pathway important for arousal, alertness and the fight-or-flight response [].

Following the hypothesis that vagus nerve stimulation functionally reorganizes the thalamo-cortical network, we tested its effects on the cortical activity of a patient lying in a vegetative state for 15 years following traumatic brain injury. Behavioral, electroencephalographic (EEG) and 18F-FDG PET recordings were performed before and after surgical implantation of a vagus nerve stimulator. Stimulation was gradually increased to a maximum intensity of 1.5 mA, and its effects were monitored over six months post-implantation. After one month of stimulation, when intensity reached 1 mA, clinical examination revealed reproducible and consistent improvements in general arousal, sustained attention, body motility and visual pursuit. Scores on the Coma Recovery Scale-Revised (CRS-R) test improved, mostly in the visual domain, as stimulation increased, from a score of 5 at baseline (last exam) to 10 at highest intensities (1.00–1.25 mA), indicating a transition from a vegetative to minimally conscious state.

8 Sitt J.D.

King J.-R.

Karoui I.E.

Rohaut B.

Faugeras F.

Gramfort A.

Cohen L.

Sigman M.

Dehaene S.

Naccache L. Large scale screening of neural signatures of consciousness in patients in a vegetative or minimally conscious state. 1 Giacino J.T.

Fins J.J.

Laureys S.

Schiff N.D. Disorders of consciousness after acquired brain injury: the state of the science. 9 Koch C.

Massimini M.

Boly M.

Tononi G. Neural correlates of consciousness: progress and problems. 10 King J.-R.

Sitt J.D.

Faugeras F.

Rohaut B.

El Karoui I.

Cohen L.

Naccache L.

Dehaene S. Information sharing in the brain indexes consciousness in noncommunicative patients. Figure 1 Information sharing increases after vagus nerve stimulation over centroposterior regions. Show full caption (A) Sagittal (left) and coronal (right) views of weighted symbolic mutual information (wSMI) shared by all channels pre- and post-vagus nerve stimulation (VNS) (top and bottom, respectively). For visual clarity, only links with wSMI higher than 0.025 are shown. (B) Topographies of the median wSMI that each EEG channel shares with all the other channels pre- and post-VNS (top and bottom, respectively). The bar graph represents the median wSMI over right centroposterior electrodes (darker dots) which significantly increases post-VNS (permutation test over sessions: Wilcoxon test, p = 0.0266). (C) Localization of the most VNS-reactive theta source showing significant increase of information sharing post-VNS. Sources’ localization is presented over the patient’s cortical surface (probability map, sLoreta current source density: light blue scale) combined with his FDG-PET metabolism (gray scale) as measured three months post-VNS. The source was localized in the inferior parietal lobule. The bar graph represents the mean wSMI shared with all other selected sources pre- and post-VNS (dark gray and light gray, respectively) (permutation test over sessions: Wilcoxon test, p < 0.01 Bonferroni corrected). CRS-R clinical score increased as a function of information sharing over a cortical posterior theta network (Robust regression, p = 0.0015). Scalp EEG data comparing the patient’s resting state pre- and post-stimulation revealed a significant increase in theta band (4–7 Hz) power (one-sample t-test, p < 0.0001 false discovery rate corrected, Figure S1 A,B in Supplemental Information, published with this article online), a brain signal found to reliably distinguish minimally conscious patients from vegetative ones []. Data driven blind source separation analysis identified eight sources responsible for the stimulation-induced power increase, distributed over the occipito-parietal, inferior temporal and fronto-central regions in addition to a deeper source most likely localized in the insula ( Figure S1 C). These areas belong to the default mode network whose activity appears to reflect the degree of consciousness in non-communicative brain-damaged patients []. The highest stimulation intensity induced an increase in theta power over the right inferior parietal and parieto-temporal-occipital border ( Figure S1 C), a region labelled as a hot-zone for conscious awareness []. We calculated weighted symbolic mutual information (wSMI), a measure of cortical connectivity and information sharing known as a sensitive index of consciousness. This measure captures activity in different frequency bands and robustly discriminates the vegetative from minimally conscious state within theta frequency signals (4–10 Hz) []. By using a parameter of τ = 32 ms we found that the median wSMI across channel pairs was significantly higher after vagus nerve stimulation over a parietal region within a cluster including the right centro-temporo-occipital electrodes ( Figure 1 A,B).

10 King J.-R.

Sitt J.D.

Faugeras F.

Rohaut B.

El Karoui I.

Cohen L.

Naccache L.

Dehaene S. Information sharing in the brain indexes consciousness in noncommunicative patients. The wSMI procedure was also applied on sources previously identified by blind source separation as reactive to vagus nerve stimulation. The purpose here was to isolate regions that most contributed to information sharing, thus suppressing sources with interfering noise activity. Cortical areas showing significant increase in mutual information after stimulation included the inferior parietal, precuneus, posterior cingulate and pre-motor/motor regions ( Figure 1 C and Figure S1 E). The highest mean wSMI value was found in the inferior parietal cortex/intraparietal sulcus ( Figure 1 C). This global increase in mean wSMI over theta sources was significantly correlated to the CRS-R scores of clinical improvement (Robust regression, t (-0.0128;3.9436), dfe = 14, p = 0.0015, Figure 1 C). These results demonstrate that vagus nerve stimulation enhances information sharing within a centro-posterior network. This is consistent with the observation reported on a large population of brain injured patients showing that activity within centro-parietal regions constitute the marker of a conscious state []. Importantly, they demonstrate the critical role of the parietal cortex as a central hub for broadcasting neural signals among posterior and central sites in order to strengthen consciousness.

Finally, 18F-FDG PET results corroborated EEG findings by showing extensive increases of activity in occipito-parieto-frontal and basal ganglia regions as early as three months after implantation of the stimulator. Vagus nerve stimulation enhanced the metabolic signal in the thalamus, a target of the vagus nerve ( Figure S1 D).