Conventional transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex (DLPFC) could improve arousal in disorders of consciousness (DOC). However, the comparative effectiveness of anodal stimulation of the left DLPFC and the electrophysiological effect of tDCS are yet to be determined. In this randomized sham-controlled design, patients were separated into three groups (left/right anodal tDCS, sham). Data on the clinical assessments and EEG were collected at baseline and after 2 weeks of tDCS. The outcome at 3-month follow-up was evaluated using the Glasgow Outcome Scale-Extended. Results showed that sessions of the left tDCS facilitated the excitability of the prefrontal cortex, whereas only one patient had a positive outcome. Targeting the right DLPFC was less effective, merely leading to activation of the stimulation site, with no effect on the state of arousal. Moreover, sham stimulation had minimal or no effect on any of the outcomes. These results provide evidence for a hemispheric asymmetry of tDCS effects in patients with DOC. Left anodal tDCS might be more effective for modulating cortical excitability compared to tDCS on the right DLPFC. However, future studies with large sample sizes are needed to confirm these findings. This trial is registered with NCT03809936.

Background: We hypothesize that the anterior insula is important for maintenance of awareness. Here, we explored the functional connectivity alterations of the anterior insula with changes in the consciousness level or over time in patients with disorders of consciousness (DOC) and determined potential correlation with clinical outcomes.Methods: We examined 20 participants (9 patients with DOC and 11 healthy controls). Each patient underwent resting-state functional magnetic resonance imaging (rs-fMRI) and a standardized Coma Recovery Scale-Revised (CRS-R) assessment on the same day. We categorized the patients according to the prognosis: those who emerged from a minimally conscious state (recovery group, n = 4) and those who remained in the unconscious state (unrecovery group, n = 5). Two rs-fMRI scans were obtained from all patients, and the second scan of patients in the recovery group was obtained after they regained consciousness. We performed seed-based fMRI analysis and selected the left ventral agranular insula (vAI) and dorsal agranular insula (dAI) as the regions of interest. Correlations with CRS-R were determined with the Spearman's correlation coefficient.Results: Compared with healthy controls, the functional connectivity between dAI and gyrus rectus of patients who recovered was significantly increased (p < 0.001, cluster-wise family-wise error rate [FWER] < 0.05). The second rs-fMRI scan of patients who remained with DOC showed a significant decreased functional connectivity between the dAI to contralateral insula, pallidum, bilateral inferior parietal lobule (IPL), precentral gyrus, and middle cingulate cortex (p < 0.001, cluster-wise FWER < 0.05) as well as the functional connectivity between vAI to caudate and cingulum contrast to controls (p < 0.001, cluster-wise FWER < 0.05). Finally, the functional connectivity strength of dAI-temporal pole (Spearman r = 0.491, p < 0.05) and dAI-IPL (Spearman r = 0.579, p < 0.05) were positively correlated with CRS-R scores in all DOC patients. The connectivity of dAI-IPL was also positively correlated with clinical scores in the recovery group (Spearman r = 0.807, p < 0.05).Conclusions: Our findings indicate that the recovery of consciousness is associated with an increased connectivity of the dAI to IPL and temporal pole. This possibly highlights the role of the insula in human consciousness. Moreover, longitudinal variations in dAI-IPL and dAI-temporal pole connectivity may be potential hallmarks in the outcome prediction of DOC patients.

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