3.2. Treatment, recovery of command following and improvement of frontal reactivity
Considering the dysconnectivity pattern, involving the bilateral mesial frontal cortex and the basal ganglia (Figure 6) and consistent with a mesocircuit hypothesis, a treatment with amantadine, a pro-dopaminergic drug with antiglutamatergic and anticholinergic properties, was attempted (Kraus & Maki, 1997; Thibaut et al. , 2019). Amantadine was administered according to the following schedule: 50mg once daily in week 13, 100 mg once daily in week 14, 100 mg twice daily in week 15, 150 mg twice daily up to the discharge (week 20) (Figure 1).
Increasing doses of amantadine were paralleled by a gradual recovery of responsiveness from a fluctuating low-level MCS- to a stable high-behavioral MCS “plus” (MCS+) diagnosis (week 17), due to the appearance of subtle but reproducible movement to command with CRS- R assessments (Figure 1). Notably, motor execution was finally achieved by the recovery of voluntary motility of the right hand, corresponding to the side where MEP, EMG and fMRI findings previously converged in predicting a residual preservation of the central and peripheral motor pathway.
Before IRU discharge (week 20), the patient underwent a final TMS-EEG exam (week 19) to reassess the state of cortical circuits. TEP revealed an increase of brain complexity not only when targeting the left parietal site (PCI from 0.40 to 0.47, Figure 4 panel B, green circle; panel C”, green TEP) but notably also over the right superior frontal gyrus; here, the recovery of fast oscillations and late component both locally and bilaterally, far from the stimulation site resulted in higher complexity responses (PCI from 0.27 to 0.32, Figure 4 panel B, green diamond; panel C’, green TEP), This change paralleled the recovery of executive functions suggesting that TMS-EEG may represent an interesting read-out of regional changes in cortical circuits that are relevant for functional recovery during the IRU stay.