1.4 Sensory-motor EP and EMG reveal a partial sensory and motor functional disconnection
To characterize the functional status of afferent sensory and efferent motor systems, sensory-motor EP and EMG were then applied as a second-level assessment (Figure 3 middle panel). Auditory brainstem responses (ABR) indicated a mild alteration of transmission along the central pathway at the midbrain level (increase of the III-V interpeak), however, not sufficient to significantly affect the CRS-R auditory function subscale. There was no alteration in visual transmission detected with flash visual EP, suggesting that the absence of visual fixation and tracking was not due to cortical blindness.
Somatosensory EP (SEP) showed the absence of the cortical N20 in the left hemisphere along with a preserved subcortical P14, suggesting an alteration of central somatosensory transmission from the right upper limb. Moreover, motor EP (MEP) elicited by TMS over primary motor cortex indicated a severe functional disconnection along the cortico-spinal tracts for both lower limbs and the left upper limb. Electromyography and electroneurography revealed a diffuse combined peripheral neuropathy and myopathy (compatible with an ICU-acquired weakness) further complicated by a left upper-trunk brachial plexopathy. Finally, a significant lack of habituation of the blink reflex reflecting the increased excitability typical of a hypo-dopaminergic state was detected (Formisano et al. , 2009).
This comprehensive neurophysiological battery, demonstrated the coexistence of multiple partial sensory and motor sites of functional disconnections, both at the central and peripheral levels, possibly confounding an accurate assessment of reflexes and volitional motor responses.
1.5 ERP analysis shows preserved P100 but lack of higher-level cognitive processing
To characterize residual sensory-cognitive abilities at a higher level, we recorded ERP by applying a binaural acoustic stimulation with a classical oddball task following the technical guidelines for clinical research previously described in (Duncan et al. , 2009). This third-level bed-side neurophysiological evaluation (Figure 3, lower panel) with a cognitive paradigm only showed a stable N1 component in response to the acoustic stimuli indicating a residual preserved activation of primary and peri-primary acoustic areas. However, we did not identify higher-level neurophysiological correlates of cognitive processing, such as the pre-attentional mismatch negativity or the late positive P3 component.
The partial sensory-motor disconnection highlighted by the multimodal EP-EMG examination and the inconclusive ERP results obtained with a clinical visual analysis, in conjunction with the marked slowing of EEG background, called for a deeper-level investigation; indeed, consciousness can be preserved even in conditions of disconnection from the sensory-motor periphery (Rohaut et al. , 2017; Bayne et al. , 2020), in the absence of a P3 (Faugeras et al. , 2012) as well as in the presence of a severely abnormal EEG pattern (Frohlichet al. , 2021).
1.6 The complexity of TEP indicates a capacity for consciousness
TMS-evoked potentials (TEP) allow probing neuronal dynamics within thalamocortical networks without engaging sensory, motor and executive functions and can be used to assess by a causal perspective to what extent distributed and differentiated groups of neurons interact as a whole to produce complex dynamics (Massimini et al. , 2005, 2009; Rosanova et al. , 2009). The Perturbational Complexity Index (PCI), has been specifically developed to quantify this form of brain complexity (Casali et al. , 2013; Sarasso et al. , 2021), and has been validated as an index of consciousness in healthy controls and brain injured patients (Casarotto et al. , 2016; Sarassoet al. , 2020). Based on this benchmark calibration, finding a maximum PCI value across stimulation sites (PCImax) higher than 0.31 indicates a capacity for consciousness irrespective of behavioral responsiveness and of the dominant EEG background pattern.
TEP were recorded on week 3, with a 62-channel TMS-compatible EEG amplifier (Brainamp DC, Brain Products GmbH, Germany) following the same procedure reported in (Casarotto et al. , 2016) and using a customized software for real-time evaluation of TEP (Casarotto et al. , 2022). Specifically, EEG responses to TMS were obtained by targeting three cortical sites: the left and right superior parietal lobule as well as the right superior frontal gyrus (Figure 4, panel A). This exam revealed high PCI values for both right (PCI=0.34, Figure 4 panel B, blue square) and left (PCI=0.33, Figure 4 panel B, blue circle; panel C”, blue TEP) parietal stimulation sites, indicating a capacity for consciousness according to published norms (Casali et al. , 2013; Casarotto et al. , 2016; Sinitsyn et al. , 2020). Interestingly and in contrast with parietal stimulation, frontal stimulation only elicited a slow, stereotypical wave resembling those typically obtained in sleeping healthy subjects (Figure 4, panel C’, blue TEP) that was associated with low complexity (PCI=0.25) (Figure 4, panel B, blue diamond). This mixed pattern whereby high-complexity brain responses can coexist with local sleep-like reactivity, especially in areas surrounding lesions, is typically found in conscious patients with (multi)-focal lesions (Sarasso et al. , 2020). Overall, the analysis of TEP documented high brain complexity (PCImax=0.34) and a substantial impairment of the reactivity of frontal circuits, consistent with a preserved capacity for consciousness in a clinical context of impaired executive and motor function.