ObjectiveValidating objective, brain‐based indices of consciousness in behaviorally unresponsive patients represents a challenge due to the impossibility of obtaining independent evidence through subjective reports. Here we address this problem by first validating a promising metric of consciousness—the Perturbational Complexity Index (PCI)—in a benchmark population who could confirm the presence or absence of consciousness through subjective reports, and then applying the same index to patients with disorders of consciousness (DOCs).MethodsThe benchmark population encompassed 150 healthy controls and communicative brain‐injured subjects in various states of conscious wakefulness, disconnected consciousness, and unconsciousness. Receiver operating characteristic curve analysis was performed to define an optimal cutoff for discriminating between the conscious and unconscious conditions. This cutoff was then applied to a cohort of noncommunicative DOC patients (38 in a minimally conscious state [MCS] and 43 in a vegetative state [VS]).ResultsWe found an empirical cutoff that discriminated with 100% sensitivity and specificity between the conscious and the unconscious conditions in the benchmark population. This cutoff resulted in a sensitivity of 94.7% in detecting MCS and allowed the identification of a number of unresponsive VS patients (9 of 43) with high values of PCI, overlapping with the distribution of the benchmark conscious condition.InterpretationGiven its high sensitivity and specificity in the benchmark and MCS population, PCI offers a reliable, independently validated stratification of unresponsive patients that has important physiopathological and therapeutic implications. In particular, the high‐PCI subgroup of VS patients may retain a capacity for consciousness that is not expressed in behavior. Ann Neurol 2016;80:718–729

Unresponsive wakefulness syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and reactive to sensory stimuli but fail to engage in complex causal interactions, resulting in loss of consciousness. Here, we show that loss of brain complexity after severe injuries is due to a pathological tendency of cortical circuits to fall into silence (OFF-period) upon receiving an input, a behavior typically observed during sleep. Spectral and phase domain analysis of EEG responses to transcranial magnetic stimulation reveals the occurrence of OFF-periods in the cortex of UWS patients (N = 16); these events never occur in healthy awake individuals (N = 20) but are similar to those detected in healthy sleeping subjects (N = 8). Crucially, OFF-periods impair local causal interactions, and prevent the build-up of global complexity in UWS. Our findings link potentially reversible local events to global brain dynamics that are relevant for pathological loss and recovery of consciousness.

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Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can excite both cortico-cortical and cortico-spinal axons resulting in TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs), respectively. Despite this remarkable difference with other cortical areas, the influence of motor output and its amplitude on TEPs is largely unknown. Here we studied TEPs resulting from M1 stimulation and assessed whether their waveform and spectral features depend on the MEP amplitude. To this aim, we performed two separate experiments. In experiment 1, single-pulse TMS was applied at the same supra-threshold intensity on primary motor, prefrontal, premotor and parietal cortices and the corresponding TEPs were compared by means of local mean field power and time-frequency spectral analysis. In experiment 2 we stimulated M1 at resting motor threshold in order to elicit MEPs characterized by a wide range of amplitudes. TEPs computed from high-MEP and low-MEP trials were then compared using the same methods applied in experiment 1. In line with previous studies, TMS of M1 produced larger TEPs compared to other cortical stimulations. Notably, we found that only TEPs produced by M1 stimulation were accompanied by a late event-related desynchronization (ERD—peaking at ~300 ms after TMS), whose magnitude was strongly dependent on the amplitude of MEPs. Overall, these results suggest that M1 produces peculiar responses to TMS possibly reflecting specific anatomo-functional properties, such as the re-entry of proprioceptive feedback associated with target muscle activation.

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Neurophysiological markers can overcome the limitations of behavioural assessments of Disorders of Consciousness (DoC). EEG alpha power emerged as a promising marker for DoC, although long-standing literature reported alpha power being sustained during anesthetic-induced unconsciousness, and reduced during dreaming and hallucinations. We hypothesized that EEG power suppression caused by severe anoxia could explain this conflict. Accordingly, we split DoC patients (n = 87) in postanoxic and non-postanoxic cohorts. Alpha power was suppressed only in severe postanoxia but failed to discriminate un/consciousness in other aetiologies. Furthermore, it did not generalize to an independent reference dataset (n = 65) of neurotypical, neurological, and anesthesia conditions. We then investigated EEG spatio-spectral gradients, reflecting anteriorization and slowing, as alternative markers. In non-postanoxic DoC, these features, combined in a bivariate model, reliably stratified patients and indexed consciousness, even in unresponsive patients identified as conscious by an independent neural marker (the Perturbational Complexity Index). Crucially, this model optimally generalized to the reference dataset. Overall, alpha power does not index consciousness; rather, its suppression entails diffuse cortical damage, in postanoxic patients. As an alternative, EEG spatio-spectral gradients, reflecting distinct pathophysiological mechanisms, jointly provide a robust, parsimonious, and generalizable marker of consciousness, whose clinical application may guide rehabilitation efforts.

Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can excite both cortico-cortical and cortico-spinal axons resulting in TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs), respectively. Despite this remarkable difference with other cortical areas, the influence of motor output and its amplitude on TEPs is largely unknown. Here we studied TEPs resulting from M1 stimulation and assessed whether their waveform and spectral features depend on the MEP amplitude. To this aim, we performed two separate experiments. In experiment 1, single-pulse TMS was applied at the same suprathreshold intensity on primary motor, prefrontal, premotor and parietal cortices and the corresponding TEPs were compared by means of local mean field power and time-frequency spectral analysis. In experiment 2 we stimulated M1 at resting motor threshold in order to elicit MEPs characterized by a wide range of amplitudes. TEPs computed from high-MEP and low-MEP trials were then compared using the same methods applied in experiment 1. In line with previous studies, TMS of M1 produced larger TEPs compared to other cortical stimulations. Notably, we found that only TEPs produced by M1 stimulation were accompanied by a late (~300 ms after TMS) event-related desynchronization (ERD), whose magnitude was strongly dependent on the amplitude of MEPs. Overall, these results suggest that M1 produces peculiar responses to TMS possibly reflecting specific anatomo-functional properties, such as the re-entry of proprioceptive feedback associated with target muscle activation.

Background: Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). Objective: We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. Methods: In thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n ¼ 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and [ 123 I]N-u-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. Results: We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. Conclusions: These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.