SLEEP-LIKE CORTICAL BISTABILITY IN VEGETATIVE STATE PATIENTS

The human brain is able to generate a wide repertoire of behavioral and psychological phenomena spanning from simple motor acts to cognition, from unimodal sensory perceptions to conscious experience. All these abilities are based on two key parameters of cortico-thalamic circuits functioning: the reactivity to a direct, local stimulation (cortical excitability) and the ability to causally interact (cortical effective connectivity). Indeed, alterations of these parameters have been suggested to underlie neurologic and psychiatric conditions. Over the last ten years, high-density electroencephalography combined with transcranial magnetic stimulation (TMS/hd-EEG) has been used to non-invasively probe cortical excitability and connectivity and to track over time pathological alterations, plastic changes and therapy-induced modifications in cortical circuits. A recently proposed theory suggests that consciousness depends on the brain’s ability to engage in complex activity patterns that are, at once, distributed among interacting cortical areas (integrated) and differentiated in space and time (information-rich). In a recent series of experiments the electroencephalographic TMS-evoked brain response was recorded in healthy subjects during wakefulness, non-rapid eyes movement sleep (NREM), under pharmacological conditions (anesthesia), and pathological conditions (severely brain-injured, vegetative state patients). Indeed, TMS/hd-EEG measurements showed that during wakefulness the brain is able to sustain long-range specific patterns of activation, while when consciousness fades in NREM sleep, anesthesia and vegetative state, the thalamo-cortical system produces either a local or a global slow wave which underlies respectively a loss of differentiation or integration. We hypothesize that, like spontaneous sleep slow waves, the slow waves triggered by TMS are due to bistability between periods of neuronal activity (up-state) and silence (down-state) in cortical networks. Thalamo-cortical bistability could impair the ability of thalamo-cortical circuits to sustain long-range, differentiated patterns of activation, a key theoretical requisite for consciousness. Animal studies show that the extracellular signature of the down-state is a transient suppression of high frequency (>20Hz) power in the local field potential (LFP). More recently, intracranial recordings during NREM sleep in humans have shown that a intracranial stimulations induce a widespread suppression of high frequencies (i.e. cortical down-states) that impair the ability of thalamo-cortical circuits to engage in causal interactions. In the present thesis we use a TMS/hd-EEG approach in patients affected by disorders of consciousness such as vegetative state (VS) and minimally conscious state (MCS) to investigate whether bistability could underlie also pathological loss of consciousness. To verify this hypothesis, we recorded TMS-evoked potentials (TEPs) in awake VS and MCS patients as well as in healthy controls (HC) during wakefulness and NREM sleep. TEPs were analyzed by means of time-frequency analyses (power and phase-locking factor - PLF). We observed that TEPs recorded in VS patients were characterized by a large positive-negative deflection, closely resembling the one recorded in HC during NREM sleep. This sleep-like slow-wave was associated with a significant suppression of power in the high frequency band (>20 Hz) together with an early drop of PLF. Interestingly, in VS patients the power suppression slowly recovered to the baseline whereas in the NREM sleep of HC it was replaced by a late increase of power. Finally, the recovery of consciousness assessed in two patients evaluated longitudinally was paralleled by the resurgence of TEPs high frequency oscillations and by an increase of PLF duration. These results suggest that the slow waves evoked by TMS in VS patients possibly reflect a condition of cortical bistability that prevents the entrainment of thalamocortical modules in effective interactions and, hence, the emergence of consciousness. Intriguingly, the resumption of TEPs high frequency oscillations and a longer duration of phase-locked components (PLF) seem to be associated with the recovery of consciousness. Since bistability is, in principle, reversible and its mechanisms are well understood at the cellular and network level, it may represent a suitable target for novel therapeutic approaches in patients in whom consciousness is impaired, in spite of preserved cortical activity.