Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness

Abstract

By employing transcranial magnetic stimulation (TMS) in combination with high-density electroencephalography (EEG), we recently reported that cortical effective connectivity is disrupted during early non-rapid eye movement (NREM) sleep. This is a time when subjects, if awakened, may report little or no conscious content. We hypothesized that a similar breakdown of cortical effective connectivity may underlie loss of consciousness (LOC) induced by pharmacologic agents. Here, we tested this hypothesis by comparing EEG responses to TMS during wakefulness and LOC induced by the benzodiazepine midazolam. Unlike spontaneous sleep states, a subject's level of vigilance can be monitored repeatedly during pharmacological LOC. We found that, unlike during wakefulness, wherein TMS triggered responses in multiple cortical areas lasting for >300 ms, during midazolam-induced LOC, TMS-evoked activity was local and of shorter duration. Furthermore, a measure of the propagation of evoked cortical currents (significant current scattering, SCS) could reliably discriminate between consciousness and LOC. These results resemble those observed in early NREM sleep and suggest that a breakdown of cortical effective connectivity may be a common feature of conditions characterized by LOC. Moreover, these results suggest that it might be possible to use TMS-EEG to assess consciousness during anesthesia and in pathological conditions, such as coma, vegetative state, and minimally conscious state.anesthesia | high-density electroencephalography | transcranial magnetic stimulation T heoretical considerations suggest that consciousness depends on the brain's ability to integrate information, and that if information integration is impaired within a complex of cortical areas, consciousness should fade (1). The most common situation in which the level of consciousness changes is early non-rapid eye movement (NREM) sleep, when subjects, if awakened, report no or little conscious experience (2), despite the fact that their brain remains highly active (3). To establish whether the brain's ability to integrate information is higher in wakefulness than in early NREM sleep, in a previous study we perturbed one brain area using transcranial magnetic stimulation (TMS) and recorded the responses of other cortical areas using TMScompatible high-density electroencephalography (hd-EEG) (4). We found that during wakefulness, TMS initially evoked a local cortical activation, which then moved to a series of distant cortical areas, whereas during NREM sleep, the initial local response to TMS did not propagate beyond the stimulation site, thus indicating a breakdown of cortical effective connectivity and a loss of cortical integration (5). Moreover, in subsequent TMS/hd-EEG studies, we established that during wakefulness, TMS of different brain regions evoked different, specific EEG patterns (6), whereas during early NREM sleep, TMS yielded EEG responses characterized by a positive wave followed by a negative deflection, suggesting a loss of information capacity ...

Signature of consciousness in the dynamics of resting-state brain activity

“…Our results are also in agreement with several theories of consciousness (22,24) and earlier observations in sleep, anesthesia, and VS (18,(40)(41)(42)(43). Several theories of consciousness posit that distributed functional networks support conscious states and that loss of consciousness is indexed by alterations of these network patterns (22,24,42).…”

Functional neuroanatomy of disorders of consciousness

“…This technique allows noninvasive stimulation of a subset of cortical neurons, measuring the effects of the perturbation across the cortex [51]. Stimulation of a superficial region of the cerebral cortex of patients with VS/UWS with TMS has been shown to either induce no response or trigger a simple, local EEG response, indicating a breakdown of effective connectivity [52,53], similar to that observed in deep sleep and anesthesia [54,55]. In contrast, in patients with MCS, TMS triggered complex EEG activations which sequentially involved distant cortical areas, similar to activations recorded in locked-in patients, in healthy awake subjects, and during vivid dreams [53,54,56].…”

Stratification of unresponsive patients by an independently validated index of brain complexity

“…This may happen, for example, following changes in the neuromodulatory milieu, when potassium currents are abnormally increased and when the balance between excitation and inhibition is disrupted 43, 44. In this regard, it is worth recalling that low complexity responses to cortical stimulation are the rule during states such as anesthesia18 and NREM sleep,45 when bistability is present but can be readily reversed 46…”

“…TMS/EEG data were recorded from healthy subjects (female, n = 63; age range = 18–80 years) in the following conditions: (1) while they were unresponsive and did not provide any subjective report upon awakening (NREM sleep, n = 18; midazolam sedation at anesthetic concentrations, n = 6; anesthesia with xenon, n = 6; anesthesia with propofol, n = 6); (2) while they were unresponsive but able to provide a delayed subjective report upon awakening (dreaming during REM sleep, n = 8; and during ketamine anesthesia, n = 6); and (3) while they were awake and able to provide an immediate subjective report (n = 102, including 48 subjects also recorded in the previously described unresponsive conditions). The experimental protocols applied during sleep and anesthesia have been detailed elsewhere 11, 17, 18. Brain‐injured conscious patients were always recorded during wakefulness and encompassed (1) individuals affected by locked‐in syndrome (LIS; n = 5); (2) conscious individuals affected by ischemic or hemorrhagic stroke involving subcortical (n = 16) or cortical regions (n = 18); and (3) individuals who recovered functional communication after a previous DOC (emergence from minimally conscious state [EMCS], n = 9).…”