Measuring Depth in Still Water: Electrophysiologic Indicators of Residual Consciousness in the Unresponsive Patient

Abstract

Searching for evidence of consciousness in outwardly unresponsive patients presents significant clinical challenges as the spectrum of disorders of consciousness has become more clearly defined, with clinical examination, functional MRI, and electrophysiologic tests having complementary roles in the investigation of minimally conscious patients, those in a locked-in state, coma, or in a vegetative state. Serial bedside electrophysiologic testing can probe for higher order cortical responses temporally and spatially propagated through cortical networks, while long-latency event-related potentials may help differentiate patients with coma or vegetative state from a state of residual consciousness. Transcranial magnetic stimulation co-registered to high-density EEG may reveal widespread pulse-stimulated cortical activation of various brain regions. These emerging electrophysiologic techniques show promise as powerful diagnostic, prognostic, and therapeutic tools.

Detection of residual or emerging consciousness in outwardly unresponsive patients has become a major clinical challenge over the past decade (1). New functional MRI (fMRI) and electrophysiologic methods probe residual network activation and responses to external stimuli in patients with acute coma and chronic disorders of consciousness (2, 3). These methods rely on either passive activation of intracortical networks in response to stimuli or measurable, active responses to specific tasks and commands in patients lacking consistent external signs of responsiveness. The term “unresponsive wakefulness syndrome” is used to describe patients outwardly unresponsive but with evidence of network activation on fMRI or electrophysiologic testing (1, 4). Detection of residual indicators of consciousness or higher order cortical network activity may help with prognostication and enable further functional recovery in acute coma and chronic disorders of consciousness (5, 6).

FMRI techniques are used to measure functional connectivity within cortical networks or consistent changes in brain perfusion with cognitive tasks (7, 8). Disadvantages limiting routine clinical use stem from reliance on aggregate data from subjects and controls to identify appropriate network components, making single-subject testing more difficult (7), and hence these techniques are not used routinely. MRI techniques require transportation to the scanner and a still patient during protocols requiring tens of minutes—challenging for patients with disordered consciousness (9). Expense and logistic difficulties make serial fMRI testing impractical and islands of consciousness may be missed on single trials (10).

Electrophysiologic Tools to Study Alternative Pathways

Chronic disorders of consciousness are caused by brain injuries that produce widespread cortical and thalamic neuronal death (cardiac arrest), disconnection of thalamocortical and intracortical networks (traumatic diffuse axonal injury), or injury to the midbrain reticular activating system and bilateral thalami (ischemic or hemorrhagic stroke) (10). Lack of response to traditional bedside clinical examination for conscious interaction—attending and tracking visual stimuli, motor responses to commands, verbalization, and localizing or purposeful movements—may not reflect permanent loss of network integrity. Rather, the network may remain intact but inaccessible to sensory and motor pathway testing. Long-latency evoked potentials/event-related potentials (ERP) and co-registration of transcranial magnetic stimulation with EEG (TMS-EEG) explore residual network integrity via alternative network pathways (11–13). With ERPs, secondary processing of sensory stimuli (visual, auditory, or somatosensory) results in long-latency potentials in cortical regions distinct from the primary sensory cortices, providing indirect evidence of intact and accessible cortical networks (14, 15). TMS directly activates cortical networks even when subcortical pathways are disrupted (16, 17), but motor outflow pathways must be intact. TMS coregistered to EEG with widespread EEG modulation reflects preserved intracortical responses to external stimulation, the sine qua non of consciousness (13, 17, 18).

Evoked Potentials in Disorders of Consciousness

In their simplest form, evoked potentials (EPs) study transmission of sensory stimuli (visual, auditory, or somatosensory) along afferent pathways through the thalamus and primary sensory cortex. These short-latency potentials measure integrity of the sensory pathway and corresponding cortical regions necessary, but are not sufficient to produce secondary processing through higher order intracortical networks. Activation of distant cortical regions requires integrity of second-order networks and produces delayed middle- and long-latency potentials (19–21). Longer latency potentials generated from sensory-evoked potentials are difficult to consistently record, limiting clinical utility. Short-latency potentials—particularly somatosensory evoked potentials (SSEPs)—are widely used as a prognostic test for recovery of consciousness after cardiac arrest (22). Sustained bilateral absence of cortical N20 potentials portends a poor prognosis for recovery of consciousness from permanent disruption of thalamocortical pathways (22). Middle-latency SSEP (N35 and N70) may provide prognostic markers for eventual recovery of consciousness after cardiac arrest as intact secondary cortical networks may permit cognitive recovery (23). Unfortunately, preserved middle-latency potentials have only modest specificity and sensitivity for recovery of consciousness (23–25).

ERPs are used to study higher order “cognitive” processing of external stimuli, and although not in widespread clinical use, there is a growing evidence of their demonstration of cortical processing of sensory stimuli in patients with preserved or emerging consciousness (26–28). A sensory mismatch paradigm can elicit consistent cortical responses to a novel “odd-ball” auditory sensory stimulus (29). In conscious patients and controls, long-latency potentials are detected 100 to 300 ms after the “oddball” sounds but not during the repetitive background sounds (29, 30), and reflect successively higher cognitive processing of nonword sounds, words and language tasks, and response to the subject's own name (31). Earlier potentials are produced by unconscious or preconscious automatic sensory processing versus “conscious” awareness indicated by later potentials (10). Although the nomenclature is inconsistent among studies, a centroparietal P300 potential (also called P3b in some studies) has been consistently associated with consciousness and used by some authors to help differentiate minimally conscious state (MCS) from coma or vegetative state (VS) (9, 30, 32). Earlier ERP such as mismatch negativity appears to represent preconscious processing of sensory stimuli within cortical networks rather than strong evidence that the patient is conscious at the time of the examination (10). As such, demonstration of earlier potentials may have greater prognostic importance as an indicator of cortical network integrity but is not evidence of consciousness per se (33).

The P300 potentials require access to working memory, categorization of the stimulus, selective attention, and language processing depending on the auditory paradigm (34, 35). A review of 16 studies using various auditory ERP paradigms in chronic disorders of consciousness demonstrated P300 potentials in 25% of VS patients and 38% of MCS patients (10). These findings suggest that many patients who appear to be vegetative actually have preserved components of consciousness, but do not clearly distinguish VS from MCS. Only 38% of patients with MCS (i.e., demonstration of periodic beside conscious interaction) had P300 potentials (10). Hence, P300 based on a single ERP test has poor sensitivity for detection of consciousness. Whether serial testing improves diagnostic sensitivity is unclear. In one study, the intertest reliability of ERP was poor (alpha coefficient 0.24) in patients with disorders of consciousness (36), possibly due to the intermittent consciousness in these patients or technical factors that limit reproducibility. Identification of the P300 has been inconsistent across studies, limiting its translation into routine clinical practice. Brain injury patients may have blunted P300 morphology, rendering detection subjective and requiring experience from operator and interpreter (28). Additionally, there may be false positives from EEG artifact and stimulus-induced periodic epileptiform discharges time-locked to the auditory stimulus (37). P300 has been recorded in patients under general anesthesia who are unlikely to be conscious, indicating that P300 may show functional underlying network integrity, rather than conscious processing (38, 39). If so, P300 may provide more prognostic information about eventual recovery of consciousness rather than reflecting preserved consciousness (33).

Transcranial Magnetic Stimulation and EEG

Transcranial magnetic stimulation uses external application of a magnetic field in order to induce direct electrical stimulation of underlying cortical regions, resulting in a directly EP that bypasses afferent sensory pathways (16, 17). Unlike typical EPs that are induced by incoming sensory stimuli—and require integrity of the sensory pathway and thalamocortical relay—TMS directly induces depolarization of populations of neurons within range of the magnetic field. Depending on the field strength that is applied, pyramidal neurons in the cortex can be directly activated or activated transsynaptically (40). In its most common application, TMS is used to stimulate the primary motor cortex in order to test the integrity of the corticospinal motor pathway through motor-evoked potentials (MEPs) recorded at the target muscle. Although TMS-induced MEPs have been studied in patients with chronic disorders of consciousness, they have had limited diagnostic or prognostic utility (41, 42). MEPs require integrity of efferent motor pathways to induce a measurable motor response—problematic in patients with disorders of consciousness with dissociation of consciousness from motor activity (i.e., “locked-in”).

Coregistration of EEG to TMS has been studied in only a few institutions. It probes the integrity of cortical networks outside of pure motor and sensory domains (16, 17) using high-density EEG recordings during and after pulses of TMS to study local EEG modulation to the EMS pulse as well as transsynaptic modulation of EEG through cortical networks remote from the TMS pulse (16, 17). TMS-evoked potentials (TEPs) are recorded after direct activation of cortical neuronal populations below the TMS pulse reflecting direct cortical reactivity (43). High-density EEG then records a wave of cortical activation propagated transsynaptically along intracortical networks (43). Unlike MEPs, TMS-EEG recordings have the advantage of being able to study the integrity of cortical networks outside of the corticospinal tract and measure activation of neuronal populations without relying on external motor signs of responsiveness (10). TMS also does not require patient cooperation with a specific task during the examination because the TMS pulse directly activates brain regions.

Although TMS-EEG is a new technique, it is emerging in recent literature as a useful tool for studying occult network activity in patients with disorders of consciousness (10, 11). In a recent study of 13 patients with disorders of consciousness, TMS induced only local TEPs or no response in patients with VS, while MCS patients demonstrated widespread intra- and interhemispheric cortical activation up to 100 ms after the TMS pulse (13). These findings demonstrate reactivity to local activation in vegetative patients, but absence of connectivity to more widely distributed networks necessary for consciousness. In another study using an algorithm to quantify the complexity of TMS-induced cortical activation, 38 patients with MCS and 43 patients with VS were compared with controls in various stages of sleep and wakefulness (44). The authors found high complexity cortical activation in controls and among 95% of the patients diagnosed with MCS. In patients with VS, 21% of patients had high complexity cortical activation while the remainder had either low complexity activation or no activation in brain regions distant from the TMS pulse (44). The authors also noted that six of nine VS patients with high-complexity evoked EEG on the initial recording subsequently evolved to meet criteria for MCS on follow-up evaluation (44). Other investigators have tested for more durable cortical activation in patients after repetitive TMS to the prefrontal cortex using quantitative EEG methods. In one study, 10-Hz TMS was applied to the left dorsolateral prefrontal cortex in 18 patients with chronic disorders of consciousness resulting in reduction of low frequencies and increased high frequencies on power spectral analysis (18). These studies begin to bridge the gap between diagnostic tests for network integrity and emerging possibilities for therapeutic modulation of brain activity through neural stimulation (10).

Conclusions

Although fMRI techniques to study activation of cortical networks in patients with outward signs of unresponsiveness have earned significant interest in the press and among neuroscience investigators, electrophysiologic methods of studying and activating cortical networks have also evolved significantly over the last decade. Electrophysiologic tests have several advantages including relatively widespread availability, bedside noninvasive testing, and greater convenience for serial testing. Despite these advantages, specialized electrophysiologic techniques like TMS-EEG and ERP have not gained widespread clinical adoption and only a few centers in the world have a true depth of experience with these techniques. Technical artifacts, inconsistent results in the medical literature, poor standardization of protocols, and subjective interpretation of results have hampered clinical adoption at this point. As a test for occult consciousness or integrity of cortical networks necessary for eventual recovery of consciousness, however, evoked-electrophysiologic responses like ERP and TMS are simply an extension of the bedside neurological examination of the unresponsive patient. The presence of more complex responses to these inputs may indicate current consciousness or herald eventual recovery of consciousness. As investigators continue to standardize electrophysiologic methods and quantification of cortical outputs, these techniques may emerge as important diagnostic tests for consciousness, prognostic tests for network integrity despite current disruption of consciousness, and therapeutic modalities to hasten or stimulate activation of cortical networks.