Evoked and event-related potentials in disorders of consciousness: A quantitative review
Introduction
Evoked and event-related brain potentials (EP and ERP, respectively) are electrical brain responses strongly phase-locked to a particular event (mostly, a stimulus). Responses largely determined by the properties of this stimulus are usually called EP, or “exogenous responses”. In contrast, responses largely determined by individual aspects of brain processing, or by the cognitive task in which the stimulus is embedded, are referred to as ERP or “endogenous responses” (Picton, 1988). Both EP and ERP should be distinguished from the background EEG oscillations, which characterize temporally extended states of cortical functioning (e.g., wakefulness and sleep), and from non-phase locked EEG responses such as event-related synchronization and desynchronization (e.g., Pfurtscheller & Aranibar, 1979).
The term Disorders of Consciousness (DoC) largely encompasses two diagnoses: vegetative state (VS) and minimally conscious state (MCS). The former has a long history of changing names, from apallic syndrome (Kretschmer, 1940) to unresponsive wakefulness syndrome (Laureys et al., 2010), none of which can be regarded as exact. In this paper the most broadly known term VS will be used, although this term can and has been criticized like any other.
In addition to VS and MCS, coma is the most severe DoC. However, pathophysiology and psychology of coma differ from those of VS and MCS. Coma is primarily characterized by the lack of wakefulness which, according to the most prevalent but not unquestioned view, is caused by organic or functional disturbance of the lower brain stem (Husain, 2006, Young, 2009). In contrast, VS and MCS patients are awake, but their subjective awareness is supposed to be lacking (VS) or severely disturbed (MCS). VS and MCS patients are not characterized by any lesion to the lower brain stem; rather, their injuries concern cortical gray matter, or white matter (diffuse axonal injury), or the thalamus (Adams et al., 2000, Kampfl et al., 1998, Newcombe et al., 2011).
The idea that EP and ERP would open the window into the mind of DoC patients emerged in the late 1980s (Reuter, Linke, & Kurthen, 1989). Larger studies were carried out in the 1990s and early 2000s (Kotchoubey et al., 2005, Witzke and Schönle, 1996). A considerable number of such studies, using a range of different paradigms and experimental designs, has been accumulated to the middle 2010s. But how reliable these studies are? What are their most common features? Which general conclusion(s) can be drawn from their results? A few years ago I (Kotchoubey, 2015) presented an informal, qualitative review of ERP studies performed in patients with severe chronic DoC. However, such informal reviews are always subjective. The aim of the present study was, therefore, to perform a quantitative analysis of the corresponding studies whose main conclusions can be expressed in bare numbers, thus minimizing the role of subjective judgment.
Together with other neurophysiological techniques such as fMRI, EP and ERP are expected to contribute to a better diagnostics of DoC, which is notoriously difficult and error-prone (Childs et al., 1993, Schnakers et al., 2009). Furthermore, EP and ERP measures were found to be reliable predictors of the emergence from coma (Daltrozzo et al., 2007, Fischer et al., 2004). Because VS and MCS are chronic conditions, in contrast to the acute coma, these measures can also be investigated in VS and MCS with the hope to reach a more exact prognosis of their long-term outcome.
Section snippets
Methods
A search performed using the terms (EEG OR Evoked Potentials OR Event-Related Potentials OR P300 OR MMN OR N400) AND (Disorders of Consciousness OR Vegetative State OR Unresponsive Wakefulness Syndrome OR Minimally Conscious State) yielded, on the first stage, a total of 2275 references. After reading the corresponding abstracts, 996 results were rejected as irrelevant (e.g., the authors did not study any DoC patients, but their data had some implications for DoC, or might be put in some
Sample size
The average total sample size in these studies was 31.1 patients with a standard error (SE) of ±4.57, and the median size was 19 patients. Fig. 1A shows the distribution of group sample sizes. A hypothesis that later studies employed larger samples was not supported: the correlation between sample size and year of publication was r = 0.10, p = 0.44.
Several ERP studies (Table: studies 21, 23, 27, 46, 56) aimed exclusively to show that some ERP effect can be present in DoC patients. Such studies,
Underpowered studies
Given the broad diversity of aims, tasks, methods of measurement and analysis, targeted EP and ERP components, as well as diagnostic, demographic, and etiological characteristics of patients, all general conclusions should be regarded as putative. Nevertheless, some conclusions can cautiously be drawn from the above results.
First, most EP/ERP studies are strongly underpowered. This might not be of much importance as long as the major aim of the early studies was the mere demonstration that some
Conclusions
Most of the studies published to date can at the very best be conceived of as preliminary reports whose results might probably indicate directions for further search, but do not yet present any scientific or medical facts. I would suggest that only the studies can be taken as more than pilot experiments that fulfil at least the following criteria: a minimum of 25 patients in each patient group to be compared; high-quality neurological diagnosis including CRS-R; reporting all methodological
Acknowledgement
The study was supported by the German Research Society (Deutsche Forschungsgemeinschaft, DFG), Grant KO 1375/13. The author thanks prof. Peter Martus (Department of Biometrics and Epidemiology, University of Tübingen) and two anonymous reviewers for valuable recommendations.
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2020, Clinical NeurophysiologyCitation Excerpt :ERP paradigms are often evaluated by “proof-of-concept” studies based on small samples of DoC patients. Larger clinical populations with an adequate and balanced size of the diagnostic subgroups are needed (Kotchoubey, 2017). To avoid confirmation bias, outcome assessment should be performed blind of the electrophysiological results; this was recently found to be the case in only 17% of neuroimaging studies in DoC patients (Kotchoubey and Pavlov, 2018a).
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2020, Brain Injury Medicine: Board ReviewSpatial characteristics of spontaneous and stimulus-induced individual functional connectivity networks in severe disorders of consciousness
2019, Brain and CognitionCitation Excerpt :Of a total of 47 data sets, 24 did not yield differences between MCS and UWS patients, in line with the findings of the present study (Liberati, Huenefeldt, & Olivetti, 2014). Another review (Kotchoubey, 2017) summarized all 61 publications about event-related brain potentials in DOC. The probability to find a difference between UWS and MCS was found to be strongly and negatively related to the reliability of the effect (indicating a possible publication bias, see Rosenthal, 1979; Franco, Malhotra, & Simonovitz, 2014).
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2018, Clinical NeurophysiologyCitation Excerpt :Among the neural variables extracted from EEG signals, the P300 event-related potential (ERP) has been widely used as a predictor of conscious recovery and has been associated with the preservation of remnant cognitive and perceptual functions (Cavinato et al., 2009; Kirschner et al., 2015; Schnakers et al., 2015). However, while the P300 could be useful to detect some covert abilities in a subgroup of patients under specific experimental paradigms (Bekinschtein et al., 2009; Faugeras et al., 2012), different systematic reviews have reported poor prognostic values based on this variable (Kotchoubey, 2017, Kotchoubey and Pavlov, 2018). Features of the P300 reflect the continuous interplay between ongoing internal brain activity and stimulus-triggered events and the ability to generate anticipatory neural activity at successive stages of processing of the incoming sensory events (Bekinschtein et al., 2009, Chennu et al., 2013, Polich 2007).