Differences in the systems-level neuropathological mechanisms that underlie the clinical symptoms of DOC between patients in the MCS and with UWS remain incompletely understood (Giacino et al., 2014). Using a novel PCA-based approach to quantitatively assess the entropy carried by rs-fMRI signals in individual neuroanatomically defined brain regions (Tzourio-Mazoyer et al., 2002), we show that, relative to healthy control individuals, the MCS is associated with a reduction of information content, as quantified by entropy of regional BOLD rs-fMRI signals, primarily in the sensory and memory but not high-order cognitive systems. In contrast, UWS is associated with a reduction of information content in all sensory, memory, and cognitive systems relative to healthy control individuals and MCS patients. The significance of the findings can be better appreciated in the contexts of the differences in clinical symptoms between the MCS and UWS as well as the theories of human consciousness.
Theoretical studies of human consciousness and investigations of the neuropathological mechanisms underlying DOC in clinical patients mutually inform each other. According to the information integration theory (Oizumi et al., 2014; Tononi, 2004; Tononi & Koch, 2008), the level and richness of consciousness are related to the information capacity and the amount of integrated information in the brain. Brain injuries in DOC patients may lead to a diminished state of consciousness by reducing the information capacity or disrupting information integration in the brain. During the past decade, extensive rs-fMRI-based studies have examined disruptions of the integrity of functional connections in large-scale brain networks in DOC patients (Boly et al., 2012; Giacino et al., 2014). Altered and mostly reduced function connectivities have been evidenced in the default mode network (Boly et al., 2009; Guldenmund, Vanhaudenhuyse, Boly, Laureys, & Soddu, 2012; Soddu et al., 2012; Soddu et al., 2011; Vanhaudenhuyse et al., 2010), thalamocortical networks (Crone et al., 2014; Laureys et al., 2000; Zhou et al., 2011), and multiple intrinsic connectivity networks (Crone et al., 2014; Demertzi et al., 2015; Demertzi et al., 2014; Heine et al., 2012; Long et al., 2016) in coma, MCS, and UWS patients. The altered functional connections in these large-scale networks were often taken as surrogate evidence of disrupted/reduced cortical information integration that may underlie DOC in patient populations. In contrast, to our knowledge, no other studies have directly addressed, especially in a region-specific manner, the possible alterations of information capacity in the brain as reflected by the signals of brain imaging modalities in DOC patients based on plausible computational measures. An element of the novelty of the present study stems from its theory-driven analytical approach that allows the obtained results to be directly discussed and interpreted in the context of the current theories of consciousness (Oizumi et al., 2014; Tononi, 2004; Tononi & Koch, 2008).
The incessant changes of spontaneous configurations of intrinsic brain activity in resting wakefulness in healthy individuals are considered to underlie the ongoing stream of consciousness that encompasses spontaneous mentation, imagery, task-independent thoughts, daydreaming, etc. (Mason et al., 2007). Such intrinsic brain activities can be captured by or reflected in signals of brain imaging modalities. It is plausible to assume that the richness or repertoire of the configurations of intrinsic brain activities as measured by rs-fMRI may be altered in various cortical and subcortical systems of the brain in DOC patients. From an information theory perspective, the amount of information generated by a dynamic system is equivalent to the degree of uncertainty of its intrinsic states measured by the system’s entropy, assuming that the noise influence is minimized (Ben-Naim, 2012). A high entropy of intrinsic brain activity indicates a high degree of uncertainty and, therefore, a rich repertoire of intrinsic metastable states that the brain can access over time (Carhart-Harris et al., 2014; Haldeman & Beggs, 2005; Shanahan, 2010; Tognoli & Kelso, 2014). Though entropy can be assessed at different spatial scales of functional imaging measurement, e.g., from a single voxel to large-scale network level, the current study focuses on examining entropy at the spatial scale defined by individual neuroanatomical regions (Tzourio-Mazoyer et al., 2002). Macroscopic anatomical boundaries have a general, though imperfect, relation to functional boundaries. By performing such region-based analysis, insights may be gained with respect to how the amount of entropy or information content as carried by rs-fMRI signals may be altered in various sensory, memory, and high-order cognitive systems in MCS and UWS patients compared with healthy control individuals. Thus, our findings provide, within the current theoretical context of human consciousness, direct evidence that diminished consciousness in MCS and UWS is associated with a reduction of information content in the brain as carried by regional BOLD rs-fMRI signals.
It is worth emphasizing that, computationally, a direct calculation of entropy (Eq. 1) using the regional voxel BOLD fMRI signals is not feasible because of the presence of a high degree of collinearity among individual voxel signal time series within the same anatomical region. In this work, we proposed a novel PCA-based approach to quantify entropy carried by regional BOLD fMRI signals, circumventing this computational limitation. Moreover, we found that data in a predominant portion (> 98.17%) of obtained PCs conforms to a Gaussian distribution, supporting the use of Eq. 1 for the entropy calculation. We consider that the observed predominant Gaussian distribution is mainly due to fact that data in each PC is a linear combination of all voxel BOLD fMRI signals in individual neuroanatomical regions. According to the central limit theorem, the resulting PC time series converges to a Gaussian distribution.
An important finding of the present study is the differential patterns of the reduction of information content in the sensory and memory compared with cognitive systems in MCS and UWS patients relative to healthy control individuals. Specifically, information content is only reduced in the sensory and memory but not in high-order cognitive systems in MCS patients; in contrast, a significant reduction of information content occurred in all sensory, memory, and cognitive systems in UWS patients compared with both healthy control individuals and MCS patients. Such differential reductions of information content in sensory and memory compared with cognitive systems in MCS and UWS patients are consistent with the manifestations of clinical symptoms in the two DOC patient populations. First, MCS patients show inconsistent but reproducible signs of awareness of the self and environment, which requires that the high-order cognitive systems still be functional to a reasonable extent for the possibility of generating meaningful perceptions. In parallel, MCS patients recently were found to have brain activation patterns to transcranial magnetic stimulation that are as widespread and differentiated as observed in healthy individuals and locked-in patients (Gosseries et al., 2015). On the other hand, the very limited capability of showing an evident possession of awareness in MCS patients is plausibly related to a functional degradation in the sensory and memory systems of the brain, as reflected by a reduction of entropy/information content in these regions. Second, for UWS patients who show no signs of any awareness at all, it is plausible that the ability in UWS patients to form any meaningful perception in the high-order cognitive systems is seriously compromised, together with a much severer degradation of functions in sensory and memory systems, even compared with MCS patients. Indeed, a convincing piece of evidence supporting our conclusions is that as the symptoms of DOC deepen from MCS to UWS patients relative to healthy control individuals, the reduction of regional information content also becomes significantly enlarged in all the sensory, memory, and cognitive systems of the brain in UWS compared with MCS patients. Such a trend of changes is less likely occasional but more convincingly a reflection of the differences in the severity of the clinical symptoms of DOC between MCS and UWS patients.
With respect to the exception to the trend of changes in the sensory systems, i.e., the visual cortex (Fig. 2A, last bar group), we consider that the variations in maintaining eye-opening and eye-closing conditions in healthy individuals and especially in MCS patients during scan may have played a role. However, it is however puzzling to us that the exception in the cognitive systems, the PCC and precuneus, an area that has been particularly implicated in consciousness and DOC in terms of its metabolism and functional connectivity (Boly et al., 2012; Giacino et al., 2014; Hannawi, Lindquist, Caffo, Sair, & Stevens, 2015), did not show significant differences in entropy among the three groups (Fig. 2B, last bar group). We speculate that the observation may be related to the inherent anatomical heterogeneity in the PCC and precuneus (Leech & Sharp, 2014), which may confine significant changes of entropy in rs-fMRI signals. Clearly, it should be highlighted that the regional information content measured by entropy, metabolism, task-related activation, and functional connectivity are not the same and that they reflect different functional properties of mass neural activities of the brain.
A few limitations of the present study are noted. First, entropy was derived from rs-fMRI BOLD signals that are indirect, coarse-grained indicators of neuronal activity. Thus, interpretations of the results shall be in the context of imaging signal acquisition. Second, estimating entropy requires noise influence to be minimized. Our concern about the denoising issue, however, was mitigated because of the observation that the trend of reduction in information content scales with severity of DOC in MCS and UWS patients, which was unlikely led by noise. In addition, PCA performed in this study eliminated a portion of nuisance components, offering an additional procedure for signal denoising. Third, another possibility is that systematic changes in the physiological conditions (blood pressure, breathing and heart beat rates, etc.) across subjects in the three groups may produce artificial changes in BOLD fMRI signals (e.g., the amplitude and variance) that affect the analysis of entropy. Considering this possibility, we performed a voxelwise standardization of BOLD fMRI signals (normalizing to zero mean and unity standard deviation, i.e., z-score) before applying low-pass filtering. Therefore, the effects of alterations of physiological parameters on the obtained results should be minimal.
In summary, using a novel PCA-based approach to quantitatively assess the entropy carried by rs-fMRI signals across individual neuroanatomically defined brain regions, we show in the theoretical context that the diminished state of consciousness in MCS and UWS patients is associated with a reduction in information content in the brain compared with healthy individuals. Importantly, our findings reveal differential patterns of reduction in information content in the sensory and memory compared with cognitive systems in MCS and UWS patients, which are consistent with their respective clinical symptoms. Together, the findings suggest a systems-level mechanism in terms of the alteration of regional information content in the brain that may underlie consciousness disorders in MCS and UWS patients.