A coordinate-based meta-analysis of brain alterations in disorders of consciousness

Introduction
The neural correlates of consciousness (NCC) are currently a matter of debate (Seth & Bayne, 2022). Insights into NCC can be obtained by studying patients with disorders of consciousness (DoC). As DoC, which allows to investigate awareness independently from wakefulness as confounding factor, represent a rare condition (prevalence: 0.2-6.1 per 100,000 (van Erp et al., 2014)), available neuroimaging evidence in DoC generally relies on small samples (≈20 patients per study). Studies with small samples are often underpowered, prone to false positive and negative results, and low replicability (Botvinik-Nezer & Wagner, 2022).
The present meta-analysis aims to shed light on the NCC, by quantitatively synthesizing existing evidence on brain structural, functional and molecular alterations in DoC.
Methods
In January 2022, we used MEDLINE via Ovid, and Scopus and Embase via Elsevier databases to search for resting-state MRI and PET studies, published from 2000 to 2022, and involving adults (≥16 years old) with prolonged DoC (≥28 days) and either a clinical diagnosis of unresponsive wakefulness syndrome (UWS; presenting arousal and reflexive movements) or minimally conscious state (MCS; presenting arousal and minimal signs of awareness) based on a validated behavioural scale (Schnakers et al., 2020). Two referees (among AS, BK, NA, SA, JA) independently screened abstracts and full texts of selected studies and extracted coordinates of whole-brain, voxel-based comparisons performed between groups of patients and controls or subgroups of patients. Coordinate-based meta-analysis was performed via activation likelihood estimation (ALE) with a cluster-level p<0.05 FWE-corrected statistical threshold and an uncorrected p<0.001 cluster-forming threshold. Distribution of brain alterations was compared to the topography of resting-state networks, based on the FINDlab atlas. The full protocol, including search strategy using controlled vocabulary and keyword terms, is available on PROSPERO (CRD42022327151).
Results
As of January 2023, of the resulting 2045 MRI and 753 PET studies, 15 MRI and 18 PET studies met criteria for inclusion, for a total of 1026 patients (454 UWS; 572 MCS) and 277 controls (Fig. 1).
The primary analysis, including studies comparing DoC patients vs. controls (29 experiments; 563 patients; 221 controls), revealed brain alterations in cortical regions, medially (precuneus, posterior/middle cingulate gyrus) and laterally (angular gyri, inferior parietal lobules), and in subcortical regions (dorsomedial thalami and head of caudate nuclei) (Fig. 2). Distribution of brain alterations was predominant in the default mode (42%), executive control (28%), and basal ganglia/thalamus (23%) networks.
Contrast analysis of UWS and MCS results revealed stronger brain alterations in UWS in the precuneus, posterior/middle cingulate gyrus, right angular gyrus and inferior parietal lobule, and dorsomedial thalami.
Conclusions
This meta-analysis provides the most extensive evidence to date on brain alterations in DoC, pointing at a specific set of regions, at cortical and subcortical level, as anatomical basis for the NCC.
Our findings are only in partial agreement with current candidate theories of consciousness (Seth & Bayne, 2022): differently from the global neural workspace’s predictions, we do not find evidence that frontal regions are necessary for consciousness and, differently from integrated information theory’s prediction, we find the ‘posterior hot zone’ to be substantially limited, without involvement of occipital and temporal regions. We also report DoC to be characterized by brain alterations in subcortical structures, a finding that can be understood in the framework of the mesocircuit hypothesis (Schiff et al., 2010).
Further investigation is needed to establish whether the anatomical structures identified in the current meta-analysis represent true NCC or whether they provide only background conditions for consciousness (Koch et al., 2016).

References
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Seth, A. K., & Bayne, T. (2022). Theories of consciousness. Nature Reviews Neuroscience, 23, 439–452
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