Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Neuroimaging.

BACKGROUND: Over the past 5 decades, advances in neuroimaging have yielded insights into the pathophysiologic mechanisms that cause disorders of consciousness (DoC) in patients with severe brain injuries. Structural, functional, metabolic, and perfusion imaging studies have revealed specific neuroanatomic regions, such as the brainstem tegmentum, thalamus, posterior cingulate cortex, medial prefrontal cortex, and occipital cortex, where lesions correlate with the current or future state of consciousness. Advanced imaging modalities, such as diffusion tensor imaging, resting-state functional magnetic resonance imaging (fMRI), and task-based fMRI, have been used to improve the accuracy of diagnosis and long-term prognosis, culminating in the endorsement of fMRI for the clinical evaluation of patients with DoC in the 2018 US (task-based fMRI) and 2020 European (task-based and resting-state fMRI) guidelines. As diverse neuroimaging techniques are increasingly used for patients with DoC in research and clinical settings, the need for a standardized approach to reporting results is clear. The success of future multicenter collaborations and international trials fundamentally depends on the implementation of a shared nomenclature and infrastructure. METHODS: To address this need, the Neurocritical Care Society's Curing Coma Campaign convened an international panel of DoC neuroimaging experts to propose common data elements (CDEs) for data collection and reporting in this field. RESULTS: We report the recommendations of this CDE development panel and disseminate CDEs to be used in neuroimaging studies of patients with DoC. CONCLUSIONS: These CDEs will support progress in the field of DoC neuroimaging and facilitate international collaboration.

Multi-session tDCS paired with passive mobilisation of the thumb modulates thalamo-cortical coupling during command following in the healthy brain.

Therapeutic options to restore responsiveness in patients with prolonged disorder of consciousness (PDOC) are limited. We have recently shown that a single session of tDCS over M1 delivered at rest can reduce thalamic self-inhibition during motor command following. Here, we build upon this by exploring whether pairing tDCS with a concurrent passive mobilisation protocol can further influence thalamo-M1 dynamics and whether these changes are enhanced after multiple stimulation sessions. Specifically, we used Dynamic Causal Modelling (DCM) of functional magnetic resonance imaging (fMRI) data from 22 healthy participants to assess changes in effective connectivity within the motor network during active thumb movements after 1 or 5 sessions of tDCS paired with passive mobilisations of the thumb. We found that a single anodal tDCS session decreased self-inhibition in M1, with five sessions further enhancing this effect. In addition, anodal tDCS increased thalamo-M1 excitation as compared to cathodal stimulation, with the effects maintained after 5 sessions. Together, our results suggest that pairing anodal tDCS with passive mobilisation across multiple sessions may facilitate thalamo-cortical dynamics that are relevant for behavioural responsiveness in PDOC. More broadly, they offer a mechanistic window into the neural underpinnings of the cumulative effects of multi-session tDCS.

Characterising stationary and dynamic effective connectivity changes in the motor network during and after tDCS.

The exact mechanisms behind the effects of transcranial direct current stimulation (tDCS) at a network level are still poorly understood, with most studies to date focusing on local (cortical) effects and changes in motor-evoked potentials or BOLD signal. Here, we explored stationary and dynamic effective connectivity across the motor network at rest in two experiments where we applied tDCS over the primary motor cortex (M1-tDCS) or the cerebellum (cb-tDCS) respectively. Two cohorts of healthy volunteers (n = 21 and n = 22) received anodal, cathodal, and sham tDCS sessions (counterbalanced) during 20 min of resting-state functional magnetic resonance imaging (fMRI). We used spectral Dynamic Causal Modelling (DCM) and hierarchical Parametrical Empirical Bayes (PEB) to analyze data after (compared to a pre-tDCS baseline) and during stimulation. We also implemented a novel dynamic (sliding windows) DCM/PEB approach to model the nature of network reorganisation across time. In both experiments we found widespread effects of tDCS that extended beyond the targeted area and modulated effective connectivity between cortex, thalamus, and cerebellum. These changes were characterised by unique nonlinear temporal fingerprints across connections and polarities. Our results support growing research challenging the classic notion of anodal and cathodal tDCS as excitatory and inhibitory respectively, as well as the idea of a cumulative effect of tDCS over time. Instead, they described a rich set of changes with specific spatial and temporal patterns. Our work provides a starting point for advancing our understanding of network-level tDCS effects and may guide future work to optimise its cognitive and clinical applications.

Use of functional magnetic resonance imaging to assess cognition and consciousness in severe Guillain-Barré syndrome.

Objective: Functional neuroimaging may provide a viable means of assessment and communication in patients with Guillain-Barré Syndrome (GBS) mimicking the complete locked-in state. Functional neuroimaging has been used to assess residual cognitive function and has allowed for binary communication with other behaviourally non-responsive patients, such as those diagnosed with unresponsive wakefulness syndrome. We evaluated the potential application of functional neuroimaging using a clinical-grade scanner to determine if individuals with severe GBS retained auditory function, command following, and communication. Methods: Fourteen healthy participants and two GBS patients were asked to perform motor imagery and spatial navigation imagery tasks while being scanned using functional magnetic resonance imaging. The GBS patients were also asked to perform additional functional neuroimaging scans to attempt communication. Results: The motor imagery and spatial navigation task elicited significant activation in appropriate regions of interest for both GBS patients, indicating intact command following. Both patients were able to use the imagery technique to communicate in some instances. Patient 1 was able to use one of four communication tasks to answer a question correctly. Patient 2 was able to use three of seven communication tasks. However, two questions were incorrectly answered while a third was non-verifiable. Conclusions: GBS patients can respond using mental imagery and these responses can be detected using functional neuroimaging. Furthermore, these patients may also be able to use mental imagery to provide answers to 'yes' or 'no' questions in some instances. We argue that the most appropriate use of neuroimaging-based communication in these patients is to allow them to communicate wishes or preferences and assent to previously expressed decisions, rather than to facilitate decision-making.

Functional Neuroimaging as an Assessment Tool in Critically Ill Patients.

OBJECTIVE: Little is known about residual cognitive function in the earliest stages of serious brain injury. Functional neuroimaging has yielded valuable diagnostic and prognostic information in chronic disorders of consciousness, such as the vegetative state (also termed unresponsive wakefulness syndrome). The objective of the current study was to determine if functional neuroimaging could be efficacious in the assessment of cognitive function in acute disorders of consciousness, such as coma, where decisions about the withdrawal of life-sustaining therapies are often made. METHODS: A hierarchical functional magnetic resonance imaging (fMRI) approach assessed sound perception, speech perception, language comprehension, and covert command following in 17 critically ill patients admitted to the intensive care unit (ICU). RESULTS: Preserved auditory function was observed in 15 patients (88%), whereas 5 (29%) also had preserved higher-order language comprehension. Notably, one patient could willfully modulate his brain activity when instructed to do so, suggesting a level of covert conscious awareness that was entirely inconsistent with his clinical diagnosis at the time of the scan. Across patients, a positive relationship was also observed between fMRI responsivity and the level of functional recovery, such that patients with the greatest functional recovery had neural responses most similar to those observed in healthy control participants. INTERPRETATION: These results suggest that fMRI may provide important diagnostic and prognostic information beyond standard clinical assessment in acutely unresponsive patients, which may aid discussions surrounding the continuation or removal of life-sustaining therapies during the early post-injury period. ANN NEUROL 2023;93:131-141.

Investigating the shift between externally and internally oriented cognition: a novel task-switching paradigm.

Despite our constant need to flexibly balance internal and external information, research on cognitive flexibility has focused solely on shifts between externally oriented tasks. In contrast, switches across internally oriented processes (and self-referential cognition specifically) and between internal and external domains have never been investigated. Here, we report a novel task-switching paradigm developed to explore the behavioural signatures associated with cognitive flexibility when self-referential processes, as well as more traditional external processes, are involved. Two hundred healthy volunteers completed an online task. In each trial, participants performed one of four possible tasks on written words, as instructed by a pre-stimulus cue. These included two externally and two internally oriented tasks: assessing whether the third letter was a consonant or the penultimate letter was a vowel versus assessing whether the adjective applied to their personality or if it described a bodily sensation they were currently experiencing. In total, 40% of trials involved switches to another task, and these were equally distributed across within-external, within-internal, internal-to-external and external-to-internal switches. We found higher response times for switches compared to repetitions both in the external and internal domains, thus demonstrating the presence of switch costs in self-referential tasks for the first time. We also found higher response times for between-domain switches compared to switches within each domain. We propose that these effects originate from the goal-directed engagement of different domain-specific cognitive systems that flexibly communicate and share domain-general control features.

Prefrontal tDCS is unable to modulate mind wandering propensity or underlying functional or effective brain connectivity.

There is conflicting evidence over the ability to modulate mind-wandering propensity with anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (prefrontal tDCS). Here, 20 participants received 20-min of active and sham prefrontal tDCS while in the MRI scanner, in two separate sessions (counterbalanced). In each session, they completed two runs of a sustained attention to response task (before and during tDCS), which included probes recording subjective responses of mind-wandering. We assessed the effects of tDCS on behavioural responses as well as functional and effective dynamics, via dynamic functional network connectivity (dFNC) and dynamic causal modelling analyses over regions of the default mode, salience and executive control networks. Behavioural results provided substantial evidence in support of no effect of tDCS on task performance nor mind-wandering propensity. Similarly, we found no effect of tDCS on frequency (how often) or dwell time (time spent) of underlying brain states nor effective connectivity. Overall, our results suggest that prefrontal tDCS is unable to modulate mind-wandering propensity or influence underlying brain function. This expands previous behavioural replication failures in suggesting that prefrontal tDCS may not lead to even subtle (i.e., under a behavioural threshold) changes in brain activity during self-generated cognition.

Applications of Advanced MRI to Disorders of Consciousness.

Disorder of consciousness (DoC) after severe brain injury presents numerous challenges to clinicians, as the diagnosis, prognosis, and management are often uncertain. Magnetic resonance imaging (MRI) has long been used to evaluate brain structure in patients with DoC. More recently, advances in MRI technology have permitted more detailed investigations of the brain's structural integrity (via diffusion MRI) and function (via functional MRI). A growing literature has begun to show that these advanced forms of MRI may improve our understanding of DoC pathophysiology, facilitate the identification of patient consciousness, and improve the accuracy of clinical prognostication. Here we review the emerging evidence for the application of advanced MRI for patients with DoC.

tDCS modulates effective connectivity during motor command following; a potential therapeutic target for disorders of consciousness.

Transcranial direct current stimulation (tDCS) is attracting increasing interest as a potential therapeutic route for unresponsive patients with prolonged disorders of consciousness (PDOC). However, research to date has had mixed results. Here, we propose a new direction by directly addressing the mechanisms underlying lack of responsiveness in PDOC, and using these to define our targets and the success of our intervention in the healthy brain first. We report 2 experiments that assess whether tDCS to the primary motor cortex (M1-tDCS; Experiment 1) and the cerebellum (cb-tDCS; Experiment 2) administered at rest modulate thalamo-cortical coupling in a subsequent command following task typically used to clinically assess awareness. Both experiments use sham- and polarity-controlled, randomised, double-blind, crossover designs. In Experiment 1, 22 participants received anodal, cathodal, and sham M1-tDCS sessions while in the MRI scanner. A further 22 participants received the same protocol with cb-tDCS in Experiment 2. We used Dynamic Causal Modelling of fMRI to characterise the effects of tDCS on brain activity and dynamics during simple thumb movements in response to command. We found that M1-tDCS increased thalamic excitation and that Cathodal cb-tDCS increased excitatory coupling from thalamus to M1. All these changes were polarity specific. Combined, our experiments demonstrate that tDCS can successfully modulate long range thalamo-cortical dynamics during command following via targeting of cortical regions. This suggests that M1- and cb-tDCS may allow PDOC patients to overcome the motor deficits at the root of their reduced responsiveness, improving their rehabilitation options and quality of life as a result.

Disruptions in Effective Connectivity within and between Default Mode Network and Anterior Forebrain Mesocircuit in Prolonged Disorders of Consciousness.

Recent research indicates prolonged disorders of consciousness (PDOC) result from structural and functional impairments to key cortical and subcortical networks, including the default mode network (DMN) and the anterior forebrain mesocircuit (AFM). However, the specific mechanisms which underpin such impairments remain unknown. It is known that disruptions in the striatal-pallidal pathway can result in the over inhibition of the thalamus and lack of excitation to the cortex that characterizes PDOC. Here, we used spectral dynamic causal modelling and parametric empirical Bayes on rs-fMRI data to assess whether DMN changes in PDOC are caused by disruptions in the AFM. PDOC patients displayed overall reduced coupling within the AFM, and specifically, decreased self-inhibition of the striatum, paired with reduced coupling from striatum to thalamus. This led to loss of inhibition from AFM to DMN, mostly driven by posterior areas including the precuneus and inferior parietal cortex. In turn, the DMN showed disruptions in self-inhibition of the precuneus and medial prefrontal cortex. Our results provide support for the anterior mesocircuit model at the subcortical level but highlight an inhibitory role for the AFM over the DMN, which is disrupted in PDOC.

Therapeutic Use of Transcranial Direct Current Stimulation in the Rehabilitation of Prolonged Disorders of Consciousness.

Patients with Prolonged Disorders of Consciousness (PDOC) have catastrophic disabilities and very complex needs for care. Therapeutic options are very limited, and patients often show little functional improvement over time. Neuroimaging studies have demonstrated that a significant number of PDOC patients retain a high level of cognitive functioning, and in some cases even awareness, and are simply unable to show this with their external behavior - a condition known as cognitive-motor dissociation (CMD). Despite vast implications for diagnosis, the discovery of covert cognition in PDOC patients is not typically associated with a more favorable prognosis, and the majority of patients will remain in a permanent state of low responsiveness. Recently, transcranial direct current stimulation (tDCS) has attracted attention as a potential therapeutic tool in PDOC. Research to date suggests that tDCS can lead to clinical improvements in patients with a minimally conscious state (MCS), especially when administered over multiple sessions. While promising, the outcomes of these studies have been highly inconsistent, partially due to small sample sizes, heterogeneous methodologies (in terms of both tDCS parameters and outcome measures), and limitations related to electrode placement and heterogeneity of brain damage inherent to PDOC. In addition, we argue that neuroimaging and electrophysiological assessments may serve as more sensitive biomarkers to identify changes after tDCS that are not yet apparent behaviorally. Finally, given the evidence that concurrent brain stimulation and physical therapy can enhance motor rehabilitation, we argue that future studies should focus on the integration of tDCS with conventional rehabilitation programmes from the subacute phase of care onwards, to ascertain whether any synergies exist.

Effect of tDCS Over the Right Inferior Parietal Lobule on Mind-Wandering Propensity.

Mind-wandering is associated with switching our attention to internally directed thoughts and is by definition an intrinsic, self-generated cognitive function. Interestingly, previous research showed that it may be possible to modulate its propensity externally, with transcranial direct current stimulation (tDCS) targeting different regions in the default mode and executive control networks (ECNs). However, these studies used highly heterogeneous montages (targeting the dorsolateral prefrontal cortex (DLPFC), the right inferior parietal lobule (IPL), or both concurrently), often showed contradicting results, and in many cases failed to replicate. Our study aimed to establish whether tDCS of the default mode network (DMN), via targeting the right IPL alone, could modulate mind-wandering propensity using a within-subjects double-blind, counterbalanced design. Participants completed sustained attention to response task (SART) interspersed with thought-probes to capture their subjective reports of mind-wandering before and after receiving anodal, cathodal, or sham tDCS over the right IPL (with the reference over the left cheek). We found evidence for the lack of an effect of stimulation on subjective reports of mind-wandering (JZS-BF01 = 5.19), as well as on performance on the SART task (errors (JZS-BF01 = 6.79) and reaction time (JZS-BF01 = 5.94). Overall, we failed to replicate previous reports of successful modulations of mind-wandering propensity with tDCS over the IPL, instead of providing evidence in support of the lack of an effect. This and other recent unsuccessful replications call into question whether it is indeed possible to externally modulate spontaneous or self-generated cognitive processes.

The neural basis of external responsiveness in prolonged disorders of consciousness.

OBJECTIVE: To investigate the structural integrity of fibre tracts underlying overt motor behaviour in PDOC. METHODS: This cross-sectional study examined 15 PDOC patients and 22 healthy participants. Eight PDOC patients met the criteria for the vegetative state, 5 met the criteria for the minimally conscious state and 2 met the criteria for emerging from the minimally conscious state. We used fibre tractography to reconstruct the white matter fibres known to be involved in voluntary motor execution (i.e., those connecting thalamus with M1, M1 with cerebellum, and cerebellum with thalamus) and used fractional anisotropy (FA) as a measure of their integrity. RESULTS: PDOC patients showed significantly reduced FA relative to controls on the fibres connecting thalamus and M1. This went above and beyond a widespread injury to the white matter and correlated with clinical severity. In a subset of patients, we also identified a similar pattern of injury in the fibres connecting M1 and cerebellum but a relative preservation of those connecting cerebellum and thalamus. CONCLUSIONS: Our results suggest that structural damage to motor fibres may lead to reduced responsiveness in PDOC patients across all diagnostic sub-categories, and therefore behavioural assessments may underestimate the level of retained cognitive function and awareness across the PDOC spectrum.

Why use a mirror to assess visual pursuit in prolonged disorders of consciousness? Evidence from healthy control participants.

BACKGROUND: Evidence of reliable smooth visual pursuit is crucial for both diagnosis and prognosis in prolonged disorders of consciousness (PDOC). However, a mirror is more likely than an object to elicit evidence of smooth pursuit. Our objective was to identify the physiological and/or cognitive mechanism underlying the mirror benefit. METHODS: We recorded eye-movements while healthy participants simultaneously completed a visual pursuit task and a cognitively demanding two-back task. We manipulated the stimulus to be pursued (two levels: mirror, ball) and the simultaneous cognitive load (pursuit only, pursuit plus two-back task) within subjects. RESULTS: Pursuit of the reflected-own-face in the mirror was associated with briefer fixations that occurred less uniformly across the horizontal plane relative to object pursuit. Secondary task performance did not differ between pursuit stimuli. The secondary task also did not affect eye movement measures, nor did it interact with pursuit stimulus. CONCLUSIONS: Reflected-own-face pursuit is no less cognitively demanding than object pursuit, but it naturally elicits smoother eye movements (i.e. briefer pauses to fixate). A mirror therefore provides greater sensitivity to detect smooth visual pursuit in PDOC because the naturally smoother eye movements may be identified more confidently by the assessor.

Somatosensory attention identifies both overt and covert awareness in disorders of consciousness.

OBJECTIVE: Some patients diagnosed with disorders of consciousness retain sensory and cognitive abilities beyond those apparent from their overt behavior. Characterizing these covert abilities is crucial for diagnosis, prognosis, and medical ethics. This multimodal study investigates the relationship between electroencephalographic evidence for perceptual/cognitive preservation and both overt and covert markers of awareness. METHODS: Fourteen patients with severe brain injuries were evaluated with an electroencephalographic vibrotactile attention task designed to identify a hierarchy of residual somatosensory and cognitive abilities: (1) somatosensory steady-state evoked responses, (2) bottom-up attention orienting (P3a event-related potential), and (3) top-down attention (P3b event-related potential). Each patient was also assessed with a clinical behavioral scale and 2 functional magnetic resonance imaging assessments of covert command following. RESULTS: Six patients produced only sensory responses, with no evidence of cognitive event-related potentials. A further 8 patients demonstrated reliable bottom-up attention-orienting responses (P3a). No patient showed evidence of top-down attention (P3b). Only those patients who followed commands, whether overtly with behavior or covertly with functional neuroimaging, also demonstrated event-related potential evidence of attentional orienting. INTERPRETATION: Somatosensory attention-orienting event-related potentials differentiated patients who could follow commands from those who could not. Crucially, this differentiation was irrespective of whether command following was evident through overt external behavior, or through covert functional neuroimaging methods. Bedside electroencephalographic methods may corroborate more expensive and challenging methods such as functional neuroimaging, and thereby assist in the accurate diagnosis of awareness. Ann Neurol 2016;80:412-423.

Relationship between the anterior forebrain mesocircuit and the default mode network in the structural bases of disorders of consciousness.

The specific neural bases of disorders of consciousness (DOC) are still not well understood. Some studies have suggested that functional and structural impairments in the default mode network may play a role in explaining these disorders. In contrast, others have proposed that dysfunctions in the anterior forebrain mesocircuit involving striatum, globus pallidus, and thalamus may be the main underlying mechanism. Here, we provide the first report of structural integrity of fiber tracts connecting the nodes of the mesocircuit and the default mode network in 8 patients with DOC. We found evidence of significant damage to subcortico-cortical and cortico-cortical fibers, which were more severe in vegetative state patients and correlated with clinical severity as determined by Coma Recovery Scale-Revised (CRS-R) scores. In contrast, fiber tracts interconnecting subcortical nodes were not significantly impaired. Lastly, we found significant damage in all fiber tracts connecting the precuneus with cortical and subcortical areas. Our results suggest a strong relationship between the default mode network - and most importantly the precuneus - and the anterior forebrain mesocircuit in the neural basis of the DOC.

The dissociation between command following and communication in disorders of consciousness: an fMRI study in healthy subjects.

Neuroimaging studies have identified a subgroup of patients with a Disorder of Consciousness (DOC) who, while being behaviorally non-responsive, are nevertheless able to follow commands by modulating their brain activity in motor imagery (MI) tasks. These techniques have even allowed for binary communication in a small number of DOC patients. However, the majority of patients who can follow commands are unable to use their responses to communicate. A similar dissociation between present command following (CF) and absent communication abilities has been reported in overt behavioral assessments. However, the neural correlates of this dissociation in both overt and covert modalities are unknown. Here, we used functional magnetic resonance imaging (fMRI) to explore the neural mechanisms underlying CF and selection of responses for binary communication using either executed or imagined movements. Fifteen healthy participants executed or imagined two different types of arm movements that were either pre-determined by the experimenters (CF) or decided by them (action selection, AS). Action selection involved greater activity in high-level associative areas in frontal and parietal regions than CF. Additionally, motor execution (ME), as compared to MI, activated contralateral motor cortex, while the opposite contrast revealed activation in the ipsilateral sensorimotor cortex and the left inferior frontal gyrus. Importantly, there was no interaction between the task (CF/AS) and modality (MI/ME). Our results suggest that the neural processes involved in following a motor command or selecting between two motor actions are not dependent on how the response is expressed (via ME/MI). They also suggest a potential neural basis for the distinction in cognitive abilities seen in DOC patients.