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.

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.

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.

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.

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.

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.

Detecting awareness after severe brain injury.

Recent developments in functional neuroimaging have provided a number of new tools for assessing patients who clinically appear to be in a vegetative state. These techniques have been able to reveal awareness and even allow rudimentary communication in some patients who remain entirely behaviourally non-responsive. The implications of these results extend well beyond the immediate clinical and scientific findings to influencing legal proceedings, raising new ethical questions about the withdrawal of nutrition and hydration and providing new options for patients and families in that decision-making process. The findings have also motivated significant public discourse about the role of neuroscience research in society.

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.

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.

Acknowledging awareness: informing families of individual research results for patients in the vegetative state.

Recent findings in cognitive neuroscience have revealed that some patients previously diagnosed as being in a vegetative state may retain some degree of covert awareness. However, it is unclear whether such findings should be disclosed to the families of these patients. Concerns about the preservation of scientific validity, reliability of results and potential harms associated with disclosure suggest that individual research results should be disclosed only under certain conditions. In the following paper, we offer four criteria for the disclosure of individual research results. Because the results of functional neuroimaging studies to detect covert awareness in vegetative patients are scientifically valid, informative and reasonably reliable and have considerable potential benefit for the patient, researchers have an obligation to disclose such results to family members. Further work is needed to develop educational materials for families and to systematically study the impact of disclosure on the families themselves.

Ethics of neuroimaging after serious brain injury.

BACKGROUND: Patient outcome after serious brain injury is highly variable. Following a period of coma, some patients recover while others progress into a vegetative state (unresponsive wakefulness syndrome) or minimally conscious state. In both cases, assessment is difficult and misdiagnosis may be as high as 43%. Recent advances in neuroimaging suggest a solution. Both functional magnetic resonance imaging and electroencephalography have been used to detect residual cognitive function in vegetative and minimally conscious patients. Neuroimaging may improve diagnosis and prognostication. These techniques are beginning to be applied to comatose patients soon after injury. Evidence of preserved cognitive function may predict recovery, and this information would help families and health providers. Complex ethical issues arise due to the vulnerability of patients and families, difficulties interpreting negative results, restriction of communication to "yes" or "no" answers, and cost. We seek to investigate ethical issues in the use of neuroimaging in behaviorally nonresponsive patients who have suffered serious brain injury. The objectives of this research are to: (1) create an approach to capacity assessment using neuroimaging; (2) develop an ethics of welfare framework to guide considerations of quality of life; (3) explore the impact of neuroimaging on families; and, (4) analyze the ethics of the use of neuroimaging in comatose patients. METHODS/DESIGN: Our research program encompasses four projects and uses a mixed methods approach. Project 1 asks whether decision making capacity can be assessed in behaviorally nonresponsive patients. We will specify cognitive functions required for capacity and detail their assessment. Further, we will develop and pilot a series of scenarios and questions suitable for assessing capacity. Project 2 examines the ethics of welfare as a guide for neuroimaging. It grounds an obligation to explore patients' interests, and we explore conceptual issues in the development of a quality of life instrument adapted for neuroimaging. Project 3 will use grounded theory interviews to document families' understanding of the patient's condition, expectations of neuroimaging, and the impact of the results of neuroimaging. Project 4 will provide an ethical analysis of neuroimaging to investigate residual cognitive function in comatose patients within days of serious brain injury.

A role for the default mode network in the bases of disorders of consciousness.

OBJECTIVE: Functional connectivity in the default mode network (DMN) is known to be reduced in patients with disorders of consciousness, to a different extent depending on their clinical severity. Nevertheless, the integrity of the structural architecture supporting this network and its relation with the exhibited functional disconnections are very poorly understood. We investigated the structural connectivity and white matter integrity of the DMN in patients with disorders of consciousness of varying clinical severity. METHODS: Fifty-two patients--19 in a vegetative state (VS), 27 in a minimally conscious state (MCS), and 6 emerging from a minimally conscious state (EMCS)--and 23 healthy volunteers participated in the study. Structural connectivity was assessed by means of probabilistic tractography, and the integrity of the resulting fibers was characterized by their mean fractional anisotropy values. RESULTS: Patients showed significant impairments in all of the pathways connecting cortical regions within this network, as well as the pathway connecting the posterior cingulate cortex/precuneus with the thalamus, relative to the healthy volunteers. Moreover, the structural integrity of this pathway, as well as that of those connecting the posterior areas of the network, was correlated with the patients' behavioral signs for awareness, being higher in EMCS patients than those in the upper and lower ranges of the MCS patients, and lowest in VS patients. INTERPRETATION: These results provide a possible neural substrate for the functional disconnection previously described in these patients, and reinforce the importance of the DMN in the genesis of awareness and the neural bases of its disorders.

Brain activation during speech perception in a patient with a massive left hemisphere infarction.

BACKGROUND: Little is known about the regions involved in recovery from global aphasia in patients with malignant infarction after decompressive hemicraniectomy. This study reports a case of brain activation during speech perception in a right-handed patient with a massive left hemispheric infarction. METHODS: Decompressive hemicraniectomy was performed in a 20-year old woman with space-occupying infarction of the speech dominant hemisphere. Complete anterior, middle and part of the posterior cerebral artery territories of the left hemisphere, as well as posterior regions of the right middle cerebral artery territory, were affected. Neuropsychological testing and functional magnetic resonance imaging (fMRI) during speech perception were performed 10 months after stroke. RESULTS: The patient was able to walk, go up and down stairs independently and perform simple tasks at home. She was also well able to match visually and orally presented words with their corresponding pictures, despite large bilateral lesions in the posterior regions. fMRI revealed strong activation of the left temporo-occipital and parieto-occipital areas. In the right hemisphere was observed a small area of activation in the posterior part of the superior and middle temporal gyrus. CONCLUSIONS: In aphasic patients, the activation of posterior bilateral associative areas might be used to support language perception.

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.

Bedside detection of awareness in the vegetative state: a cohort study.

BACKGROUND: Patients diagnosed as vegetative have periods of wakefulness, but seem to be unaware of themselves or their environment. Although functional MRI (fMRI) studies have shown that some of these patients are consciously aware, issues of expense and accessibility preclude the use of fMRI assessment in most of these individuals. We aimed to assess bedside detection of awareness with an electroencephalography (EEG) technique in patients in the vegetative state. METHODS: This study was undertaken at two European centres. We recruited patients with traumatic brain injury and non-traumatic brain injury who met the Coma Recovery Scale-Revised definition of vegetative state. We developed a novel EEG task involving motor imagery to detect command-following--a universally accepted clinical indicator of awareness--in the absence of overt behaviour. Patients completed the task in which they were required to imagine movements of their right-hand and toes to command. We analysed the command-specific EEG responses of each patient for robust evidence of appropriate, consistent, and statistically reliable markers of motor imagery, similar to those noted in healthy, conscious controls. FINDINGS: We assessed 16 patients diagnosed in the vegetative state, and 12 healthy controls. Three (19%) of 16 patients could repeatedly and reliably generate appropriate EEG responses to two distinct commands, despite being behaviourally entirely unresponsive (classification accuracy 61-78%). We noted no significant relation between patients' clinical histories (age, time since injury, cause, and behavioural score) and their ability to follow commands. When separated according to cause, two (20%) of the five traumatic and one (9%) of the 11 non-traumatic patients were able to successfully complete this task. INTERPRETATION: Despite rigorous clinical assessment, many patients in the vegetative state are misdiagnosed. The EEG method that we developed is cheap, portable, widely available, and objective. It could allow the widespread use of this bedside technique for the rediagnosis of patients who behaviourally seem to be entirely vegetative, but who might have residual cognitive function and conscious awareness. FUNDING: Medical Research Council, James S McDonnell Foundation, Canada Excellence Research Chairs Program, European Commission, Fonds de la Recherche Scientifique, Mind Science Foundation, Belgian French-Speaking Community Concerted Research Action, University Hospital of Liège, University of Liège.

Thalamic changes in a preterm sample with periventricular leukomalacia: correlation with white-matter integrity and cognitive outcome at school age.

INTRODUCTION: Thalamic abnormalities have been well documented in preterms with periventricular leukomalacia (PVL), although their contribution to long-term cognitive dysfunctions has not been thoroughly investigated. RESULTS: Significant differences between groups were observed for global thalamic volume. Neuropsychological assessments showed that preterms with PVL scored within the normal range, although significantly below controls in the full intelligence quotient and the specific cognitive domains of processing speed and working memory. Correlations of several thalamic regions with Working Memory Index and FIQ were found in the PVL group. Moreover, thalamic atrophy correlated with white-matter (WM) damage indexes (fractional anisotropy and radial diffusivity) assessed by diffusion tensor imaging. DISCUSSION: The findings suggest that thalamic damage is a common correlate of WM microstructural alterations and might be involved in the cognitive deficits seen in premature infants with PVL at school age. METHODS: We analyzed the impact of PVL-associated thalamic injury on cognitive status at school age and its correlation with WM integrity as measured by magnetic resonance imaging techniques. Thalamic volume and shape of 21 preterm children with PVL were compared with those of 11 preterm children of similar gestational age and birth weight with no evidence of focal WM abnormality.

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.

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.