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Patients in a vegetative state are considered to lack awareness of themselves or the environment, but preserve respiratory and cardiac functions, as well as sleep/wake cycles. These patients are incapable of producing intentional responses to external stimulation and do not demonstrate any communication skills. Recent studies have shown that around 40% of vegetative state patients have been misdiagnosed. However, in recent years there has been a revolution in the tools that are available for the assessment of these patients. The objective of this article is to discuss the role of behavioural scales, as well as advanced neuroimaging techniques, in reducing the misdiagnosis rate. We review the scope and limitations of these approaches for the identification of overt and covert signs of awareness, and we present evidence to support a multimodal assessment that combines information from behavioural, structural, and functional imaging tools to ensure an accurate diagnosis for each individual patient. [ABSTRACT FROM AUTHOR]

Patients in a vegetative state are considered to lack awareness of themselves or the environment, but preserve respiratory and cardiac functions, as well as sleep/wake cycles. These patients are incapable of producing intentional responses to external stimulation and do not demonstrate any communication skills. Recent studies have shown that around 40% of vegetative state patients have been misdiagnosed. However, in recent years there has been a revolution in the tools that are available for the assessment of these patients. The objective of this article is to discuss the diagnostic role of behavioural scales, as well as advanced neuroimaging techniques in reducing the misdiagnosis rate. We review the scope and limitations of these approaches for the identification of overt and covert signs of awareness, and we present evidence to support a multimodal assessment that combines information from behavioural, structural, and functional imaging tools to ensure an accurate diagnosis for each individual patient. [ABSTRACT FROM AUTHOR]

In the last few years, mental imagery fMRI paradigms have been used successfully to identify covert command-following and awareness in some patients who are thought to be entirely vegetative. However, to date there is only evidence supporting their use at magnetic fields of 3T, which limits their applicability in clinical settings where lower field strengths are typically used. Here, we test the ‘gold standard’ fMRI paradigm for detecting residual awareness in non-responsive patients by comparing its sensitivity at 1.5T and 3T in the same group of healthy volunteers. We were able to successfully detect brain activity showing command-following in most participants at both 3T and 1.5T, with similar reliability. These results demonstrate that fMRI assessment of covert awareness is clinically viable and therefore justify a broader use of these methods in standard assessments in severely brain injured patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Ann Neurol 2012;72:335-343. [ABSTRACT FROM AUTHOR]

Abstract: The vegetative (VS) and minimally conscious (MCS) states are currently distinguished on the basis of exhibited behaviour rather than underlying pathology. Although previous histopathological studies have documented different degrees of diffuse axonal injury as well as damage to the thalami and brainstem regions in VS and MCS, these differences have not been assessed in vivo, and therefore, do not provide a measurable pathological marker to aid clinical diagnosis. Currently, the diagnostic decision-making process is highly subjective and prone to error. Indeed, previous work has suggested that up to 43% of patients in this group may be misdiagnosed. We used diffusion tensor imaging (DTI) to study the neuropathology of 25 vegetative and minimally conscious patients in vivo and to identify measures that could potentially distinguish the patients in these two groups. Mean diffusivity (MD) maps of the subcortical white matter, brainstem and thalami were generated. The MCS and VS patients differed significantly in subcortical white matter and thalamic regions, but appeared not to differ in the brainstem. Moreover, the DTI results predicted scores on the Coma Recovery Scale (p <0.001) and successfully classified the patients in to their appropriate diagnostic categories with an accuracy of 95%. The results suggest that this method may provide an objective and highly accurate method for classifying these challenging patient populations and may therefore complement the behavioural assessment to inform the diagnostic decision making process. [ABSTRACT FROM AUTHOR]

Background: The rate of recovery from the vegetative state (VS) is low. Currently, little is known of the mechanisms and cerebral changes that accompany those relatively rare cases of good recovery. Here, we combined functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to study the evolution of one VS patient at one month post-ictus and again twelve months later when he had recovered consciousness. Methods: fMRI was used to investigate cortical responses to passive language stimulation as well as task-induced deactivations related to the default-mode network. DTI was used to assess the integrity of the global white matter and the arcuate fasciculus. We also performed a neuropsychological assessment at the time of the second MRI examination in order to characterize the profile of cognitive deficits. Results: fMRI analysis revealed anatomically appropriate activation to speech in both the first and the second scans but a reduced pattern of task-induced deactivations in the first scan. In the second scan, following the recovery of consciousness, this pattern became more similar to that classically described for the default-mode network. DTI analysis revealed relative preservation of the arcuate fasciculus and of the global normal-appearing white matter at both time points. The neuropsychological assessment revealed recovery of receptive linguistic functioning by 12-months post-ictus. Conclusions: These results suggest that the combination of different structural and functional imaging modalities may provide a powerful means for assessing the mechanisms involved in the recovery from the VS. [ABSTRACT FROM AUTHOR]

Primary objective: To study cerebral response in a functional magnetic resonance imaging (fMRI) task of speech perception in a sample of patients in vegetative state (VS) and minimally conscious state (MCS) after traumatic brain injury. Methods: Three patients in VS, four patients in MCS and 19 healthy volunteers were enrolled for the study. All subjects underwent an fMRI task of passive listening of narratives played forward and backward, alternated with periods of silence. This study analysed cerebral response to language and to complex sound processing in the healthy subjects' group and in each patient, using SPM5. Results: One patient in VS and one in MCS showed cerebral responses to language and to complex sound very similar to those shown by the healthy volunteers. Two more patients, one in VS and one in MCS, showed significant responses to complex sound only. Finally, one patient in VS and one patient in MCS failed to show significant activation in response to either stimulus. Conclusions: Some patients in VS and MCS can preserve cerebral responses to language and auditory stimuli. fMRI may be useful to identify these responses, which may pass unnoticed in a bedside examination. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• We collected resting-state fMRI before, during and after M1 and cerebellar tDCS. • We used DCM to explore effective connectivity changes in the motor network. • tDCS successfully modulated connectivity between cortex, thalamus and cerebellum. • Each connection responded to tDCS with a unique nonlinear temporal fingerprint. 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. [ABSTRACT FROM AUTHOR]

Patients in the Vegetative State (VS) do not produce overt motor behavior to command and are therefore considered to be unaware of themselves and of their environments. However, we recently showed that high-density electroencephalography (EEG) can be used to detect covert command-following in some VS patients. Due to its portability and inexpensiveness, EEG assessments of awareness have the potential to contribute to a standard clinical protocol, thus improving diagnostic accuracy. However, this technique requires refinement and optimization if it is to be used widely as a clinical tool. We asked a patient who had been repeatedly diagnosed as VS for 12-years to try to move his left and right hands, between periods of rest, while EEG was recorded from four scalp electrodes. We identified appropriate and statistically reliable modulations of sensorimotor beta rhythms following commands to try to move, which could be significantly classified at a single-trial level. These reliable effects indicate that the patient attempted to follow the commands, and was therefore aware, but was unable to execute an overtly discernable action. The cognitive demands of this novel task are lower than those used previously and, crucially, allow for awareness to be determined on the basis of a 20-minute EEG recording made with only four electrodes. This approach makes EEG assessments of awareness clinically viable, and therefore has potential for inclusion in a standard assessment of awareness in the VS. [ABSTRACT FROM AUTHOR]

• We delivered multiple tDCS sessions paired with passive mobilisations of the thumb. • We used DCM of fMRI to characterise motor dynamics during command following. • Anodal M1-tDCS decreased M1 self-inhibition and increased thalamocortical coupling. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recent neuroscientific findings suggest that functional magnetic resonance imaging (fMRI)-based brain–computer interfaces may be a viable strategy for detecting covert awareness in patients clinically diagnosed as being in a vegetative state. This research may open a promising new avenue for developing neuroimaging techniques that provide prognostic and diagnostic information that complements current behavioral tests for assessing disorders of consciousness, thereby increasing the effectiveness of diagnostic screening. These techniques may also permit patients who are behaviorally nonresponsive yet retain high levels of preserved cognition to meaningfully engage in clinical decision making. Before this application can occur, certain ethical issues associated with decision-making capacity must be addressed. Although it is not currently possible to assess decision-making capacity through neuroimaging methods, it may be in the future, provided that certain conceptual and empirical steps are taken to demonstrate that brain–computer interfaces satisfy requisite criteria of capacity assessment. In this article we lay out the conceptual foundations for a mechanistic explanation of capacity that would allow the necessary empirical steps for incorporating neuroimaging techniques into the standard capacity assessment battery utilized in clinical practice. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the bedside detection of awareness in patients in the vegetative state. The study uses electroencephalography (EEG) technique involving motor imagery to detect command-following of patients who met the Coma Recovery Scale-Revised definition of vegetative state in two European centres. Result shows that patients in the vegetative state are misdiagnosed due to their appropriate EEG responses to two distinct commands.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]