[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury is a major cause of morbidity and mortality worldwide. Ameliorating the neurocognitive and physical deficits that accompany traumatic brain injury would be of substantial benefit, but the mechanisms that underlie them are poorly characterized. This study aimed to use diffusion tensor imaging to relate clinical outcome to the burden of white matter injury.
Sixty-eight patients, categorized by the Glasgow Outcome Score, underwent magnetic resonance imaging at a median of 11.8 months (range 6.6 months to 3.7 years) years post injury. Control data were obtained from 36 age-matched healthy volunteers. Mean fractional anisotropy, apparent diffusion coefficient (ADC), and eigenvalues were obtained for regions of interest commonly affected in traumatic brain injury. In a subset of patients where conventional magnetic resonance imaging was completely normal, diffusion tensor imaging was able to detect clear abnormalities. Significant trends of increasing ADC with worse outcome were noted in all regions of interest. In the white matter regions of interest worse clinical outcome corresponded with significant trends of decreasing fractional anisotropy.
This study found that clinical outcome was related to the burden of white matter injury, quantified by diffusivity parameters late after traumatic brain injury. These differences were seen even in patients with the best outcomes and patients in whom conventional magnetic resonance imaging was normal, suggesting that diffusion tensor imaging can detect subtle injury missed by other techniques. An improved in vivo understanding of the pathology of traumatic brain injury, including its distribution and extent, may enhance outcome evaluation and help to provide a mechanistic basis for deficits that remain unexplained by other approaches.
PLoS ONE 01/2011; 6(5):e19214. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The differential diagnosis of disorders of consciousness is challenging. The rate of misdiagnosis is approximately 40%, and new methods are required to complement bedside testing, particularly if the patient's capacity to show behavioral signs of awareness is diminished.
At two major referral centers in Cambridge, United Kingdom, and Liege, Belgium, we performed a study involving 54 patients with disorders of consciousness. We used functional magnetic resonance imaging (MRI) to assess each patient's ability to generate willful, neuroanatomically specific, blood-oxygenation-level-dependent responses during two established mental-imagery tasks. A technique was then developed to determine whether such tasks could be used to communicate yes-or-no answers to simple questions.
Of the 54 patients enrolled in the study, 5 were able to willfully modulate their brain activity. In three of these patients, additional bedside testing revealed some sign of awareness, but in the other two patients, no voluntary behavior could be detected by means of clinical assessment. One patient was able to use our technique to answer yes or no to questions during functional MRI; however, it remained impossible to establish any form of communication at the bedside.
These results show that a small proportion of patients in a vegetative or minimally conscious state have brain activation reflecting some awareness and cognition. Careful clinical examination will result in reclassification of the state of consciousness in some of these patients. This technique may be useful in establishing basic communication with patients who appear to be unresponsive.
New England Journal of Medicine 02/2010; 362(7):579-89. · 51.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate whether vegetative state patients maintain circadian rhythms.
An observational study of five single cases.
Five chronic vegetative state patients underwent clinical and neurological evaluations and 2-week continuous temperature measurements.
The two patients with traumatic brain injury showed well-formed circadian temperature rhythms and had more reflexive behaviours and relatively low cortical and sub-cortical atrophy, whereas the three patients from anoxic-hypoxic origin demonstrated no cycles or rhythmic behaviour.
The presence of periods of wakefulness does not imply preserved sleep-wake cycling capacity, nor preserved circadian rhythms and it should not be taken as a distinguishing feature for the definition of the vegetative state.
[Show abstract][Hide abstract] ABSTRACT: Pavlovian trace conditioning depends on the temporal gap between the conditioned and unconditioned stimuli. It requires, in mammals, functional medial temporal lobe structures and, in humans, explicit knowledge of the temporal contingency. It is therefore considered to be a plausible objective test to assess awareness without relying on explicit reports. We found that individuals with disorders of consciousness (DOCs), despite being unable to report awareness explicitly, were able to learn this procedure. Learning was specific and showed an anticipatory electromyographic response to the aversive conditioning stimulus, which was substantially stronger than to the control stimulus and was augmented as the aversive stimulus approached. The amount of learning correlated with the degree of cortical atrophy and was a good indicator of recovery. None of these effects were observed in control subjects under the effect of anesthesia (propofol). Our results suggest that individuals with DOCs might have partially preserved conscious processing, which cannot be mediated by explicit reports and is not detected by behavioral assessment.
[Show abstract][Hide abstract] ABSTRACT: Clinical audits have highlighted the many challenges and dilemmas faced by clinicians assessing persons with disorders of consciousness (vegetative state and minimally conscious state). The diagnostic decision-making process is highly subjective, dependent upon the skills of the examiner and invariably dictated by the patients' ability to move or speak. Whilst a considerable amount has been learnt since Jennett and Plum coined the term 'vegetative state', the assessment process remains largely unchanged; conducted at the bedside, using behavioural assessment tools, which are susceptible to environmental and physiological factors. This has created a situation where the rate of misdiagnosis is unacceptably high (up to 43%). In order to address these problems, various functional brain imaging paradigms, which do not rely upon the patient's ability to move or speak, have been proposed as a source of additional information to inform the diagnostic decision making process. Although accumulated evidence from brain imaging, particularly functional magnetic resonance imaging (fMRI), has been encouraging, the empirical evidence is still based on relatively small numbers of patients. It remains unclear whether brain imaging is capable of informing the diagnosis beyond the behavioural assessment and whether brain imaging has any prognostic utility. In this study, we describe the functional brain imaging findings from a group of 41 patients with disorders of consciousness, who undertook a hierarchical speech processing task. We found, contrary to the clinical impression of a specialist team using behavioural assessment tools, that two patients referred to the study with a diagnosis of vegetative state did in fact demonstrate neural correlates of speech comprehension when assessed using functional brain imaging. These fMRI findings were found to have no association with the patient's behavioural presentation at the time of investigation and thus provided additional diagnostic information beyond the traditional clinical assessment. Notably, the utility of brain imaging was further underlined by the finding that the level of auditory processing revealed by functional brain imaging, correlated strongly (rs = 0.81, P < 0.001) with the patient's subsequent behavioural recovery, 6 months after the scan, suggesting that brain imaging may also provide valuable prognostic information. Although further evidence is required before consensus statements can be made regarding the use of brain imaging in clinical decision making for disorders of consciousness, the results from this study clearly highlight the potential of imaging to inform the diagnostic decision-making process for persons with disorders of consciousness.
[Show abstract][Hide abstract] ABSTRACT: The accurate assessment of patients with impaired consciousness following a brain injury often remains a challenge to the most experienced clinician. A diagnosis of vegetative or minimally conscious state is made on the basis of the patient's clinical history and detailed behavioral examinations, which rely upon the patient being able to move or speak in order to demonstrate residual cognitive function. Recently, the development of noninvasive neuroimaging techniques has fostered a rapid increase in the exploration of residual cognitive abilities in these patient populations. However, while this body of literature is growing rapidly, at present the enterprise remains one of scientific endeavor with no inclusion in standard clinical practice. Correctly administered behavioral testing in survivors of brain injury may provide sufficient information to identify patients who are aware and are able to signal that this is the case via a recognized motor output. However, it remains possible that a subgroup of these patients may retain some level of awareness, but lack the ability to produce any motor output and are therefore mistakenly diagnosed as vegetative. It is in this latter situation that functional neuroimaging may prove to be most valuable, as a unique clinical tool for probing volition and residual cognition without necessarily assuming that the patient is able to produce any motor output.
Annals of the New York Academy of Sciences 04/2009; 1157:81-9. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: One of the major challenges in the clinical evaluation of brain injury survivors is to comprehensively assess the level of preserved cognitive function in order to inform diagnostic decisions and suggest appropriate rehabilitation strategies. However, the limited (if any) capacity for producing behavior in some of these patients often limits the extent to which cognitive functions can be explored via standard bedside methods. We present a novel neuroimaging paradigm that allows the assessment of residual executive functions without requiring the patient to produce any behavioral output. In particular, we target processes such as active maintenance of information through time and willful adoption of "mind-sets" that have been proposed to require conscious awareness. Employing an fMRI block design paradigm, healthy volunteers were presented with a series of neutral (i.e., not emotionally salient) words, and alternatively instructed to listen to all the words, or to count the number of times a given target is repeated. Importantly, the perceptual stimulation in the passive listening and the counting tasks was carefully matched. Contrasted with passive listening, the counting task revealed a fronto-parietal network previously associated with target detection and working memory. Remarkably, when tested on this same procedure, a minimally conscious patient presented a highly similar pattern of activation. Furthermore, the activity in these regions appeared highly synchronous to the onset and offset of the counting blocks. Considering the close matching of sensory stimulation across the two tasks, these findings strongly suggest that the patient could willfully adopt differential "mind-sets" as a function of condition, and could actively maintain information across time. Neither cognitive function was apparent when the patient was (behaviorally) tested at the bedside. This paradigm thus exemplifies the potential for fMRI to explore high-level cognitive functions, and awareness, in the absence of any behavioral response.
Progress in brain research 01/2009; 177:249-60. · 4.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Unlike other neurological conditions, the heterogeneous pathology linked to disorders of consciousness currently excludes a distinction between the vegetative and minimally conscious states based upon pathological presentation. The clinical assessment is therefore made on the basis of the patient's clinical history and exhibited behaviour. This creates a particular challenge for the clinician who has to decide whether a certain behaviour, which might be inconsistent or incomplete, reflects a conscious or an unconscious process. In an alarmingly high number of cases, identified during clinical audit, this decision process has been shown to be particularly fallible. The behavioural assessment is not only highly subjective, but also dependent upon the ability of the patient to move or speak; it is the only way someone can demonstrate they are aware. To address this problem we propose a multimodal approach, which integrates objective tools, such as electrophysiology and functional brain imaging, with traditional behavioural scales. Together this approach informs the clinical decision process and resolves many of the dilemmas faced by clinicians interpreting solely behavioural indices. This approach not only provides objective information regarding the integrity of residual cognitive function, but also removes the dependency on the patient to move or speak by using specially designed paradigms that do not require a motor output in order to reveal awareness of self or environment. To demonstrate this approach we describe the case of BW, who sustained a traumatic brain injury seven months prior to investigation. BW was admitted to a five-day assessment programme, which implemented our multimodal approach. On behavioural assessment BW demonstrated evidence of orientation and visual pursuit. However, he showed no response to written or verbal command, despite holding command cards and scanning text. Electrophysiology confirmed that he retained a preserved neural axis supporting vision and hearing, and suggested some evidence that he was able to create a basic memory trace. A hierarchical fMRI auditory paradigm suggested he was able to perceive sound and speech, but revealed no evidence of speech comprehension or ability to respond to command. This was corroborated in the visual modality using a hierarchical paradigm demonstrating that he was able to perceive motion, objects and faces, but retained no evidence of being able to respond to command. We briefly review work by other teams advocating the use of brain imaging and electrophysiology and discuss the steps that are now required in order to create an international standard for the assessment of persons with impaired consciousness after brain injury.
Progress in brain research 01/2009; 177:231-48. · 4.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transcranial magnetic stimulation (TMS) is a noninvasive means of investigating the function, plasticity, and excitability of the human brain. TMS induces a brief intracranial electrical current, which produces action potentials in excitable cells. Stimulation applied over the motor cortex can be used to measure overall excitability of the corticospinal system, somatotopic representation of muscles, and subsequent plastic changes following injury. The facilitation and inhibition characteristics of the cerebral cortex can also be compared using the modulatory effect of a conditioning stimulus preceding a test stimulus. So called paired-pulse protocols have been used in humans and animals to assess GABA (gamma-amino-butyric acid)-ergic function and may have a future role directing therapeutic interventions. Indeed, repetitive magnetic stimulation, where intracranial currents are induced by repetitive stimulation higher than 1 Hz, has been shown to modulate brain responses to sensory and cognitive stimulation. Here, we summarize information gathered using TMS with patients in coma, vegetative state, and minimally conscious state. Although in the early stages of investigation, there is preliminary evidence that TMS represents a promising tool by which to elucidate the pathophysiological sequelae of impaired consciousness and potentially direct future therapeutic interventions. We will discuss the methodology of work conducted to date, as well as debate the general limitations and pitfalls of TMS studies in patients with altered states of consciousness.
Progress in brain research 01/2009; 177:191-200. · 4.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Determining conscious processing in unresponsive patients relies on subjective behavioural assessment. Using data from hand electromyography, the authors studied the occurrence of subthreshold muscle activity in response to verbal command, as an objective indicator of awareness in 10 disorders of consciousness patients. One out of eight vegetative state patients and both minimally conscious patients (n = 2) demonstrated an increased electromyography signal specifically linked to command. These findings suggest electromyography could be used to assess awareness objectively in pathologies of consciousness.
Journal of neurology, neurosurgery, and psychiatry 08/2008; 79(7):826-8. · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A number of recent studies have demonstrated a role for state-of-the-art neuroimaging methods in the assessment of patients in the vegetative state and other so-called 'disorders of consciousness'. In several cases, functional MRI has been used to show that aspects of speech perception, emotional processing, language comprehension and even conscious awareness might be retained in some patients who behaviourally meet all of the criteria that define the vegetative state. This work has profound implications for clinical care, diagnosis, prognosis and medical-legal decision making (relating to the prolongation, or otherwise, of life after severe brain injury), as well as for more basic scientific questions about the nature of consciousness and the neural representation of our own thoughts and intentions.
[Show abstract][Hide abstract] ABSTRACT: The assessment of residual brain function in the vegetative state, is extremely difficult and depends frequently on subjective interpretations of observed spontaneous and volitional behaviors. For those patients who retain peripheral motor function, rigorous behavioral assessment supported by structural imaging and electrophysiology is usually sufficient to establish a patient's level of wakefulness and awareness. However, it is becoming increasingly apparent that, in some patients, damage to the peripheral motor system may prevent overt responses to command, even though the cognitive ability to perceive and understand such commands may remain intact. Advances in functional neuroimaging suggest a novel solution to this problem; in several recent cases, so-called "activation" studies have been used to identify residual cognitive function and even conscious awareness in patients who are assumed to be vegetative, yet retain cognitive abilities that have evaded detection using standard clinical methods.
Annals of the New York Academy of Sciences 02/2008; 1129:130-8. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An accurate and reliable evaluation of the level and content of cognitive processing is of paramount importance for the appropriate management of severely brain-damaged patients with disorders of consciousness. 1 Objective behavioral assessment of residual cognitive function can be extremely challenging in these patients, as motor responses may be minimal, inconsistent, and difficult to document, or may be undetectable because no cognitive output is possible. This difficulty leads to much confusion and a high-level of misdiagnoses in the vegetative state (VS), minimally conscious state, and locked-in syndrome. 2,3 Recent advances in functional neuroimaging suggest a novel solution to this problem; so-called ''activation'' studies can be used to assess cognitive functions in altered states of consciousness without the need for any overt response on the part of the patient. In several recent studies, this approach has been used to detect residual cognitive function and even conscious awareness in patients who behaviorally meet the criteria defining the VS. 4-6 Similarly, these techniques have been used in other studies to guide therapeutic interventions and track recovery processes. 7,8 Such studies suggest that the future integration of emerging functional neuroimaging techniques with existing clinical and behavioral methods of assessment will be essential in reducing the current rate of misdiagnosis. Moreover, such
International anesthesiology clinics 02/2008; 46(3):147-57.
[Show abstract][Hide abstract] ABSTRACT: This article is concerned with patients in coma, the vegetative, or minimally conscious states. Studies addressing the issue of assessment and management of these patients are described. These include (a) the development of an assessment tool (Wessex Head Injury Matrix, WHIM); (b) use of the WHIM to assess the effects of posture on arousal, showing that some 75% of patients show more behaviours when assessed while they are in a standing frame than when supine; (c) a comparison of the WHIM with the Glasgow Coma Scale, demonstrating that the WHIM is more sensitive than the GCS for measuring the behavioural repertoire of people in states of reduced consciousness; (d) a discussion of situations when neuro-imaging techniques are required to assess residual functioning; and (e) the long term outcome of one of the first vegetative patients to be scanned with Positron Emission Tomography (PET). We conclude with a discussion about neuropsychology and patients in states of impaired consciousness.
[Show abstract][Hide abstract] ABSTRACT: We discuss recent developments in the use of neuroimaging and, in particular, functional MRI, in the assessment of patients diagnosed as vegetative state or minimally conscious state.
In the last year, there has been a substantial increase in the number of research studies published which have used state-of-the-art neuroimaging methods to assess residual cognitive functioning in patients diagnosed with disorders of consciousness. Work using functional MRI has demonstrated aspects of retained speech processing, emotional processing, comprehension and even conscious awareness in a small number of patients behaviourally meeting the criteria defining the vegetative and minimally conscious states.
The assessment of patients with disorders of consciousness relies heavily upon the subjective and consequently fallible interpretation of observed behaviour. Recent studies have demonstrated an important role for functional MRI in the identification of residual cognitive function in these patients. Such studies may be particularly useful when there is concern about the accuracy of the diagnosis and the possibility that residual cognitive function has remained undetected. In our opinion, the future use of functional MRI will substantially increase our understanding of disorders of consciousness following severe brain injury.
Current Opinion in Neurology 01/2008; 20(6):632-7. · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We used functional MRI and the anesthetic agent propofol to assess the relationship among neural responses to speech, successful comprehension, and conscious awareness. Volunteers were scanned while listening to sentences containing ambiguous words, matched sentences without ambiguous words, and signal-correlated noise (SCN). During three scanning sessions, participants were nonsedated (awake), lightly sedated (a slowed response to conversation), and deeply sedated (no conversational response, rousable by loud command). Bilateral temporal-lobe responses for sentences compared with signal-correlated noise were observed at all three levels of sedation, although prefrontal and premotor responses to speech were absent at the deepest level of sedation. Additional inferior frontal and posterior temporal responses to ambiguous sentences provide a neural correlate of semantic processes critical for comprehending sentences containing ambiguous words. However, this additional response was absent during light sedation, suggesting a marked impairment of sentence comprehension. A significant decline in postscan recognition memory for sentences also suggests that sedation impaired encoding of sentences into memory, with left inferior frontal and temporal lobe responses during light sedation predicting subsequent recognition memory. These findings suggest a graded degradation of cognitive function in response to sedation such that "higher-level" semantic and mnemonic processes can be impaired at relatively low levels of sedation, whereas perceptual processing of speech remains resilient even during deep sedation. These results have important implications for understanding the relationship between speech comprehension and awareness in the healthy brain in patients receiving sedation and in patients with disorders of consciousness.
Proceedings of the National Academy of Sciences 11/2007; 104(41):16032-7. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A diagnosis of vegetative state is made if a patient demonstrates no evidence of awareness of self or environment, no evidence of sustained, reproducible, purposeful or voluntary behavioural response to sensory stimuli and critically no evidence of language comprehension. For those patients who retain peripheral motor function, rigorous behavioural assessment is usually able to determine retained function. However, some patients do not retain the ability to respond overtly to command and it is becoming increasingly accepted that assessment of these patients should include techniques, which do not rely on any 'motor action' on the part of the patient. Here, we apply a hierarchical functional magnetic resonance imaging (fMRI) auditory processing paradigm to determine the extent of retained language processing in a group of 14 aetiologically heterogeneous patients who met the diagnostic criteria for either the vegetative state (n = 7), the minimally conscious state (n = 5), or who were in a severely disabled condition having emerged from a minimally conscious state (n = 2). Three different levels of speech processing were assessed: (i) Low-level auditory responses were measured using a contrast between a set of auditory stimuli and a silence baseline; (ii) mid-level speech perception processing abilities were assessed by comparing intelligible speech to unintelligible noise stimuli and (iii) high-level semantic aspects of speech processing were assessed by comparing sentences that were made difficult to understand by the presence of words that were semantically ambiguous compared to matched low-ambiguity sentences. As expected the two severely disabled, but conscious patients showed preserved speech processing at all three levels. However, contrary to the diagnostic criteria defining the vegetative state, three patients (1 traumatic, 2 non-traumatic aetiology) demonstrated some evidence of preserved speech processing. The remaining four patients (1 traumatic, 3 non-traumatic aetiology) with a diagnosis of vegetative state showed no significant activation in response to sound compared with silence. These results provide further evidence that a subset of patients fulfilling the behavioural criteria for the vegetative state retain islands of preserved cognitive function.
[Show abstract][Hide abstract] ABSTRACT: The assessment of patients with disorders of consciousness, including the vegetative state, is difficult and depends frequently on subjective interpretations of the observed spontaneous and volitional behavior. For those patients who retain peripheral motor function, rigorous behavioral assessment supported by structural imaging and electrophysiological findings is usually sufficient to establish a patient's level of wakefulness and awareness. However, it is becoming increasingly apparent that in some patients damage to the peripheral motor system may prevent overt responses to command although the cognitive ability to perceive and understand such commands may remain intact. Recent advances in functional neuroimaging suggest a novel solution to this problem; in several cases, so-called activation studies have been used to identify residual cognitive function and conscious awareness in patients who are assumed to be in a vegetative state yet retain cognitive abilities that have evaded detection using standard clinical methods.