Diffusion weighted imaging distinguishes the vegetative state from the minimally conscious state.

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.

Willful modulation of brain activity in disorders of consciousness.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Disorders of consciousness: further pathophysiological insights using motor cortex transcranial magnetic stimulation.

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.

Executive functions in the absence of behavior: functional imaging of the minimally conscious state.

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.

Classical conditioning in the vegetative and minimally conscious state.

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.

Neuroimaging and the vegetative state: resolving the behavioral assessment dilemma?

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.

Detecting awareness in the vegetative state.

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.

Functional neuroimaging of the vegetative state.

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.

Using neuroimaging to detect awareness in disorders of consciousness.

The assessment of residual brain function in the vegetative state is extremely difficult and depends frequently on subjective interpretations of observed spontaneous and volitional behaviours. For those patients who retain peripheral motor function, rigorous behavioural 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 commands, 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.

Functional MRI in disorders of consciousness: advantages and limitations.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Dissociating speech perception and comprehension at reduced levels of awareness.

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.

Do vegetative patients retain aspects of language comprehension? Evidence from fMRI.

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.

Using functional magnetic resonance imaging to detect covert awareness in the vegetative state.

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.

Hyperventilation following head injury: effect on ischemic burden and cerebral oxidative metabolism.

OBJECTIVE: To determine whether hyperventilation exacerbates cerebral ischemia and compromises oxygen metabolism (CMRO2) following closed head injury. DESIGN: A prospective interventional study. SETTING: A specialist neurocritical care unit. PATIENTS: Ten healthy volunteers and 30 patients within 10 days of closed head injury. INTERVENTIONS: Subjects underwent oxygen-15 positron emission tomography imaging of cerebral blood flow, cerebral blood volume, CMRO2, and oxygen extraction fraction. In patients, positron emission tomography studies, somatosensory evoked potentials, and jugular venous saturation (SjO2) measurements were obtained at Paco2 levels of 36+/-3 and 29+/-2 torr. MEASUREMENTS AND MAIN RESULTS: We estimated the volume of ischemic brain and examined the efficiency of coupling between oxygen delivery and utilization using the sd of the oxygen extraction fraction distribution. We correlated CMRO2 to cerebral electrophysiology and examined the effects of hyperventilation on the amplitude of the cortical somatosensory evoked potential response. Patients showed higher ischemic brain volume than controls (17+/-22 vs. 2+/-3 mL; p

Detecting awareness in the vegetative state.

We used functional magnetic resonance imaging to demonstrate preserved conscious awareness in a patient fulfilling the criteria for a diagnosis of vegetative state. When asked to imagine playing tennis or moving around her home, the patient activated predicted cortical areas in a manner indistinguishable from that of healthy volunteers.

Hydrocephalus, ventriculomegaly and the vegetative state: a review.

The revised guidelines from the Royal College of Physicians make it clear that structural problems such as hydrocephalus should be excluded before the diagnosis of vegetative state (VS) can be made. Ventriculomegaly is common after severe head injury but the distinction between atrophy and potentially treatable hydrocephalus cannot be made on the basis of conventional computerised tomographic (CT) or magnetic resonance (MR) scanning alone--physiological measurements of intracranial pressure (ICP) and cerebrospinal fluid (CSF) outflow resistance may be helpful. These techniques are reviewed together with the limited literature available that documents the effect of CSF diversion on outcome in "vegetative" patients.

Residual auditory function in persistent vegetative state: a combined PET and fMRI study.

In recent years, a number of studies have demonstrated an important role for functional neuroimaging in the identification of residual cognitive function in persistent vegetative state. Such studies, when successful, may be particularly useful where there is concern about the accuracy of the diagnosis and the possibility that residual cognitive function has remained undetected. Unfortunately, functional neuroimaging in persistent vegetative state is extremely complex and subject to numerous methodological, clinical and theoretical difficulties. Here, we describe the strategy used to study residual auditory and speech processing in a single patient with a clinical diagnosis of persistent vegetative state. Identical positron emission tomography studies, conducted nine months apart, revealed preserved and consistent responses in predicted regions of auditory cortex in response to intelligible speech stimuli. Moreover, a preliminary functional magnetic resonance imaging examination at the time of the second session revealed partially intact responses to semantically ambiguous stimuli, which are known to tap higher aspects of speech comprehension. In spite of the multiple logistic and procedural problems involved, these results have major clinical and theoretical implications and provide a strong basis for the systematic study of possible residual cognitive function in patients diagnosed as being in a persistent vegetative state.

Using a hierarchical approach to investigate residual auditory cognition in persistent vegetative state.

Persistent vegetative state is arguably one of the least understood and most ethically troublesome neurological conditions in modern medicine. The term describes a rare disorder in which patients who emerge from coma appear to be awake, but show no signs of awareness. In recent years, a number of studies have demonstrated an important role for functional neuroimaging in the identification of residual cognitive function in patients meeting the clinical criteria for persistent vegetative state. Such studies, when successful, may be particularly useful where there is a concern about the accuracy of the diagnosis and the possibility that residual cognitive function has remained undetected. Unfortunately, functional neuroimaging in persistent vegetative state is extremely complex and subject to numerous methodological, clinical and theoretical difficulties. In this chapter, we argue that in order to most effectively define the degree and extent of preserved cognitive function in persistent vegetative state, a hierarchical approach to cognition is required. To illustrate this point, a series of functional neuroimaging paradigms in the auditory domain are described, which systematically increase in complexity in terms of the auditory and/or linguistic processes required and, therefore, the degree of preserved cognition that can be inferred from "normal" patterns of activation in persistent vegetative patients. Preliminary results in a small series of patients provide a strong basis for the systematic study of possible residual cognitive function in persistent vegetative state.

Neurophysiological architecture of functional magnetic resonance images of human brain.

We investigated large-scale systems organization of the whole human brain using functional magnetic resonance imaging (fMRI) data acquired from healthy volunteers in a no-task or 'resting' state. Images were parcellated using a prior anatomical template, yielding regional mean time series for each of 90 regions (major cortical gyri and subcortical nuclei) in each subject. Significant pairwise functional connections, defined by the group mean inter-regional partial correlation matrix, were mostly either local and intrahemispheric or symmetrically interhemispheric. Low-frequency components in the time series subtended stronger inter-regional correlations than high-frequency components. Intrahemispheric connectivity was generally related to anatomical distance by an inverse square law; many symmetrical interhemispheric connections were stronger than predicted by the anatomical distance between bilaterally homologous regions. Strong interhemispheric connectivity was notably absent in data acquired from a single patient, minimally conscious following a brainstem lesion. Multivariate analysis by hierarchical clustering and multidimensional scaling consistently defined six major systems in healthy volunteers-- corresponding approximately to four neocortical lobes, medial temporal lobe and subcortical nuclei- - that could be further decomposed into anatomically and functionally plausible subsystems, e.g. dorsal and ventral divisions of occipital cortex. An undirected graph derived by thresholding the healthy group mean partial correlation matrix demonstrated local clustering or cliquishness of connectivity and short mean path length compatible with prior data on small world characteristics of non-human cortical anatomy. Functional MRI demonstrates a neurophysiological architecture of the normal human brain that is anatomically sensible, strongly symmetrical, disrupted by acute brain injury, subtended predominantly by low frequencies and consistent with a small world network topology.