Modeling the minimally conscious state: measurements of brain function and therapeutic possibilities

doi:10.1016/S0079-6123(05)50033-5

Progress in Brain Research

Volume 150, 2005, Pages 473-493, 609-610

https://doi.org/10.1016/S0079-6123(05)50033-5 Get rights and content

Abstract

The minimally conscious state (MCS) defines a functional level of recovery following severe brain injuries. Patients in MCS demonstrate unequivocal evidence of response to their environment yet fail to recover the ability to communicate. Drawing on recent functional brain-imaging studies, pathological data, and neurophysiological investigations, models of brain function in MCS are proposed. MCS models are compared and contrasted with models of the vegetative state (VS), a condition characterized by wakeful appearance and unconsciousness. VS reflects a total loss of cognitive function and failure to recover basic aspects of the normal physiologic brain state associated with wakefulness. MCS may represent a recovery of the minimal dynamic architecture required to organize behavioral sets and respond to sensory stimuli. Several pathophysiological mechanisms that might limit further recovery in MCS patients are considered. Implications for future research directions and possible therapeutic strategies are reviewed.

Introduction

The recent definition of the minimally conscious state (MCS) challenges neurologists to improve the rational basis of evaluation and treatment of severely brain-injured patients (Giacino et al., 2002; Giacino, this volume). The ultimate impact of this nosological distinction is likely to rival the importance of the definition of the vegetative state (VS) by Jennett and Plum (1972; Jennett, this volume). Unlike VS, a condition characterized by the dissociation of behavioral unconsciousness and wakeful appearance, MCS classifies patients with unequivocal evidence of contingent response to their environment. The range of clinical phenotypes in MCS is quite large (see Giacino and Whyte, in press) and includes patients with relatively high-level behavioral responses such as complex command following or intelligible verbalizations. Detractors have raised ethical concerns that distinguishing MCS will lead to undervaluing the patients by leading to their conflation with VS (Burke, 2002; Coleman, 2002) and alternatively, futility concerns that there is no point to drawing further distinctions with the category of severe disability. The later concern is often expressed as a conclusion that this patient population is uniformly hopeless. To support the need for the MCS category and further refinement of the severe disability category of the Glasgow Outcome Scale (Jennett and Bond, 1975), neurobiological models of VS and MCS are examined and contrasted below. The conceptual models are considered in light of new measurements of brain function in severely brain-injured patients. Despite a limited number of studies, significant differences in underlying brain function are already unfolding (cf. Kobylarz and Schiff, 2004; Laureys et al., 2004). These advances make diagnostic clarity an imperative in the evaluation of severe brain damage (Fins and Plum, 2004). Furthermore, the potential that specific measurements of brain function may provide a basis for selective therapeutic interventions in some severely disabled patients supports continued efforts to identify the different pathophysiological mechanisms arising in this context.

Akin to the dissociation of arousal and consciousness observed in VS, MCS dissociates the appearance of wakefulness and some level of responsiveness from a capacity to communicate and organize goal-directed behaviors. Models of MCS must therefore consider the neurobiological basis for supporting continuous interactive behaviors. Below, conceptual models of MCS are advanced and contrasted to current models of VS. Patients near the point of emergence from MCS, where late recoveries are sometimes identified, are proposed to primarily suffer failures of the initiation, maintenance, and completion of behavioral sets. Similar, but less profound impairments of general cognitive function are common across a spectrum of outcomes of severe brain injuries. Identifying and quantifying the necessary and sufficient conditions to emerge from MCS will require a neuroscientific framework that accounts for basic mechanisms underlying consciousness and cognition in the human brain. Thus, another motivation for detailed studies and models of MCS is this set of fundamental questions in neuroscience.

Section snippets

Nosology

Figure 1 provides a schematic overview of the nosology of global disorders of consciousness following severe brain damage. The initial brain state produced by severe brain damage is coma. Coma is a state of unarousable unresponsiveness and reflects overwhelming functional impairment of the forebrain arousal mechanisms (Plum and Posner, 1982). Coma is typically a transient state that, if uncomplicated by intercurrent processes (e.g., infection, metabolic derangement), will resolve within 1 or 2

Models of the vegetative state

Before considering models of mechanisms underlying VS, it is useful to distinguish VS as a transient functional disturbance versus a permanent condition. VS often arises following an acute brain insult and can give way to significant further recovery. A wide range of outcomes, etiologies and structural injury patterns can be associated with transient VS. Similarly, the available literature of electrodiagnostic and functional imaging studies examining VS patients vary significantly with respect

Models of MCS

The diagnostic category of MCS canvasses a wider range of clinical phenotypes and structural pathologies than VS. At this time only a few studies have focused on patients fulfilling the diagnostic criteria for the condition and conceptual models must accordingly be seen as tentative. It is anticipated that as additional investigational studies are done this category will become further refined, hopefully based on mechanistic distinctions. Nonetheless, existing data provide evidence that brain

Possible therapeutic strategies

Spontaneous emergence late in the course of MCS indicates that some patients with non-progressive encephalopathies retain reserve capacities. The observations raise the question of how these capacities might be recruited in MCS patients and others with less severe cognitive disability. Recent efforts have begun to examine the effects of dopaminergic and other neuromodulators early in the course of treatment of MCS patients (Giacino, this volume). As discussed above, in some patients,

Implications and research directions

Why should we carefully study MCS patients and others with severe brain dysfunction? The most general answer is that it appears that functional disabilities may often exceed the obvious burden of structural brain injuries and that neuroimaging studies may show more distributed functional activation of cerebral networks than anticipated by the bedside examination. Further research efforts must focus on what these activations may mean, when the data present reasons to expect potential improvement

Acknowledgments

This paper was originally presented at The Satellite Symposium on Coma and Impaired Consciousness, University of Antwerp, Antwerp, Belgium, June 24, 2004. The author thanks Dr. Steven Laureys, the Mind Science Foundation and the Association for the Scientific Study of Consciousness, for the invitation to speak at this symposium and Dr. Joseph Fins and Andrew Hudson for comments on the manuscript. The support of the Charles A. Dana Foundation and the NIH-NINDS (NS02172, NS43451) are gratefully

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A novel closed-loop EEG-tDCS approach to promote responsiveness of patients in minimally conscious state: A study protocol
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A major challenge in the application of tDCS to DOC patients is the variability in the underlying brain state of individuals, impacting their behavioural response. Indeed, DOC patients typically present fluctuations in vigilance impacting their responsiveness to external stimuli [3,24–28]. Piarulli and colleagues used spectral entropy as measured in resting EEG to highlight the periodicity of fluctuations and suggested that spectral entropy variability in MCS could mirror the aforementioned behavioural fluctuations.
Transcranial direct current stimulation (tDCS) applied over the prefrontal cortex has been shown to improve behavioral responsiveness in patients with disorders of consciousness following severe brain injury, especially those in minimally conscious state (MCS). However, one potential barrier of clinical response to tDCS is the timing of stimulation with regard to the fluctuations of vigilance that characterize this population. Indeed, a previous study showed that the vigilance of MCS patients has periodic average cycles of 70 min (range 57−80 min), potentially preventing them to be in an optimal neural state to benefit from tDCS when applied randomly. To tackle this issue, we propose a new protocol to optimize the application of tDCS by selectively stimulating at high and low vigilance states. Electroencephalography (EEG) real-time spectral entropy will be used as a marker of vigilance and to trigger tDCS, in a closed-loop fashion. We will conduct a randomized controlled crossover clinical trial on 16 patients in prolonged MCS who will undergo three EEG-tDCS sessions 5 days apart (1. tDCS applied at high vigilance; 2. tDCS applied at low vigilance; 3. tDCS applied at a random moment). Behavioral effects will be assessed using the Coma Recovery Scale-Revised at baseline and right after the stimulations. EEG will be recorded throughout the session and for 30 min after the end of the stimulation. This unique and novel approach will provide patients’ tailored treatment options, currently lacking in the field of disorders of consciousness.
Increased brain glucose metabolism in chronic severe traumatic brain injury as determined by longitudinal 18F-FDG PET/CT
2018, Journal of Clinical Neuroscience
Citation Excerpt :
Neurological manifestations of chronic severe traumatic brain injury (sTBI) can include severe motor deficits, sensory deficits, and disorders of consciousness, such as unresponsive wakefulness syndrome and a minimally conscious state [1–3].
Little is known about changes in glucose metabolism in patients with chronic severe traumatic brain injury (sTBI). It remains to be elucidated how neurological manifestations of sTBI are associated with brain glucose metabolism during longitudinal follow-up. We show here that neurological manifestations are associated with changes of brain glucose metabolism by using two serial 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images. In this longitudinal observational study, two serial 18F-FDG PET/CT images from each of 45 patients were analyzed for whole-brain maximum standardized uptake values (SUVmax). For clinical assessment, we applied two different scales: the coma recovery scale-revised and the original Chiba score with additional information regarding nutrition, excretion, facial expression, and position change of the patient's relative immobility and bedridden state. As a result, the increased FDG uptake group was associated with a high level of wakefulness (first PET, p = 0.04; second PET, p = 0.01) and small ventricular size (first PET, p = 0.01; second PET, p = 0.01). In addition, anticonvulsant withdrawal (p = 0.001), improvement of total Chiba score (p = 0.01), language expression (p = 0.03), position change (p = 0.03), and communication (p = 0.03) were accelerated in the increased FDG uptake group. Spearman’s rank correlation coefficients of change in SUVmax and language expression between the first and second PET were 0.4 (p = 0.01). Our results indicate that chronic severe traumatic head injury patients have changed brain glucose metabolism.
Heart rate variability: An index of brain processing in vegetative state? An artificial intelligence, data mining study
2010, Clinical Neurophysiology
Brain processing at varying levels of functional complexity has been documented in vegetative state. In this study, data mining procedures are applied to identify significant changes in heart rate variability (an emerging objective descriptor of autonomic correlates of brain activation) in response to complex auditory stimuli with emotional value (music).
The heart rate of subjects in vegetative state from brain damage (n = 6) or spontaneous hemorrhage (n = 3) and 16 healthy controls was recorded while they passively listened to four pre-selected music samples by different authors (mean recording time: 3 m and 36 s ± 24 s). The parametric and non-parametric frequency spectra were computed on the heart rate, spectra were compared within/across subjects and music authors, and the spectra descriptors were entered into a 1-R rules data mining procedure (WEKA software Leave One Out and Ten Fold Cross validation). The procedure independently classified the heart rate spectral patterns of both patients and controls and the emotions reported by healthy subjects as “positive” or “negative”.
In both healthy controls and vegetative state subjects, the power spectra while passively listening to music differed from baseline when compared irrespective of the music authorship and from each other when compared across music samples. Data mining sorted the nu_LF (normalized parameter unit of the spectrum low frequency range) as the significant descriptor of heart rate variability in the conditions of the study. The nu_LF classification of the healthy controls’ HRV changes in response to music replicated that based on subjective reports with 75–93.7% accuracy.
Although preliminary, these findings suggest that autonomic changes with possible emotional value can be induced by complex stimuli also in vegetative state, with implications on the residual responsiveness of these subjects.
Heart rate variability descriptors and data mining methods appear applicable to investigate brain function in the absence of consciousness.
How can we know if patients in coma, vegetative state or minimally conscious state are conscious?
2009, Progress in Brain Research
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The distinction between the stages is based on behavioural criteria. VS patients are generally thought to differ from comatose patients as coma patients can be aroused, yet they are believed to be equally unconscious (Schiff, 2005). MCS patients, however, are believed to have “some” or “fluctuating” consciousness.
This paper examines the claim that patients in coma, vegetative state and minimally conscious state may in fact be conscious. The topic is of great importance for a number of reasons — not least ethical. As soon as we know a given creature has any experiences at all, our ethical attitude towards it changes completely. A number of recent experiments looking for signs of intact or partially intact cognitive processing in the various stages of decreased level of consciousness are reviewed. Whether or not vegetative or coma patients are in fact conscious is an empirical issue that we yet do not know how to resolve. However, the simple fact that this is an unresolved empirical issue implies that the standard behavioural assessment is not sufficient to decide what it is like to be these patients. In other words, different and more sophisticated methods are necessary. From a theoretical position, the paper moves on to discuss differences in validity between reports (e.g. verbal) and signals (e.g. brain activations) in the study of consciousness, and whether results from experiments on the contents of consciousness may be of any use in the study of levels of consciousness. Finally, an integrated approach is suggested, which does not separate research in level and content as clearly as in current practice, and which may show a path to improved paradigms to determine whether patients in coma or vegetative state are conscious.
The Use of Functional MRI in Traumatic Brain Injury Diagnosis and Treatment
2007, Physical Medicine and Rehabilitation Clinics of North America
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Schiff and colleagues [5] published the first fMRI activation maps in two minimally conscious patients using language and sensory stimulation paradigms. They were interested in these domains of cognitive activity because evidence of residual functional skills in these domains would indicate potential communication avenues [12]. Their activation paradigms included recorded speech from an involved family member, digitally reversed speech, and passive tactile stimulation on both hands.
Recent advances in MRI have provided the opportunity to map changes in hemodynamics that correspond to cognitive and sensory operations. These advances in noninvasive, low-risk, imaging environments have extended the traditional role of medical imaging into new domains that include investigations into the interplay between brain anatomy, physiology, and function. This interplay is mandatory for examination of the complex effects of diffuse damage caused by traumatic brain injury. Functional MRI (fMRI) provides relatively high-resolution indirect assessment of neuronal activity. Three main factors interact to affect the quality of fMRI data that is acquired: (1) MRI hardware, (2) the paradigm (or experimental) design, and (3) subject cooperation. This article focuses on paradigm design and subject cooperation.
Arterial spin labeling and altered cerebral blood flow patterns in the minimally conscious state
2011, Neurology
To use arterial spin labeling (ASL) to compare cerebral blood flow (CBF) patterns in minimally conscious state (MCS) patients with those in normal controls in an observational study design.
Subjects meeting MCS criteria and normal controls were identified. A pseudocontinuous ASL sequence was performed with subjects and controls in the resting awake state. Multiple CBF values for 10 predetermined regions of interest were sampled and average CBF was calculated and compared between controls and subjects.
Ten normal controls were identified, with ages ranging from 26 to 54 years. Four subjects met the MCS criteria and received an ASL study, with one patient receiving a second study at a later date. Subjects ranged in age from 19 to 58 years and had traumatic brain injury, stroke, or hypoxic-ischemic encephalopathy. Regional CBF for controls ranged from 21.6 to 57.2 mL/100 g/min, with a pattern of relatively increased blood flow posteriorly including the posterior cingulate, parietal, and occipital cortices. CBF patterns for MCS subjects showed greater variability (from 7.7 to 33.1 mL/100 g/min), demonstrating globally decreased CBF in gray matter compared with that in normal controls, especially in the medial prefrontal and midfrontal regions. In the one subject studied longitudinally, global CBF values increased over time, which correlated with clinical improvement.
We identified globally decreased CBF and a selective reduction of CBF within the medial prefrontal and midfrontal cortical regions as well as gray matter in MCS patients. ASL may serve as an adjunctive method to assess functional reserve in patients recovering from severe brain injuries.
ASL = arterial spin labeling; CBF = cerebral blood flow; CRS-R = Coma Recovery Score–Revised; DMN = default mode network; GM = gray matter; MCS = minimally conscious state; WM = white matter.

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Modeling the minimally conscious state: measurements of brain function and therapeutic possibilities

Abstract

Introduction

Section snippets

Nosology

Models of the vegetative state

Models of MCS

Possible therapeutic strategies

Implications and research directions

Acknowledgments

Clin. Neurophysiol.

Lancet

Lancet

Trends Neurosci.

Lancet

Lancet

Neuroimage

Lancet Neurol.

Trends Cogn. Sci.

Lancet

Biophys. J.

NeuroImage

Clin. Neurophys.

Electroen. Clin. Neuro.

Trends Cogn. Sci.

Cognitive Brain Res.

Neuroscience

The neuropathology of the vegetative state after acute insult

Brain

The structural basis of moderate disability after traumatic brain damage

J. Neurol. Neurosur. Ps.

Visual and eye movement functions of the posterior parietal cortex

Annual Rev. Neurosci.

Emotion processing in the minimally conscious state

J. Neurol. Neurosur. Ps.

Random Data: Analysis and Measurement Procedures

Obsessive compulsive disorder and traumatic brain injury: behavioral, cognitive, and neuroimaging findings

Neuropsy. Neuropsy. Be.

Paroxysmal autonomic instability with dystonia after brain injury

Arch. Neurol.

Auditory processing in severely brain injured patients: differences between the minimally conscious state and the persistent vegetative state

Arch. Neurol.

The minimally conscious state: definition and diagnostic criteria

Neurology

Episodically remitting akinetic mutism following subarachnoid hemorrhage

J. Neuropsychiatry Clin. Neurosci.

Thalamocortical diaschisis: single-photon emission tomographic study of cortical blood flow changes after focal thalamic infarction

Neuropsy. Neuropsy. Be.

Paramedian thalamic and midbrain infarcts: clinical and neuropathological study

Ann. Neurol.

Arousal from a semi-comatose state on zolpidem

S. Afr. Med. J.

The minimally conscious state

Neurology

Axonal recovery after severe traumatic brain injury demonstrated in vivo by 1 H MR spectroscopy

Neuroradiology

Brain glucose metabolism in postanoxic syndrome. Positron emission tomographic study

Arch. Neurol.

Hypoxic-ischemic brain injury and the vegetative state: clinical and neuropathologic correlation

Neurology

Metabolic correlates of pallidal neuronal activity in Parkinson's disease

Brain

Constructing ethical stereotaxy for severe brain injury; balancing risks, benefits and access

Nat. Rev. Neurosci.

Neurological diagnosis is more than a state of mind: diagnostic clarity and impaired consciousness

Arch. Neurol.

Modulation of oscillatory neuronal synchronization by selective visual attention

Science

Unit activity in prefrontal cortex during delayed-response performance: neuronal correlates of transient memory

J. Neurophysiol.

The minimally conscious state: definition and diagnostic criteria

Neurology

Neuronal deactivation explains decreased cerebellar blood flow in response to focal cerebral ischemia or suppressed neocortical function

Proc. Natl. Acad. Sci.

The specificity of the ‘nonspecific’ midline and intralaminar thalamic nuclei

Trends Neurosci.

Searching for a baseline: functional imaging and the resting human brain

Nat. Rev. Neurosci.

Persistent vegetative state. Review and report of electrodiagnostic studies in eight cases

Arch. Neurol.