Nicholas D. Schiff

Brain function in coma, vegetative state, and related disorders

We review the nosological criteria and functional neuroanatomical basis for brain death, coma, vegetative state, minimally conscious state, and the locked-in state. Functional neuroimaging is providing new insights into cerebral activity in patients with severe brain damage. Measurements of cerebral metabolism and brain activations in response to sensory stimuli with PET, fMRI, and electrophysiological methods can provide information on the presence, degree, and location of any residual brain function. However, use of these techniques in people with severe brain damage is methodologically complex and needs careful quantitative analysis and interpretation. In addition, ethical frameworks to guide research in these patients must be further developed. At present, clinical examinations identify nosological distinctions needed for accurate diagnosis and prognosis. Neuroimaging techniques remain important tools for clinical research that will extend our understanding of the underlying mechanisms of these disorders.

Behavioural improvements with thalamic stimulation after severe traumatic brain injury

Widespread loss of cerebral connectivity is assumed to underlie the failure of brain mechanisms that support communication and goal-directed behaviour following severe traumatic brain injury. Disorders of consciousness that persist for longer than 12 months after severe traumatic brain injury are generally considered to be immutable; no treatment has been shown to accelerate recovery or improve functional outcome in such cases. Recent studies have shown unexpected preservation of large-scale cerebral networks in patients in the minimally conscious state (MCS), a condition that is characterized by intermittent evidence of awareness of self or the environment. These findings indicate that there might be residual functional capacity in some patients that could be supported by therapeutic interventions. We hypothesize that further recovery in some patients in the MCS is limited by chronic underactivation of potentially recruitable large-scale networks. Here, in a 6-month double-blind alternating crossover study, we show that bilateral deep brain electrical stimulation (DBS) of the central thalamus modulates behavioural responsiveness in a patient who remained in MCS for 6 yr following traumatic brain injury before the intervention. The frequency of specific cognitively mediated behaviours (primary outcome measures) and functional limb control and oral feeding (secondary outcome measures) increased during periods in which DBS was on as compared with periods in which it was off. Logistic regression modelling shows a statistical linkage between the observed functional improvements and recent stimulation history. We interpret the DBS effects as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain. These findings provide evidence that DBS can promote significant late functional recovery from severe traumatic brain injury. Our observations, years after the injury occurred, challenge the existing practice of early treatment discontinuation for patients with only inconsistent interactive behaviours and motivate further research to develop therapeutic interventions.

General anesthesia, sleep, and coma

This review discusses the clinical and neurophysiological features of general anesthesia and their relationships to sleep and coma, focusing on the neural mechanisms of unconsciousness induced by selected intravenous anesthetic drugs.

Harnessing neuroplasticity for clinical applications

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

fMRI reveals large-scale network activation in minimally conscious patients

Background: The minimally conscious state (MCS) resulting from severe brain damage refers to a subset of patients who demonstrate unequivocal, but intermittent, behavioral evidence of awareness of self or their environment. Although clinical examination may suggest residual cognitive function, neurobiological correlates of putative cognition in MCS have not been demonstrated. Objective: To test the hypothesis that MCS patients retain active cerebral networks that underlie cognitive function even though command following and communication abilities are inconsistent. Methods: fMRI was employed to investigate cortical responses to passive language and tactile stimulation in two male adults with severe brain injuries leading to MCS and in seven healthy volunteers. Results: In the case of the patient language-related tasks, auditory stimulation with personalized narratives elicited cortical activity in the superior and middle temporal gyrus. The healthy volunteers imaged during comparable passive language stimulation demonstrated responses similar to the patients’ responses. However, when the narratives were presented as a time-reversed signal, and therefore without linguistic content, the MCS patients demonstrated markedly reduced responses as compared with volunteer subjects, suggesting reduced engagement for “linguistically” meaningless stimuli. Conclusions: The first fMRI maps of cortical activity associated with language processing and tactile stimulation of patients in the minimally conscious state (MCS) are presented. These findings of active cortical networks that serve language functions suggest that some MCS patients may retain widely distributed cortical systems with potential for cognitive and sensory function despite their inability to follow simple instructions or communicate reliably.

Possible axonal regrowth in late recovery from the minimally conscious state

We used diffusion tensor imaging (DTI) to study 2 patients with traumatic brain injury. The first patient recovered reliable expressive language after 19 years in a minimally conscious state (MCS); the second had remained in MCS for 6 years. Comparison of white matter integrity in the patients and 20 normal subjects using histograms of apparent diffusion constants and diffusion anisotropy identified widespread altered diffusivity and decreased anisotropy in the damaged white matter. These findings remained unchanged over an 18-month interval between 2 studies in the first patient. In addition, in this patient, we identified large, bilateral regions of posterior white matter with significantly increased anisotropy that reduced over 18 months. In contrast, notable increases in anisotropy within the midline cerebellar white matter in the second study correlated with marked clinical improvements in motor functions. This finding was further correlated with an increase in resting metabolism measured by PET in this subregion. Aberrant white matter structures were evident in the second patients DTI images but were not clinically correlated. We propose that axonal regrowth may underlie these findings and provide a biological mechanism for late recovery. Our results are discussed in the context of recent experimental studies that support this inference.

Disorders of consciousness after acquired brain injury: The state of the science

The concept of consciousness continues to defy definition and elude the grasp of philosophical and scientific efforts to formulate a testable construct that maps to human experience. Severe acquired brain injury results in the dissolution of consciousness, providing a natural model from which key insights about consciousness may be drawn. In the clinical setting, neurologists and neurorehabilitation specialists are called on to discern the level of consciousness in patients who are unable to communicate through word or gesture, and to project outcomes and recommend approaches to treatment. Standards of care are not available to guide clinical decision-making for this population, often leading to inconsistent, inaccurate and inappropriate care. In this Review, we describe the state of the science with regard to clinical management of patients with prolonged disorders of consciousness. We review consciousness-altering pathophysiological mechanisms, specific clinical syndromes, and novel diagnostic and prognostic applications of advanced neuroimaging and electrophysiological procedures. We conclude with a provocative discussion of bioethical and medicolegal issues that are unique to this population and have a profound impact on care, as well as raising questions of broad societal interest.

Coma and consciousness: paradigms (re)framed by neuroimaging.

The past 15 years have provided an unprecedented collection of discoveries that bear upon our scientific understanding of recovery of consciousness in the human brain following severe brain damage. Highlighted among these discoveries are unique demonstrations that patients with little or no behavioral evidence of conscious awareness may retain critical cognitive capacities and the first scientific demonstrations that some patients, with severely injured brains and very longstanding conditions of limited behavioral responsiveness, may nonetheless harbor latent capacities for significant recovery. Included among such capacities are particularly human functions of language and higher-level cognition that either spontaneously or through direct interventions may reemerge even at long time intervals or remain unrecognized. Collectively, these observations have reframed scientific inquiry and further led to important new insights into mechanisms underlying consciousness in the human brain. These studies support a model of consciousness as the emergent property of the collective behavior of widespread frontoparietal network connectivity modulated by specific forebrain circuit mechanisms. We here review these advances in measurement and the scientific and broader implications of this rapidly progressing field of research.

Central thalamic contributions to arousal regulation and neurological disorders of consciousness.

This review focuses on the contributions of the central thalamus to normal mechanisms of arousal regulation and to neurological disorders of consciousness. Forebrain arousal is regulated by ascending influences from brainstem/basal forebrain neuronal populations (“arousal systems”) and control signals descending from frontal cortical systems. These subcortical and cortical systems have converging projections to the central thalamus that emphasize their role in maintaining organized behavior during wakefulness. Central thalamic neurons appear to be specialized both anatomically and physiologically to support distributed network activity that maintains neuronal firing patterns across long‐range cortico–cortical pathways and within cortico–striatopallidal–thalamocortical loop connections. Recruitment of central thalamic neurons occurs in response to increasing cognitive demand, stress, fatigue, and other perturbations that reduce behavioral performance. In addition, the central thalamus receives projections from brainstem pathways evolved to rapidly generate brief shifts of arousal associated with the appearance of salient stimuli across different sensory modalities. Through activation of the central thalamus, neurons across the cerebral cortex and striatum can be depolarized and their activity patterns selectively gated by descending or ascending signals related to premotor attention and alerting stimuli. Direct injury to the central thalamus or prominent deafferentation of these neurons as a result of complex, multifocal, brain insults are both associated with severe impairment of forebrain functional integration and arousal regulation. Interventions targeting neurons within the central thalamus may lead to rational therapeutic approaches to the treatment of impaired arousal regulation following nonprogressive brain injuries. A model accounting for present therapeutic strategies is proposed.

Dissociations between behavioural and functional magnetic resonance imaging-based evaluations of cognitive function after brain injury

Functional neuroimaging methods hold promise for the identification of cognitive function and communication capacity in some severely brain-injured patients who may not retain sufficient motor function to demonstrate their abilities. We studied seven severely brain-injured patients and a control group of 14 subjects using a novel hierarchical functional magnetic resonance imaging assessment utilizing mental imagery responses. Whereas the control group showed consistent and accurate (for communication) blood-oxygen-level-dependent responses without exception, the brain-injured subjects showed a wide variation in the correlation of blood-oxygen-level-dependent responses and overt behavioural responses. Specifically, the brain-injured subjects dissociated bedside and functional magnetic resonance imaging-based command following and communication capabilities. These observations reveal significant challenges in developing validated functional magnetic resonance imaging-based methods for clinical use and raise interesting questions about underlying brain function assayed using these methods in brain-injured subjects.