Brain Function and Responsiveness in Disorders of

Consciousness

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Preface

Over the past 20 years, functional neuroimaging has revealed that even the severely
injured brain suffering from a disorder of consciousness can retain several aspects
of relatively high-level functions, including sensory and linguistic processing and
learning dynamics. In 2006, a provocative report presented the case of a subject in
vegetative state who appeared able to voluntarily engage in mental tasks as revealed
by her pattern of brain activations.
As widely reported as these neuroimaging studies have been, the interpretation
of regional brain activations in the vegetative state remains highly debated. These
observations nevertheless challenge the current definitions and our understanding of
both responsiveness and consciousness after severe brain injury, with an impact in
the clinical decision-making process. It is unclear the extent to which regional brain
activations can be considered equivalent to behavioral responses in indicating con-
sciousness. The very clinical standards by which patients surviving severe brain
injury are judged as being conscious or unconscious have been called into question.
In this respect, scientific research has somehow added a conceptual and professional
burden to the clinician by introducing novel criteria of evaluation not yet fully inte-
grated in the current nosography of disorders of consciousness, which is now under-
going a tacit, but not uncontroversial, revision.
This multiauthored book is aimed at reviewing the scientific evidence available
to date and the current different points of view in the field. Its task is to provide
neuroscientists and clinicians (as well as ethicists, philosophers, and lawyers) with
tools to incorporate the recent scientific advances in the understanding of disorders
of consciousness.

Los Angeles, CA, USA Martin M. Monti, PhD

Genova, Italy Walter G. Sannita, MD
Stony Brook, NY, USA

v
Contents

1 Responsiveness in DoC: A Quest for Consciousness? . . . . . . . . . . . . . 1

Walter G. Sannita
2 Advances in the Scientific Investigation of Consciousness . . . . . . . . . 13
Daniel Bor
3 Behavioral Responsiveness in Patients with Disorders
of Consciousness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Lizette Heine, Steven Laureys, and Caroline Schnakers
4 Clinical Evaluation of Residual Brain Function
and Responsiveness in Disorders of Consciousness . . . . . . . . . . . . . . . 37
Heinrich Binder
5 Measuring Consciousness Through Imaging . . . . . . . . . . . . . . . . . . . . 51
Carol Di Perri, Jitka Annen, Georgios Antonopoulos,
Enrico Amico, Carlo Cavaliere, and Steven Laureys
6 Decoding Thoughts in Disorders of Consciousness . . . . . . . . . . . . . . . 67
Adrian M. Owen and Lorina Naci
7 Brain Responsiveness After Severe Brain Injury:
Revolutions and Controversies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Evan S. Lutkenhoff and Martin M. Monti
8 Exploring the Neurophysiological Correlates of Loss
and Recovery of Consciousness: Perturbational Complexity . . . . . . . 93
Silvia Casarotto, Mario Rosanova, Olivia Gosseries,
Mélanie Boly, Marcello Massimini, and Simone Sarasso
9 Brain Electrophysiology in Disorders of Consciousness:
Diagnostic and Prognostic Utility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Damian Cruse, G. Bryan Young, Francesco Piccione,
Marianna Cavinato, and Aldo Ragazzoni

vii
viii Contents

10 The Persistent Vegetative State: Evidence That the Lower

Brain Survives Because Its Neurons Intrinsically
Resist Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
R. David Andrew
11 Responsiveness and the Autonomic Control–CNS
Two-Way Interaction in Disorders of Consciousness . . . . . . . . . . . . . 145
Francesco Riganello
12 The Medical Practice Impact of Functional Neuroimaging
Studies in Patients with Disorders of Consciousness . . . . . . . . . . . . . . 157
James L. Bernat
13 Vegetative State Two Decades After the Multi-Society Task
Force (MSTF) Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Gastone G. Celesia
14 Moving Beyond End of Life: The Ethics of Disorders
of Consciousness in an Age of Discovery and Uncertainty . . . . . . . . . 185
L. Syd M. Johnson

15 Mesocircuit Mechanisms Underlying Recovery of Consciousness

Following Severe Brain Injuries: Model and Predictions . . . . . . . . . . 195
Nicholas D. Schiff

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Contributors

Enrico Amico Coma Science Group, Neurology Department,

Cyclotron Research Center, University of Liège, Liège, Belgium
R. David Andrew Department of Biomedical & Molecular Sciences,
Queen’s University, Kingston, ON, Canada
Jitka Annen Coma Science Group, Neurology Department, Cyclotron
Research Center, University of Liège, Liège, Belgium
Georgios Antonopoulos Coma Science Group, Neurology Department,
Cyclotron Research Center, University of Liège, Liège, Belgium
James L. Bernat Department of Neurology, Geisel School of Medicine
at Dartmouth, Hanover, NH, USA
Heinrich Binder Department für Klinische Medizin und Präventionsmedizin,
Neurological Center, Karl Landsteiner Institut für Neurorehabilitation und
Raumfahrtneurologie, Vienna, Austria
Neurological Centre, Otto Wagner Hospital, Vienna, Austria
Mélanie Boly Coma Science Group, Cyclotron Research Center
and Neurology Department, University and University Hospital
of Liège, Liège, Belgium
Daniel Bor Sackler Centre for Consciousness Science, University of Sussex,
Brighton, UK
Department of Informatics, University of Sussex, Brighton, UK
Silvia Casarotto Department of Biomedical and Clinical Sciences Luigi Sacco,
University of Milan, Milan, Italy
Carlo Cavaliere Coma Science Group, Neurology Department, Cyclotron
Research Center, University of Liège, Liège, Belgium

ix
x Contributors

Marianna Cavinato Fondazione Ospedale San Camillo, I.R.C.C.S., Venezia,

Italy
Gastone G. Celesia Department of Neurology, Loyola University of Chicago,
Maywood, IL, USA
Chicago Council on Science and Technology, Chicago, IL, USA
Damian Cruse The Brain and Mind Institute, University of Western Ontario,
London, ON, Canada
Carol Di Perri Coma Science Group, Nceurology Department,
Cyclotron Research Center, University of Liège, Liège, Belgium
Olivia Gosseries Coma Science Group, Cyclotron Research Center and
Neurology Department, University and University Hospital of Liège, Liège,
Belgium
Lizette Heine Coma Science Group, Cyclotron Research Centre, University of
Liège, Liège, Belgium
L. Syd M. Johnson Department of Humanities, Michigan Technological
University, Houghton, MI, USA
Steven Laureys Coma Science Group and Department of Neurology,
Cyclotron Research Center, University Hospital of Liège, Liège, Belgium
Evan S. Lutkenhoff Department of Psychology, Univeristy of California
Los Angeles, Los Angeles, CA, USA
Marcello Massimini Department of Biomedical and Clinical Sciences
Luigi Sacco, University of Milan, Milan, Italy
Martin M. Monti Department of Psychology, University of California
Los Angeles, Los Angeles, CA, USA
Department of Neurosurgery, Brain Injury Research Center, Geffen
School of Medicine at University of California Los Angeles,
Los Angeles, CA, USA
Lorina Naci Department of Psychology, The Brain and Mind Institute, The
University of Western Ontario, London, Canada
Adrian M. Owen Department of Psychology, The Brain and Mind Institute,
The University of Western Ontario, London, Canada
Francesco Piccione Fondazione Ospedale San Camillo, I.R.C.C.S.,
Venezia, Italy
Aldo Ragazzoni Unit of Neurology & Clinical Neurophysiology,
Fondazione PAS, Scandicci, Firenze, Italy
Contributors xi

Francesco Riganello Research in Advanced Neurorehabilitation (RAN),

Institute S. Anna, Crotone, Italy
Mario Rosanova Department of Biomedical and Clinical Sciences
Luigi Sacco, University of Milan, Milan, Italy
Walter G. Sannita Department of Neuroscience, Ophthalmology
and Genetics, University of Genova, Genova, Italy
Department of Psychiatry, State University of New York,
Stony Brook, NY, USA
Simone Sarasso Department of Biomedical and Clinical Sciences
Luigi Sacco, University of Milan, Milan, Italy
Nicholas D. Schiff The Jerold B. Katz Professor of Neurology and Neuroscience,
Feil Family Brain and Mind Research Institute, Weill Cornell Medical College,
New York, NY, 10065, USA
Caroline Schnakers Department of Neurosurgery, Geffen School
of Medicine at University of California Los Angeles, Brain Injury
Research Center, Los Angeles, CA, USA
G. Bryan Young Department of Clinical Neurological Sciences,
University of Western Ontario, London, ON, Canada
Chapter 1
Responsiveness in DoC:
A Quest for Consciousness?

Walter G. Sannita

Abstract Interest on consciousness is growing, but how it arises in the brain

remains fundamentally unsolved. The variety of brain mechanisms, the impairment
of which is observed in DoC, has implication in neuroscience, in suggesting that
consciousness results of a complex functional arrangement interacting with but dis-
tinct from other higher brain processes. Neuroimaging has challenged the current
criteria for consciousness and responsiveness by documenting residual high-level
aspects of brain activity in DoC. The clinical standards to classify patients as con-
scious or unconscious are questioned, and neurologists are confronted with unre-
solved issues about diagnosis, pain, and predictability of recovery. The
epistemological issue remains the definition of consciousness beyond subjective
feeling, verbal report, probabilistic inference, and pragmatic principles. Classification
rests on responsiveness in the absence of a theory about consciousness inclusive of
its quantitative characterization. Proper definitions for and an up-to-date scrutiny of
the available descriptors are needed to think scientifically about consciousness.

Keywords Consciousness • Definition • Evolution • Descriptors of consciousness

• Responsiveness • Brain functions • Clinical applications • Disorders of
consciousness

1.1 Consciousness and Evolution

The eye structure (lenses plus a molecular detector of photons equal or comparable
to rhodopsin) is an ancient contrivance remarkably invariant over time and across
animal species. Double-structured lenses optically corrected in full accord with

W.G. Sannita, MD
Department of Neuroscience, Ophthalmology and Genetics,
University of Genova, Genova, Italy
Department of Psychiatry, State University of New York,
Stony Brook, NY, USA
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 1

M.M. Monti, W.G. Sannita (eds.), Brain Function and Responsiveness
in Disorders of Consciousness, DOI 10.1007/978-3-319-21425-2_1
2 W.G. Sannita

constructions by Des Carts and Huygens and the laws of optics appeared with
Trilobites in early Cambrian [1]. The living fossil Limulus polyphemus began fea-
turing retinal mechanisms of lateral inhibition and recurrent interaction (equivalent
to those allowing higher mammals to identify objects) in early Triassic, long before
the development of brain structures with matching functional complexity [2]1. The
sophistication of these early components the visual system exemplifies how nature
can be conservative about efficient implements even when not yet usable to their full
potential.
Individual consciousness seems instead to have evolved late in the progression
from low- to higher-order brain organization. Children spontaneously learn self-
recognition in front of a mirror at about 18 mo. of age [3]; among mammals, only
young chimpanzees (4.5–8 years) can be trained to this task, and the evidence with
dolphins remains unclear [4]. The mirror test marks the obvious in the child, i.e., the
emergence of higher brain functions and cognitive processes we associate with con-
sciousness; its reliability in animal investigation is by contrast questioned.
Methodological issues aside, the declining of self-recognition with adulthood in the
chimpanzee suggests learning processes rather than self-awareness [3, 5]. Nonhuman
primates and cetacean brains seem to have evolved to levels of complexity not too
dissimilar from ours. However, the (individual and collective) adaptation to environ-
mental requirements and the cognitive, social, and intellectual developments of
humankind stand as unique, while in no other species there is evidence of conscious
continuity with the past and planning for the future comparable to humans. Evidence
of animal consciousness is intrinsically difficult to detect, and the hypothesis is often
dismissed as a false problem no matter how ancient the neurophysiological processes
thought to support consciousness in humans. Markers of evolution, nosographic cri-
teria, and underlying physiological processes need to be unambiguously identified in
approaching questions such as these, in order to qualitatively and quantitatively
define consciousness (and its possible different states or levels) in a general taxon-
omy independent of self-experiencing, verbal reporting, and cultural biases [6–23].

1
The early development of the visual system, the remarkable similarities over time and across
animal species, and the loss of intermediate eye structures that appeared before the Cambrian
were unknown at Charles Darwin’s time. This ignorance allowed him to fully develop his theories
but did not spare him troublesome concerns: “…To suppose that the eye with all its inimitable
contrivances for adjusting the focus to different distances, for admitting different amounts of
light, and for the correction of spherical and chromatic aberration, could have been formed by
natural selection, seems, I freely confess, absurd in the highest degree. […] Reason tells me, that
if numerous gradations from a simple and imperfect eye to one complex and perfect can be shown
to exist, each grade being useful to its possessor, as is certain the case; if further, the eye ever
varies and the variations be inherited, as is likewise certainly the case; and if such variations
should be useful to any animal under changing conditions of life, then the difficulty of believing
that a perfect and complex eye could be formed by natural selection, should not be considered as
subversive of the theory…” (Ch. Darwin, On the Origin of Species, chapter VI: Difficulties of the
theory, London, John Murray, 1858).
1 Responsiveness in DoC: A Quest for Consciousness? 3

1.2 Consciousness and Brain Functions

Research on consciousness focuses mostly on cortical/brain activation, network

complexity, long-range connectivity, neuronal synchronization in selected frequency
ranges, uni/multimodal perception, motor activation, etc. Consciousness is thought
to result of large-scale information processing and neurobiological mechanisms [24–
28], as opposed to hypotheses assimilating consciousness and conscious perception
[29] that are based on evidence of regionally mediated synchronization between
large neuronal populations of distinct areas during conscious perception [24, 30].
Sensory inflow and sensorimotor integration, brainstem activating ascending sys-
tems, thalamocortical interaction, primitive motor systems, metabolic supply, and
neuromodulation balance are crucial [31]. Synchronization in the gamma-band fre-
quency range is thought to be a mechanism for bottom-up activation of neuronal
assemblies [32–37] and is reportedly maintained in disorders of consciousness (DoC)
when top-down synchronization appears lost [38]. However, the contributions of
these processes in sustaining consciousness are defined indirectly by the effects of
damage. The extent to which surgical anesthesia actually affects consciousness
remains poorly understood, with different pharmacological mechanisms of drug
action apparently inducing the same main effect [39–43]. Sleep mechanisms evolved
early and are ancient: the patterns of brain activation and network functional organi-
zation which sustain wakefulness, non-REM sleep, and REM sleep are incompatible
to each other [44, 45], but we remain ourselves and self-conscious also in the most
unrealistic dream and even happen to be aware of our dreaming [46]. The variety of
brain mechanisms thought to contribute in sustaining consciousness (and the impair-
ment of which results in DoC) has implication in neuroscience in suggesting that it
results of a complex functional arrangement interacting with but distinct from all
other higher brain processes (e.g., attention) [9, 28, 47–49]. In this respect, the mas-
ter unsolved problem pervading neuroscience remains how the combination of bil-
lions of robust individual components (neurons) with flexible weak linkages between
regulatory processes works together to create brain functions, including conscious-
ness [50, 51].

1.3 Consciousness and Responsiveness in DoC

Neuroimaging has documented residual high-level aspects of brain activity across

sensory modalities, language and learning dynamics, emotions, or pain also in sub-
jects otherwise diagnosed as being in vegetative state/unresponsive wakefulness syn-
drome (VS/UWS) [52, 53]. Responses varied in complexity, from local activation of
primary sensory cortices, to the involvement of associative areas, to activation of
cortical-subcortical networks to either mental imagery tasks or distinction of ambig-
uous/nonambiguous words [16, 54–68]. Retained connectivity in segregated net-
works provides evidence of the severely damaged brain capability to express
surviving modular functions that do not necessarily give rise to phenomenological
4 W.G. Sannita

awareness, in the absence of the integrative processes deemed necessary to con-

sciousness [65, 69]. This has been understood as indicative of residual covert cogni-
tion or consciousness as opposed to alternative interpretations that markers of neural
activity not necessarily are surrogates for these functions [63, 70–76]. The surviving
networks observed in these studies compare as to anatomy and modes of activation
to those observable in healthy subjects under comparable conditions. The similarity
validates the hypothesis that stimulus- or condition-related regional brain activations
do not occur at random in DoC. It also reinforces the evidence that neuronal and
network mechanisms of the brain (mediating, e.g., in sensory data processing or
motor action) can operate with limited or null interference from conscious processes
[77–81].
Brain activation reflecting some awareness and cognition was observed by neu-
roimaging in only a small number of subjects [61]. The preservation of specific
neural structures and available residual functional resources has been suggested to
vary because of the heterogeneity of etiology and pathophysiology or extension and
severity of brain damage [82]. Individual variability aside, the reports of subjects
classified as being in VS/UWS according to clinical protocols who have proven able
to produce voluntary “brain behavior” suggestive of partially retained conscious-
ness during neuroimaging or neurophysiologic assessments [53, 61, 62, 83, 84] can-
not be easily dismissed.

1.4 Responsiveness and the Clinical Scenario

Neurophysiology and neuroimaging have rapidly become alternative methodologi-

cal approaches, and results proved scientifically seminal. These technologies have
revolutionized our understanding of DoC and emphasized the possible relationship
between brain response and consciousness. A general discussion is currently under-
way in the scientific and clinical communities concerning the meaning of regional
brain activations in DoC, the circumstances under which brain responsiveness
should be considered equivalent to consciousness, and the reliability of brain activa-
tions as a marker of consciousness [60, 85, 86]. The current definitions and tradi-
tional understanding of both responsiveness and consciousness are being challenged.
The focus is on whether this line of scientific evidence may result misleading in
research on the lower boundaries of consciousness [15]. It is also a matter of discus-
sion whether patients who clinically fulfill the clinical criteria for VS/UWS but
show regional brain responses should be considered conscious nonetheless and
which is the acceptable discrepancy between clinical and neuroscientific evidence.
According to the international guidelines [76, 87–91], the observation of each
aspect of consciousness is based on the detection of recognizable behavioral signs,
including sustained cycles of eye-opening. While practical in the clinical environ-
ment, retrospective audits and studies comparing diagnostic protocols have consis-
tently reported a high rate of misdiagnosis between the VS/UWS and minimally
conscious state (MCS) [67, 92–94]. Individual variability, either spontaneous or
1 Responsiveness in DoC: A Quest for Consciousness? 5

reflecting changes in the neuronal or non-neuronal factors modulating the brain

functional state [95], appears relevant in DoC and should be taken in proper account
when testing responsiveness [96, 97].
The very clinical standards by which patients are classified as conscious or
unconscious have also been called into question. In the clinical community, the
resulting dichotomy between traditional criteria based on observation (currently the
golden standard) and evidence from advanced neuroimaging research is creating
difficulties in the patient’s diagnosis and early prognosis. Neurologists are con-
fronted with unresolved issues that involve pain, sensory or emotional/affective
responsiveness, and predictability of recovery and vex both the patients’ families
and the health team. The responsibility of diagnosis and early prognosis remains
with the clinician and is mainly based on the observation of clinical responsiveness.
Despite their known shortcomings [54, 59], the current behavioral markers of
responsiveness have major consequences on the commitment in resources, logistics,
dedicated staff, and costs needed for the management of these patients or even dra-
matic in ethical controversies inviting media coverage and discussion in the public
forum [72, 98, 99]. VS/UWS and MCS appear today neither static nor homoge-
neous, and a tacit revision of the current descriptive categories is de facto underway
[60, 100]. A close scrutiny of the pathophysiology of responsiveness and its rele-
vance in diagnosis/prognosis and in the definition of the boundaries between reac-
tive VS/UWS and MCS is mandatory if scientific inquiry is to resolve the practical
problem of determining a patient’s state of consciousness. In an effort to address
this issue, the clinical and scientific communities have begun evaluating the poten-
tial usefulness of novel technologies to integrate and supplement standard clinical
procedures and to investigate the mechanisms underlying the loss and recovery of
consciousness [19, 43, 62, 83, 84, 90, 101–111].

1.5 Consciousness and Its Descriptors

Interest on consciousness is growing in neuroscience and medicine as well as in

neurocomputing, artificial intelligence, and robotics with the rapid progress in the
investigation of higher brain functions, advance in artificial intelligence, and diffuse
perception of the inadequacy of traditional mind/body separations [8, 10, 112–114].
As a result, the concept of consciousness may vary depending on context, scientific
approach, and background (from neurophysiological state of activation to self-
awareness, to momentary interaction with the environment, etc.), and the definitions
of consciousness and related terms remain to a significant extent inadequately char-
acterized and ambiguous. The binary classification of consciousness vs. uncon-
sciousness is being questioned on the ground of the neurophysiological correlates of
preconscious processes [115–117], whereas the evidence for non-unitary models
remains not definite [15]. The main epistemological issue about consciousness in
humans and possibly in other species remains its definition beyond subjective feel-
ing, verbal report, probabilistic inference (since by definition anyone’s own
6 W.G. Sannita

experience is inaccessible to others), and pragmatic principle of “revealed con-

sciousness” [59, 60].
How consciousness arises in the brain remains fundamentally unsolved. It has been
noted in his respect how research relies to a relevant extent on the linguistic neutrality
of neurophysiological and pathophysiological “correlates” when the experimental
paradigms and explanatory canons are not neutral about the mechanical relations with
the brain and are supposed to investigate causes [118]. Neuroscience has advanced to
the point that consciousness seems treatable as a scientific problem like others, disre-
garding objections that it may be epiphenomenal, not evolutionary in function, unac-
countable by brain processes, intrinsically unsuitable to objective investigated, etc.
[112]. Yet, a classification of DoC remains bound to the idea of responsiveness until a
theory of consciousness inclusive of its quantitative characterization emerges from
current scientific proposals. To this end, proper definitions for consciousness and
responsiveness and an up-to-date scrutiny of the descriptors are needed in order to
think scientifically about consciousness and start experimental studies.

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