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AIN't NO REST for the BRAIN Neuroimaging and Neuroethics in Dialogue for Patients with Disorders of Consciou

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AIN't NO REST for the BRAIN Neuroimaging and Neuroethics in Dialogue for Patients with Disorders of Consciou UNIVERSITÉ DE LIÈGE Faculté de Médecine AAAIIINNN’’’TTT NNNOOO RRREEESSSTTT FFFOOORRR TTTHHHEEE BBBRRRAAAIIINNN NNeeuurrooiimmaaggiinngg aanndd nneeuur rooeetthhiiccss iinn ddiiaalloogguuee ffoorr ppaattiieennttss wwiitthh ddiissoorrdde errss oof ccoonnsscciioouussnneessss DEMERTZI Athena Coma Science Group Centre de Recherches du Cyclotron & CHU Service de Neurologie Université de Liège Belgique Sous la direction de Prof. LAUREYS Steven Thèse présentée en vue de l’obtention du grade de Docteur en Sciences Médicales Année Académique 2011‐2012 To those for whom I wish I had been more present i ii Table of contents Summary ...................................................................................................... v Résumé ........................................................................................................ vii Acknowledgements ..................................................................................... ix 1Introduction ............................................................................................... 1 1.1 CONSCIOUSNESS ....................................................................................... 3 AN OPERATIONAL DEFINITION OF CONSCIOUSNESS ............................................ 3 ATTITUDES TOWARDS CONSCIOUSNESS .............................................................. 3 1.2 DISORDERS OF CONSCIOUSNESS ................................................................ 9 A SHORT HISTORY ............................................................................................. 9 CLINICAL ASSESSMENT ................................................................................... 10 CONCLUSIONS ............................................................................................... 13 2 The ethics of treating patients with disorders of consciousness: Attitudes ..................................................................................................... 17 2.1 THE ETHICAL SIGNIFICANCE OF STUDYING ATTITUDES ............................ 19 2.2 PAIN PERCEPTION IN DISORDERS OF CONSCIOUSNESS? ............................ 19 DEFINITION OF PAIN AND RELATED NOTIONS ................................................... 19 PAIN IS IN THE BRAIN: DIFFERENTIAL CEREBRAL ACTIVITY IN PATIENTS WITH DISORDERS OF CONSCIOUSNESS ...................................................................... 20 2.3 ATTITUDES TOWARDS PAIN PERCEPTION ................................................. 23 2.4 ATTITUDES TOWARDS END-OF-LIFE OPTIONS .......................................... 25 2.5 ATTITUDES ON PAIN PERCEPTION MEDIATE END-OF-LIFE VIEWS .............. 29 CONCLUSIONS ............................................................................................... 35 3 Functional neuroimaging in resting state ............................................. 39 3.1 THE RESTING STATE PARADIGM .............................................................. 41 3.2 RESTING STATE IN CONSCIOUS WAKEFULNESS ........................................ 42 BEHAVIORAL “RESTING STATE” EXPERIMENT .................................................. 42 NEUROIMAGING FMRI “RESTING STATE” EXPERIMENT ................................... 44 3.3 RESTING STATE IN HYPNOSIS ................................................................... 48 3.4 RESTING STATE IN DISORDERS OF CONSCIOUSNESS ................................. 61 CONCLUSIONS ............................................................................................... 67 4 Perspectives ............................................................................................. 71 iii References ................................................................................................... 75 APPENDIX I: Scientific publications ...................................................... 87 iv Summary The sheer amount of different opinions about what consciousness is highlights its multifaceted character. The clinical study of consciousness in coma survivors provides unique opportunities, not only to better comprehend normal conscious functions, but also to confront clinical and medico-ethical challenges. For example, pain in vegetative state/unresponsive wakefulness syndrome patients (VS/UWS; i.e. awaken, but unconscious) and patients in minimally conscious states (MCS; awaken, with fluctuating signs of awareness) cannot be communicated and needs to be inferred. Behaviorally, we developed the Nociception Coma Scale, a clinical tool which measures patients’ motor, verbal, visual, and facial responsiveness to noxious stimulation. Importantly, the absence of proof of a behavioral response cannot be taken as proof of absence of pain. Functional neuroimaging studies show that patients in VS/UWS exhibit no evidence of control-like brain activity, when painfully stimulated, in contrast to patients in MCS. Similarly, the majority of clinicians ascribe pain perception in MCS patients. Interestingly, their opinions appear less congruent with regards to pain perception in VS/UWS patients, due to personal and cultural differences. The imminent bias in clinical practice due to personal beliefs becomes more ethically salient in complex clinical scenarios, such as end-of-life decisions. Surveys among clinicians show that the majority agrees with treatment withdrawal for VS/UWS, but fewer respondents would do so for MCS patients. For the issue of pain in patients with disorders of consciousness, the more the respondents ascribed pain perception in these states the less they supported treatment withdraw from these patients. Such medico-ethical controversies require an objective and valid assessment of pain (and eventually of consciousness) in non- communicating patients. Functional neuroimaging during “resting state” (eyes closed, no task performance) is an ideal paradigm to investigate residual cognition in non- communicating patients, because it does not require sophisticated technical support or subjective input on patients’ behalf. With the ultimate intention to use this paradigm in patients, we first aimed to validate it in controls. We initially found that, in controls, fMRI “resting state” activity correlated with subjective reports of “external” (perception of the environment through the senses) or “internal” awareness (self-related mental processes). Then, using hypnosis, we showed that there was reduced fMRI connectivity in the “external network”, reflecting decreased sensory awareness. When more cerebral networks were tested, increased functional connectivity was observed for most of the studied networks (except the visual). These results indicate that resign state fMRI activity reflects, at least partially, ongoing conscious cognition, which changes under different conditions. Using the resting state paradigm in patients with disorders of consciousness, we v showed intra- and inter-network connectivity breakdown in sensory- sensorimotor and “higher-order” networks, possibly accounting for patients’ limited capacities for conscious cognition. We have further observed positive correlation between the Nociception Coma Scale scores and the pain-related (salience) network connectivity, potentially reflecting nociception-related processes in these patients, measured in the absence of an external stimulus. These results highlight the utility of resting state analyses in clinical settings, where short and simple setups are preferable to activation protocols with somatosensory, visual, and auditory stimulation devices. Especially for neuroimaging studies, it should be stressed that such experimental investigations tackle the necessary conditions supporting conscious processing. The sufficiency of the identified neural correlates accounting for conscious awareness remains to be identified via dynamic and causal information flow investigations. Importantly, the quest of subjectivity in non-communicating patients can be better understood by adopting an interdisciplinary biopsychosocial approach, combining basic neuroscience (bio), psychological-cognitive-emotional processing (psycho), and the influence of different socioeconomic, cultural, and technological factors (social). vi Résumé L’abondance d'opinions sur la définition scientifique de la conscience met en évidence son caractère multiforme. C’est la raison pour laquelle l’étude clinique de la conscience chez les patients qui survivent à un accident cérébral sévère procure d’une part une opportunité unique de comprendre le fonctionnement « normal » et « pathologique » de la conscience, mais également de confronter les données cliniques obtenues lors des différentes recherches avec les questions socio-éthiques omniprésentes au sein de notre société. Un exemple marquant peut être mis en évidence lors de l’étude de la douleur chez les patients qui ne peuvent communiquer leurs ressentis tels que les patients en état végétatif/syndrome d’éveil non répondant (EV/SEN) et en état de conscience minimale (ECM ; patients éveillés présentant des signes clairs mais fluctuants de conscience). Afin de pallier ce problème, nous avons mis en au point la « Nociception Coma Scale », un outil clinique qui permet de mesurer et d’évaluer les réponses motrices, verbales, visuelles et faciales des patients en réponses à diverses stimulations nociceptives. Toutefois, il est important de signaler que l’absence de réponse comportementale ne doit pas être interprétée comme une absence de preuve de douleur. Des études en neuroimagerie fonctionnelle chez des patients EV/SEN démontrent une absence de réactions cérébrales en réponse
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