This narrative review aims to elucidate an emerging state of consciousness termed "cognitive- motor dissociation", characterized by brain activity patterns closely resembling those observed in healthy individuals. This distinctive phenomenon is notably evident in patients diagnosed with comatose states, unresponsive wakefulness states, or minimally conscious states. Employing functional magnetic resonance imaging or electroencephalography holds promise for identifying cognitive-motor dissociation. The emergence of cognitive-motor dissociation not only introduces a fresh conceptual framework but  also provides valuable predictive insights into outcomes and prognoses for individuals with disorders of consciousness. However, the recognition of cognitive-motor dissociation raises ethical considerations, particularly in evaluating the decision-making capacity regarding life-or-death choices for individuals in this state. Therefore, it is crucial to advocate for further scientific and comprehensive research to enhance our understanding of cognitive-motor dissociation and navigate its nuanced complexities.

INTRODUCTION

Consciousness can be defined as a state marked by both arousal and an awareness of oneself and one's surroundings (1). Much research has been conducted to uncover the neuronal foundations of consciousness. This exploration has led to the proposition of the existence of an ascending reticular activating system (ARAS) situated in the upper brainstem tegmentum (reticular formation) and the central thalamus, which plays a pivotal role in facilitating widespread cortical activation(2). Thus, disorders of consciousness encompass a spectrum of conditions that disrupt this pathway and are broadly categorized into three main groups. These categories consist of coma, unresponsive wakefulness state (UWS) (formerly referred to as vegetative state), and minimally conscious state (MCS), each defined by distinct levels  of awareness and alertness(3). Coma is characterized by the complete failure of the arousal system, marked by the absence of spontaneous eye opening and an inability to be roused even with vigorous sensory stimulation(4). UWS is distinguished by the total absence of any observable behavioral signs indicating self-awareness or environmental awareness, while the capacity for spontaneous or stimulus-induced arousal remains intact(5). To diagnose a MCS and differentiate it from UWS, one relies on the observation of cognitively-mediated behaviors(3). These behaviors must be reproducible or sustained for a sufficient duration to distinguish them from reflexive actions(3). Advancements in the field of imaging and electrophysiological tools have led to the emergence of a novel concept within the realm of disorders of consciousness. It is now possible to demonstrate brain activity patterns of UWS, MCS or comatose patients resembling those of individuals considered to have normal cognitive function(6). This intriguing state of consciousness has been designated with a new term, “cognitive- motor dissociation (CMD)”, also referred to covert consciousness(7). This groundbreaking concept challenges our understanding of consciousness and raises important questions about the nature of awareness in individuals who outwardly appear to be unconscious. In this review, we aimed to introduce and elucidate CMD.

THE CONCEPT OF CMD

The concept of CMD is originated in a  report of   a 26-year-old female patient diagnosed with acute disseminated encephalomyelitis(8). At the time of her diagnosis, she presented with a clinical profile consistent with a persistent vegetative state, characterized by apparent unresponsiveness. However, what added a layer of intrigue to this case was the surprising outcome of a face-recognition test administered to her(8). Unexpectedly, positron emission tomography (PET) scans revealed that her brain's activation patterns closely resembled those observed in previous studies involving healthy individuals(8). This observation challenged the established assumptions regarding her cognitive function and sparked a reevaluation of our understanding of consciousness in disorders of consciousness.

THE PREVALENCE OF CMD

Dr. Adrian Owen has dedicated many years to advancing this field(9). In 2006, he and his colleagues introduced two verbal instructions to elicit mental imagery tasks in a 23-year-old female patient who was diagnosed in a UWS state. The functional magnetic resonance imaging (fMRI) findings showed that activated cortical areas in this patient closely resembled those observed in healthy volunteers, despite her condition(6). A study involving 54 patients (23 UWS and 31 MCS) with disorders of consciousness demonstrated 5 (9.3%) patients were able  to willfully modulate their brain activity through fMRI using the above-mentioned two mental imagery tasks(10). Of them, one patient was able to use this technique to express yes or no to questions during fMRI(10). Another study showed 3 of 16 (19%) patients with UWS were able to generate electroencephalography (EEG) responses to two distinct commands of mental imagery tasks, i.e., squeeze your right hand and squeeze your toes(11). Overall, the prospect of utilizing task-based fMRI and EEG are two potential tools for detecting CMD in patients with disorders of consciousness for their adoption and implementation(12,13), and EEG may be easier than fMRI in the intensive care unit settings. A systematic review and meta-analysis demonstrated that CMD ratio in disorders  of consciousness was 25.0% and 21.3% by using task- based fMRI and EEG tests respectively(13). However, the incidence of CMD in various case series or cohort studies can exhibit substantial variability, with reported rates ranging from as low as 9.3% to as high as 43.6%(10,13,14). This variability appears to be influenced by the diversity of mental imagery tasks, and techniques employed in these studies and unmeasurable false negative results.

THE PROGNOSIS OF CMD

A long-term follow-up of severe disorders of consciousness in 102 patients (59 UWS and 43 MCS) showed 30 (29.4%) patients regained consciousness and developed some communicative capacities(14). Among them, 6 (5.9%) patients regained consciousness 3 years more after the acute brain injury(15). Much research has been dedicated to investigate the relationship between the CMD and the prognosis of these severe disorders of consciousness. A study included 78 patients (45 UWS and 33 MCS) in an experiment utilizing an EEG-based brain-computer interface(14). Among these participants, statistically significant brain-computer interface accuracies were identified as indicators of CMD(14). For the UWS patients, 15 of 18 patients diagnosed with CMD (83.3%) regained consciousness, while only 5 of the remaining 27 patients without CMD (18.5%) experienced such a positive outcome(14). Among the MCS patients, 14 of 16 patients diagnosed with CMD (87.5%) demonstrated improvements in their Coma Recovery Scale-Revised scores, while only 4 of the other 17 patients without CMD (23.5%) exhibited gain of the scores(14). In another prospective study, 104 patients with acute brain injuries admitted to the intensive care unit were enrolled(16). Utilizing machine learning techniques, EEG recordings were analyzed to detect brain activation in response to commands instructing patients to move their hands(16). Brain activation in response to commands, indicative of CMD, was present in 16 patients. Among them, 8 (50%) demonstrated an improvement, resulting capabilities to follow commands before their discharge(16). In contrast, among the 88 patients who did not display this brain activation, indicative of non-CMD, only 23 of them (26%) experienced improvements(16). When assessing the long- term outcomes at 12 months, 7 out of the 16 patients with CMD (44%) achieved a Glasgow Outcome Scale- Extended (GOS-E) level of 4 or higher(16). In contrast, only 12 of the 84 patients without CMD (14%) reached a GOS-E level of 4 or higher(16). These results indicated that patients diagnosed with CMD have notably good prognoses compared to those without CMD. Besides, the recovery trajectories of clinically unresponsive patients diagnosed with CMD after brain injury exhibit clear distinctions from those without CMD(17).

1. Goldfine AM, Schiff Consciousness: its neurobiology and the major classes of impairment. Neurol Clin. 2011;29(4):723-737.
2. Llinás R, Ribary U, Contreras D, Pedroarena C. The neuronal basis for consciousness. Philos Trans R Soc Lond B Biol Sci. 1998;353(1377):1841-1849.
3. Giacino JT, Ashwal S, Childs N, et al. The minimally conscious state: definition and diagnostic Neurology. 2002;58(3):349-353.
4. Teasdale G, Jennett Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2(7872):81-84.

5. Laureys S, Celesia GG, Cohadon F, et Unre- sponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med. 2010;8:68.
6. Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard Detecting awareness in the vegetative state. Science. 2006;313(5792):1402.
7. Schiff ND. Cognitive Motor Dissociation Following Severe Brain Injuries. JAMA Neurol. 2015;72(12): 1413-1415.
8. Menon DK, Owen AM, Williams EJ, et al. Cortical processing in persistent vegetative Wolfson Brain Imaging Centre Team. Lancet. 1998;352(9123): 200.
9. Cyranoski D. Neuroscience: The mind reader. 2012;486(7402):178-180.
10. Monti MM, Vanhaudenhuyse A, Coleman MR, et al. Willful modulation of brain activity in disorders of N Engl J Med. 2010;362(7):579-589.
11. Cruse D, Chennu S, Chatelle C, et Bedside detection of awareness in the vegetative state: a cohort study. Lancet. 2011;378(9809):2088-2094.
12. Edlow BL, Claassen J, Schiff ND, Greer Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies. Nature Reviews Neurology. 2021;17(3):135-156.
13. Kondziella D, Friberg CK, Frokjaer VG, Fabricius M, Møller K. Preserved consciousness in vegetative and minimal conscious states: systematic review and meta-analysis. J Neurol Neurosurg 2016;87(5):485-492.
14. Pan J, Xie Q, Qin P, et al. Prognosis for patients with cognitive motor dissociation identified by brain- computer interface. Brain. 2020;143(4):1177-1189.
15. Steppacher I, Kaps M, Kissler Will time heal? A long-term follow-up of severe disorders of consciousness. Ann Clin Transl Neurol. 2014;1(6): 401-408.
16. Claassen J, Doyle K, Matory A, et al. Detection of Brain Activation in Unresponsive Patients with Acute Brain Injury. N Engl J Med. 2019;380(26):2497-2505.
17. Egbebike J, Shen Q, Doyle K, et Cognitive- motor dissociation and time to functional recovery in patients with acute brain injury in the USA: a prospective observational cohort study. Lancet Neurol. 2022;21(8):704-713.

18. Bruno MA, Bernheim JL, Ledoux D, Pellas F, Demertzi A, Laureys A survey on self-assessed well-being in a cohort of chronic locked-in syndrome patients: happy majority, miserable minority. BMJ Open. 2011;1(1):e000039.
19. Laureys S, Pellas F, Van Eeckhout P, et al. The locked- in syndrome : what is it like to be conscious but paralyzed and voiceless? Prog Brain Res. 2005;150: 495-511.

20. Fins JJ, Bernat Ethical, palliative, and policy considerations in disorders of consciousness. Neurology. 2018;91(10):471-475.
21. Claassen J, Kondziella D, Alkhachroum A, et Cognitive Motor Dissociation: Gap Analysis and Future Directions. Neurocrit Care. 2023 Jun 22. doi: 10.1007/s12028-023-01769-3. Epub ahead of print.