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Emerging Treatments for Patients with Disorders of Consciousness

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Behavioral Neuroscience".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 36871

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Prof. Dr. Martin M. Monti

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Guest Editor

Department of Psychology, University of California, Los Angeles, CA, USA
Interests: brain injury; consciousness; coma; vegetative state; unresponsive wakefulness syndrome; minimally conscious state; neuroimaging

Dr. Caroline Schnakers

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Guest Editor

Research Institute, Casa Colina Hospital and Centers for Healthcare, Pomona, CA 91767, USA
Interests: brain injury; consciousness; coma; vegetative state; unresponsive wakefulness syndrome; minimally conscious state; post-traumatic confusional state; locked-in syndrome
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Dear Colleagues,

Treating patients with severe acquired brain injuries remains a true conundrum for clinicians. Thanks to an impressive number of prospective neurocognitive studies performed on chronic patients and recent multi-center studies with larger sample size, precious information has been gathered on the functional recovery of cohorts of these patients through the years. In this context, the American Academy of Neurology (AAN) and the European Academy of Neurology (EAN) recently published guidelines regarding the management of patients with disorders of consciousness, representing a first step in improving care for these patients and helping scientists to develop an agenda. There is now a real need to develop and validate treatments. In this Special Issue, we would like to offer readers an overview of the latest research aiming to develop new therapeutic options for this challenging but certainly not hopeless population.

Prof. Dr. Martin M. Monti
Dr. Caroline Schnakers
Guest Editors

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Keywords

severe brain injury
consciousness
coma
vegetative state
unresponsive wakefulness syndrome
minimally conscious state
treatment

Published Papers (11 papers)

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Research

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15 pages, 443 KiB

Open AccessArticle

Treatment Trials in Disorders of Consciousness: Challenges and Future Directions

by Michael H. Marino and John Whyte

Brain Sci. 2022, 12(5), 569; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12050569 - 28 Apr 2022

Cited by 4 | Viewed by 2245

Abstract

The evidence base supporting treatment interventions for patients with disorders of consciousness is limited, and rigorous treatment trials are needed to guide future management of this complex patient population. There are many potential study designs that can be employed to develop this evidence, but the process of selecting the optimal study design is challenging. This article reviews common obstacles that impede research progress in this population and a range of study designs that may be employed. In addition, we consider how the particular practical and scientific obstacles may drive selection of the optimal design and, in particular, how the optimal design changes as treatment research proceeds along the translational continuum from mechanistic discovery to real-world clinical impact. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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16 pages, 1335 KiB

Open AccessEditor’s ChoiceArticle

Transcranial Pulsed-Current Stimulation versus Transcranial Direct Current Stimulation in Patients with Disorders of Consciousness: A Pilot, Sham-Controlled Cross-Over Double-Blind Study

by Alice Barra, Martin Rosenfelder, Sepehr Mortaheb, Manon Carrière, Geraldine Martens, Yelena G. Bodien, Leon Morales-Quezada, Andreas Bender, Steven Laureys, Aurore Thibaut and Felipe Fregni

Brain Sci. 2022, 12(4), 429; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12040429 - 24 Mar 2022

Cited by 10 | Viewed by 3038

Abstract

Transcranial direct-current stimulation (tDCS) over the prefrontal cortex can improve signs of consciousness in patients in a minimally conscious state. Transcranial pulsed-current stimulation (tPCS) over the mastoids can modulate brain activity and connectivity in healthy controls. This study investigated the feasibility of tPCS as a therapeutic tool in patients with disorders of consciousness (DoC) and compared its neurophysiological and behavioral effects with prefrontal tDCS. This pilot study was a randomized, double-blind sham-controlled clinical trial with three sessions: bi-mastoid tPCS, prefrontal tDCS, and sham. Electroencephalography (EEG) and behavioral assessments were collected before and after each stimulation session. Post minus pre differences were compared using Kruskal–Wallis and Wilcoxon signed-rank tests. Twelve patients with DoC were included in the study (eight females, four traumatic brain injury, 50.3 ± 14 y.o., 8.8 ± 10.5 months post-injury). We did not observe any side-effects following tPCS, nor tDCS, and confirmed their feasibility and safety. We did not find a significant effect of the stimulation on EEG nor behavioral outcomes for tPCS. However, consistent with prior findings, our exploratory analyses suggest that tDCS induces behavioral improvements and an increase in theta frontal functional connectivity. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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15 pages, 20465 KiB

Open AccessEditor’s ChoiceArticle

Ultrasonic Deep Brain Neuromodulation in Acute Disorders of Consciousness: A Proof-of-Concept

by Josh A. Cain, Norman M. Spivak, John P. Coetzee, Julia S. Crone, Micah A. Johnson, Evan S. Lutkenhoff, Courtney Real, Manuel Buitrago-Blanco, Paul M. Vespa, Caroline Schnakers and Martin M. Monti

Brain Sci. 2022, 12(4), 428; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12040428 - 23 Mar 2022

Cited by 15 | Viewed by 3355

Abstract

The promotion of recovery in patients who have entered a disorder of consciousness (DOC; e.g., coma or vegetative states) following severe brain injury remains an enduring medical challenge despite an ever-growing scientific understanding of these conditions. Indeed, recent work has consistently implicated altered cortical modulation by deep brain structures (e.g., the thalamus and the basal ganglia) following brain damage in the arising of, and recovery from, DOCs. The (re)emergence of low-intensity focused ultrasound (LIFU) neuromodulation may provide a means to selectively modulate the activity of deep brain structures noninvasively for the study and treatment of DOCs. This technique is unique in its combination of relatively high spatial precision and noninvasive implementation. Given the consistent implication of the thalamus in DOCs and prior results inducing behavioral recovery through invasive thalamic stimulation, here we applied ultrasound to the central thalamus in 11 acute DOC patients, measured behavioral responsiveness before and after sonication, and applied functional MRI during sonication. With respect to behavioral responsiveness, we observed significant recovery in the week following thalamic LIFU compared with baseline. With respect to functional imaging, we found decreased BOLD signals in the frontal cortex and basal ganglia during LIFU compared with baseline. In addition, we also found a relationship between altered connectivity of the sonicated thalamus and the degree of recovery observed post-LIFU. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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17 pages, 2732 KiB

Open AccessFeature PaperArticle

Does the Heart Fall Asleep?—Diurnal Variations in Heart Rate Variability in Patients with Disorders of Consciousness

by Monika Angerer, Frank H. Wilhelm, Michael Liedlgruber, Gerald Pichler, Birgit Angerer, Monika Scarpatetti, Christine Blume and Manuel Schabus

Brain Sci. 2022, 12(3), 375; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12030375 - 11 Mar 2022

Cited by 1 | Viewed by 2417

Abstract

The current study investigated heart rate (HR) and heart rate variability (HRV) across day and night in patients with disorders of consciousness (DOC). We recorded 24-h electrocardiography in 26 patients with DOC (i.e., unresponsive wakefulness syndrome (UWS; n = 16) and (exit) minimally conscious state ((E)MCS; n = 10)). To examine diurnal variations, HR and HRV indices in the time, frequency, and entropy domains were computed for periods of clear day- (forenoon: 8 a.m.–2 p.m.; afternoon: 2 p.m.–8 p.m.) and nighttime (11 p.m.–5 a.m.). The results indicate that patients’ interbeat intervals (IBIs) were larger during the night than during the day, indicating HR slowing. The patients in UWS showed larger IBIs compared to the patients in (E)MCS, and the patients with non-traumatic brain injury showed lower HRV entropy than the patients with traumatic brain injury. Additionally, higher HRV entropy was associated with higher EEG entropy during the night. Thus, cardiac activity varies with a diurnal pattern in patients with DOC and can differentiate between patients’ diagnoses and etiologies. Moreover, the interaction of heart and brain appears to follow a diurnal rhythm. Thus, HR and HRV seem to mirror the integrity of brain functioning and, consequently, might serve as supplementary measures for improving the validity of assessments in patients with DOC. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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8 pages, 937 KiB

Open AccessCommunication

Changes of Spasticity across Time in Prolonged Disorders of Consciousness: A Retrospective Study

by Benjamin Winters, Bruce Kuluris, Rita Pathmanaban, Hannelise Vanderwalt, Aurore Thibaut and Caroline Schnakers

Brain Sci. 2022, 12(2), 295; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12020295 - 21 Feb 2022

Cited by 4 | Viewed by 1535

Abstract

Objectives: In this retrospective study, we investigated how spasticity developed in patients diagnosed with a prolonged DOC over an almost two-year observation period (21 months), and how it related to the patients’ age, gender, time since injury, etiology, level of consciousness, and anti-spastic medications. Methods: In total, 19 patients with a severe brain injury and prolonged DOC admitted to a long-term care facility were included in this study (14 male, age: 45.8 ± 15.3 years, 10 traumatic brain injury, 1.01 ± 0.99 years after brain injury, 11 minimally conscious state vs. 8 vegetative state). Each patient was assessed at admission and then quarterly, totaling eight assessments over 21 months. Spasticity was measured with the Modified Ashworth Scale (MAS) for both upper and lower limbs. The Western Neuro Sensory Stimulation Profile (WNSSP) was administered to assess the level of consciousness. Any other medical and demographic information of interest was obtained through medical records. Linear mixed models were used to assess each variable’s impact on the change of spasticity over time. Results: Significant differences were observed in the evolution of spasticity in patients based on their etiology for the upper limbs [F (7, 107.29) = 2.226; p = 0.038], and on their level of consciousness for the lower limbs [F (7, 107.07) = 3.196; p = 0.004]. Conclusion: Our preliminary results suggest that spasticity evolves differently according to the type of brain lesion and the level of consciousness. Spasticity in DOCs might therefore be mediated by different mechanisms and might have to be treated differently among patients. Future longitudinal studies should be performed prospectively in a bigger cohort and with data collection beginning earlier after brain injury to confirm our results and better understand the evolution of spasticity in this population. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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21 pages, 365 KiB

Open AccessEditor’s ChoiceArticle

Ethical Considerations in Clinical Trials for Disorders of Consciousness

by Michael J. Young, Yelena G. Bodien and Brian L. Edlow

Brain Sci. 2022, 12(2), 211; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12020211 - 02 Feb 2022

Cited by 11 | Viewed by 3352

Abstract

As the clinical trial landscape for patients with disorders of consciousness (DoC) expands, consideration of associated ethical challenges and opportunities is of ever-increasing importance. Responsible conduct of research in the vulnerable population of persons with DoC, including those with coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), covert cortical processing (CCP), and cognitive motor dissociation (CMD), demands proactive deliberation of unique ethical issues that may arise and the adoption of robust protections to safeguard patients, surrogates, and other key stakeholders. Here we identify and critically evaluate four central categories of ethical considerations in clinical trials involving participants with DoC: (1) autonomy, respect for persons and informed consent of individuals with liminal consciousness; (2) balancing unknown benefits and risks, especially considering the epistemological gap between behavior and consciousness that complicates ordinary ascription of subjective states; (3) disclosure to surrogates and clinical teams of investigational results pertaining to consciousness; and (4) justice considerations, including equitable access to clinical trial enrollment across communities and geographies. We outline guiding principles and research opportunities for clinicians, neuroethicists, and researchers engaged in DoC clinical trials to advance ethical study design and deployment in this complex yet crucial area of investigation. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

16 pages, 279 KiB

Open AccessArticle

A Retrospective Analysis on Clinical Practice-Based Approaches Using Zolpidem and Lorazepam in Disorders of Consciousness

by Bei Zhang, Katherine O’Brien, William Won and Sheng Li

Brain Sci. 2021, 11(6), 726; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11060726 - 29 May 2021

Cited by 11 | Viewed by 3907

Abstract

This is a retrospective study to investigate the results of using zolpidem and lorazepam in persons with disorders of consciousness (DoC) and to provide practical information for clinical application and further studies. The cohort included 146 patients (11 hemorrhagic stroke, 87 traumatic brain injury (TBI), 48 anoxic brain injury (ABI)) admitted to a specialized DoC rehabilitation program. A positive trial indicated a patient responded to either zolpidem or lorazepam with prominent functional improvements necessitating routine use of the medication. Non-responders had equivocal or negative (i.e., went to sleep) responses. Eleven patients with a stroke who had either medication were all non-responders. Of the remaining 135 patients, 95 received at least one medication trial. The overall positive rate was 11.6% (11/95), with 6.3% (5/79) for zolpidem and 14.0% (6/43) for lorazepam. Among TBI patients, the positive rate of the zolpidem trial (10.2%, 5/49) was slightly higher than that of the lorazepam trial (6.9%, 2/29; p > 0.05). Among ABI patients, the positive rate of the lorazepam trial (28.6%, 4/14) was significantly higher than that of the zolpidem trial (0%, 0/30; p = 0.007). Following a positive trial, most patients were continued on the medications on a regular basis before eventual discontinuation. Our results suggested the etiology of DoC, considering traumatic vs. anoxic injuries, may serve in guiding the clinical application of these medications in the treatment of DoC and in future prospective studies. We advocate for screening all patients with DoC using zolpidem and/or lorazepam. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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17 pages, 582 KiB

Open AccessEditor’s ChoiceReview

Pain in Persons with Disorders of Consciousness

by Nathan D. Zasler, Rita Formisano and Marta Aloisi

Brain Sci. 2022, 12(3), 300; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12030300 - 23 Feb 2022

Cited by 12 | Viewed by 5941

Abstract

Pain and suffering in persons with disorders of consciousness (DoC) remain poorly understood, frequently unaddressed or inadequately addressed, and controversial on numerous levels. This narrative literature review will address a number of critical issues germane to pain and suffering in this challenging group of patients, providing an introductory overview of the topic, perspectives on current knowledge regarding pain pathoanatomy and pathophysiology, and a review of common pain generators and factors that can lead to the chronifcation of pain. Caveats on bedside pain assessment challenges, as well as electrophysiologic and neuroimaging findings in these patients, will also be explored. Pain management techniques, including non-pharmacological and pharmacological, will be reviewed. Ethical considerations in the context of pain and suffering in persons with disorders of consciousness will round out the review prior to our concluding comments. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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Other

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15 pages, 1400 KiB

Open AccessCase Report

The Importance of Material Used in Speech Therapy: Two Case Studies in Minimally Conscious State Patients

by Alice Sautet, Laura Hurtado, Anna Fiveash, Leslie Baron, Mélaine De Quelen and Fabien Perrin

Brain Sci. 2022, 12(4), 483; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12040483 - 08 Apr 2022

Cited by 1 | Viewed by 2140

Abstract

Speech therapy can be part of the care pathway for patients recovering from comas and presenting a disorder of consciousness (DOC). Although there are no official recommendations for speech therapy follow-up, neuroscientific studies suggest that relevant stimuli may have beneficial effects on the behavioral assessment of patients with a DOC. In two case studies, we longitudinally measured (from 4 to 6 weeks) the behavior (observed in a speech therapy session or using items from the Coma Recovery Scale—Revised) of two patients in a minimally conscious state (MCS) when presenting music and/or autobiographical materials. The results highlight the importance of using relevant material during a speech therapy session and suggest that a musical context with a fast tempo could improve behavior evaluation compared to noise. This work supports the importance of adapted speech therapy for MCS patients and encourages larger studies to confirm these initial observations. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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17 pages, 705 KiB

Open AccessCommentary

Emerging Treatments for Disorders of Consciousness in Paediatric Age

by Hassna Irzan, Marco Pozzi, Nino Chikhladze, Serghei Cebanu, Artashes Tadevosyan, Cornelia Calcii, Alexander Tsiskaridze, Andrew Melbourne, Sandra Strazzer, Marc Modat and Erika Molteni

Brain Sci. 2022, 12(2), 198; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12020198 - 31 Jan 2022

Cited by 8 | Viewed by 3848

Abstract

The number of paediatric patients living with a prolonged Disorder of Consciousness (DoC) is growing in high-income countries, thanks to substantial improvement in intensive care. Life expectancy is extending due to the clinical and nursing management achievements of chronic phase needs, including infections. However, long-known pharmacological therapies such as amantadine and zolpidem, as well as novel instrumental approaches using direct current stimulation and, more recently, stem cell transplantation, are applied in the absence of large paediatric clinical trials and rigorous age-balanced and dose-escalated validations. With evidence building up mainly through case reports and observational studies, there is a need for well-designed paediatric clinical trials and specific research on 0–4-year-old children. At such an early age, assessing residual and recovered abilities is most challenging due to the early developmental stage, incompletely learnt motor and cognitive skills, and unreliable communication; treatment options are also less explored in early age. In middle-income countries, the lack of rehabilitation services and professionals focusing on paediatric age hampers the overall good assistance provision. Young and fast-evolving health insurance systems prevent universal access to chronic care in some countries. In low-income countries, rescue networks are often inadequate, and there is a lack of specialised and intensive care, difficulty in providing specific pharmaceuticals, and lower compliance to intensive care hygiene standards. Despite this, paediatric cases with DoC are reported, albeit in fewer numbers than in countries with better-resourced healthcare systems. For patients with a poor prospect of recovery, withdrawal of care is inhomogeneous across countries and still heavily conditioned by treatment costs as well as ethical and cultural factors, rather than reliant on protocols for assessment and standardised treatments. In summary, there is a strong call for multicentric, international, and global health initiatives on DoC to devote resources to the paediatric age, as there is now scope for funders to invest in themes specific to DoC affecting the early years of the life course. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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7 pages, 201 KiB

Open AccessBrief Report

Many Faces of the Hidden Souls: Medical and Neurological Complications and Comorbidities in Disorders of Consciousness

by Bei Zhang, Karen Huang, Jay Karri, Katherine O’Brien, Craig DiTommaso and Sheng Li

Brain Sci. 2021, 11(5), 608; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11050608 - 10 May 2021

Cited by 17 | Viewed by 3228

Abstract

Early and goal-directed management of complications and comorbidities is imperative to facilitate neurorecovery and to optimize outcomes of disorders of consciousness (DoC). This is the first large retrospective cohort study on the primary medical and neurological complications and comorbidities in persons with DoC. A total of 146 patients admitted to a specialized inpatient DoC rehabilitation program from 1 January 2014 to 31 October 2018 were included. The incidences of those conditions since their initial brain injuries were reviewed per documentation. They were categorized into reversible causes of DoC, confounders and mimics, and other medical/neurological conditions. The common complications and comorbidities included pneumonia (73.3%), pain (75.3%), pressure ulcers (70.5%), oral and limb apraxia (67.1%), urinary tract infection (69.2%), and 4-limb spasticity (52.7%). Reversible causes of DoC occurred very commonly. Conditions that may confound the diagnosis of DoC occurred at surprisingly high rates. Conditions that may be a source of pain occurred not infrequently. Among those that may diminish or confound the level of consciousness, 4.8 ± 2.0 conditions were identified per patient. In conclusion, high rates of various complications and comorbidities occurred in persons with DoC. Correcting reversible causes, identifying confounders and mimics, and managing general consequences need to be seriously considered in clinical practice. Full article

(This article belongs to the Special Issue Emerging Treatments for Patients with Disorders of Consciousness)

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