by Patricia Grady-Dominguez, PhD • Lauren Teague • Jennifer Weaver, PhD, OTR/L
Patients with disorders of consciousness (DoC) are characterized by a continuum of clinical states (Table 1) 1,2 and emerging research suggests that neuromodulatory interventions may lead to improved neurobehavioral function. 3,4 In the context of brain injury rehabilitation, neuromodulation has been defined as “the alteration of nerve activity through targeted delivery of stimulation provided to modulate dysfunctional as well as functional neural pathways to support neural repair and neural alterations necessary for sustained recovery of functional skills valued by the patient” (p. 368). 5 Neuromodulatory interventions may aid in reconfiguring neural networks, improve the structure and function of viable networks after injury, engage dormant networks, and create new neural connections. For patients with DoC, these benefits may contribute to increases in neurobehavioral function including arousal and awareness, subsequently leading to an improved state of consciousness.
In this article, we draw upon two recent literature reviews to briefly summarize the current evidence and clinical utility of six non-invasive neuromodulatory interventions for patients with DoC (Table 2). Murtaugh and colleagues (2024) 4 conducted an umbrella review of systematic reviews for allied health interventions (i.e., music,
occupational, physical, and speech therapy). To include additional information about emerging stimulation interventions that are less available in clinical practice, we also include evidence from a systematic review conducted by Weaver and colleagues (2022). 3 Non-invasive brain stimulation techniques based on medical devices
(noted with an ‘*’ in Table 2) are regulated in the United States (US) by the Food and Drug Administration (FDA) and companies marketing these devices are required to comply with regulatory requirements before they can legally sell their devices in the US. US based clinicians considering the purchase of a device should have
the company confirm the FDA approval status for use in brain injury rehabilitation.
Sensory Stimulation
Sensory stimulation is provided to individuals with DoC to increase arousal and awareness. Research has largely examined two types of sensory stimulation interventions: unimodal and multimodal (i.e., interventions where more than one of the visual, auditory, tactile, olfactory, gustation, vestibular, and/or proprioception senses are addressed). Protocols typically involve providing 2 to 5 minutes of stimulation several times per day. 4 Low to moderate evidence supports the use of unimodal sensory stimulation. There is moderate evidence for the use of structured, familiar storytelling and low evidence for the use of unstructured
storytelling and music. 3 All studies examining unimodal stimulation have, to date, focused on auditory stimuli including structured and unstructured storytelling, familiar voices, and music (within and outside the context of music therapy). These studies have low methodological quality, limiting the ability to provide evidence for
their efficacy. Systematic reviews of music therapy interventions indicate promise for improving arousal and awareness, but current research is largely exploratory. 4
Strong evidence supports the use of multimodal sensory stimulation to improve neurobehavioral function in patients with DoC. 3,6 Approaches include a combination of at least two types of sensory stimuli, including storytelling (auditory), familiar music (auditory), footbaths (tactile), massage (tactile), positioning (vestibular/
proprioceptive), and other types of stimulation. Some studies used structured protocols, while others used stimuli tailored to the patient’s preferences. Two studies showed that patients had better recovery in neurobehavioral function when sensory stimulation was delivered by family. Median Nerve Stimulation Peripheral nerve stimulation has been studied as it can increase bilateral cerebral blood flow, directly stimulate the brainstem and cerebral cortex, and enhance the secretion of neurotransmitters in patients with DoC. 7 Most research has focused on stimulation of the right median nerve at the wrist, a simple, inexpensive, and safe
approach to peripheral nerve stimulation.
Emerging research suggests that median nerve stimulation may have a positive impact on improving state of consciousness.4 However, as with other interventions, significant heterogeneity in dosing and frequency prevents conclusive evaluation of this intervention. Individual patient responses vary significantly across studies. No
research has determined which patients (i.e., UWS or MCS) are most likely to benefit from this intervention.
Clinical Takeaway
Median nerve stimulation, like other non-invasive neuromodulatory interventions, shows some promise for increasing arousal and awareness in patients with DoC. More research is necessary to establish appropriate dosing and determine which patients are most likely to respond to this therapy. Advantages to be considered
include that, relative to other interventions, median nerve stimulation is safe and inexpensive.
Non-Invasive Brain Stimulation
Non-invasive brain stimulation can be used to induce electrical currents in the brain via the delivery of electrical stimuli or magnetic pulses. These methods vary in cost and availability to clinicians for use with patients in DoC. Evidence for using these devices to treat patients with DoC is just beginning to emerge, and we include it to
highlight potential future clinical applications.
Transcranial Direct Current Stimulation
Transcranial Direct Current Stimulation (tDCS) is a technique that involves delivering low, constant current to the brain using electrodes placed on the scalp. Depending on the parameters applied, it may increase viable synaptic connections (anodal tDCS) or decrease undesirable connections (cathodal tDCS). 3 tDCS units
are relatively inexpensive, portable, and can be used for multiple patients. This intervention has gained attention in recent years for its potential therapeutic benefits in patients with DoC. Moderate evidence supports the use of tDCS on the dorsolateral prefrontal cortex. Studies included in the Weaver review ranged in frequency from a single session to 20 sessions over four weeks. 3 Patients in the MCS showed gains in neurobehavioral outcomes, suggesting a potential benefit for enhancing neurobehavioral function. Results were mixed for patients with UWS; two studies showed benefits for these patients while two did not. Weaver and colleagues also identified a single study examining tDCS stimulating the primary motor cortex; this study found no benefit from the intervention. 3
Repetitive Transcranial Magnetic Stimulation
Repetitive transcranial magnetic stimulation (rTMS) uses alternating magnetic fields to up- or down-regulate nerve cells in the brain. 3 rTMS has been applied to many neurological conditions, and recent evidence has examined its efficacy in increasing arousal and awareness in patients with DoC. rTMS units are large and more
expensive than tDCS devices, limiting their availability for use with this population. While randomized placebo-controlled clinical trials of rTMS are underway, only one low-quality study was identified by Weaver and colleagues, and this report indicated no clinical benefit. While the currently published evidence of clinical efficacy is limited, an in-press article in Journal of Head Trauma Rehabilitation, 8 is aseminal report of rTMS-related seizure risk indicating low likelihood that rTMS elevates baseline seizure risk for the majority of patients with DoC. This evidence and emerging evidence of efficacy from rigorous trials should be considered by researchers studying the clinical benefits of rTMS in isolation and when combined with other interventions provided to patients with DoC.
Near Infrared Laser Therapy and Focused Shockwaves
Near infrared laser therapy may increase the availability of adenosine triphosphate in the brain, leading to improved cellular respiration and oxygenation. 3 Focused shockwaves are also thought to produce biologic responses including anti-inflammatory actions and improved cellular function. One small study, included in the
Weaver review, compared these two approaches and reported that both groups experienced statistically significant increases in neurobehavioral function. Both approaches require costly, specialized equipment and trained personnel and, at this time, these approaches are not readily available for use in rehabilitation for
patients in DoC. These techniques may improve neurobehavioral function, but the current evidence is low due to the small sample size and lack of control group.
Clinical Takeaway
Evidence supporting clinical use of tDCS, rTMS, near-infrared laser therapy, and focused shockwaves is slowly emerging. tDCS applied to the dorsolateral prefrontal cortex shows moderate evidence for improvements in arousal and awareness in patients in the minimally conscious state. The other approaches currently have limited
evidentiary support and are largely unavailable in current clinical settings. Notably, at this time the FDA has not approved clinical use of these devices in the United States to treat patients in DoC. Further research is needed to establish safety, clinical benefits, optimal protocols, understand long-term effects, for patients in
both the minimally conscious state and those with unresponsive wakefulness syndrome.
Concluding Remarks
The American Congress of Rehabilitation Medicine and the American Academy of Neurology (ACRM/AAN) published joint clinical practice guidelines for the evaluation and treatment of patients with prolonged DoC. 9 They noted that existing treatments for DoC generally lack strong evidentiary support, leading to uncertainty in clinical decision-making for these patients. While the neuromodulatory interventions reviewed in this article present some benefits and/or merit further study for enhancing
neurobehavioral recovery, there are no clinical practice guidelines for their use. For both existing and emerging treatments, variability in study methodologies and patient responses to treatments pose substantive challenges to providing clinical guidance. Given the paucity of clear guidance, clinicians should engage in transparent
communication and shared decision-making with family caregivers while selecting neuromodulatory interventions. Continued research efforts should focus on establishing safety, clinical benefits, optimal protocols, understanding long-term effects, for both existing and emerging treatments for patients in the minimally conscious state and with unresponsive wakefulness syndrome.
References
1. Giacino JT, Ashwal S, Childs N, et al. The minimally conscious state: Definition and diagnostic criteria. Neurology. 2002;58(3):349-353. doi:10.1212/WNL.58.3.349
2. Thibaut A, Bodien YG, Laureys S, Giacino JT. Minimally conscious state “plus”: diagnostic criteria and relation to functional recovery. J Neurol. 020;267(5):1245-1254. doi:10.1007/s00415-019-09628-y
3. Weaver JA, Watters K, Cogan AM. Interventions facilitating recovery of consciousness following traumatic brain injury: A systematic review. OTJR: Occupation, Participation and Health. Published online September 1, 2022:153944922211177. doi:10.1177/15394492221117779
4. Murtaugh B, Morrissey AM, Fager S, Knight HE, Rushing J, Weaver J. Music, occupational, physical, and speech therapy interventions for patients in disorders of consciousness: An umbrella review. Schnakers C, Zasler ND, eds. NRE. 2024;54(1):109-127. doi:10.3233/NRE-230149
5. Bender Pape TL, Herrold AA, Guernon A, Aaronson A, Rosenow JM. Neuromodulatory interventions for traumatic brain injury. Journal of Head Trauma Rehabilitation. 2020;35(6):365-370. doi:10.1097/HTR.0000000000000643
6. Padilla R, Domina A. Effectiveness of sensory stimulation to improve arousal and alertness of people in a coma or persistent vegitative state after traumatic brain injury: A systematic review. The American Journal of Occupational Therapy. 2016;70(3):7003180030p1-7003180030p8. doi:10.5014/ajot.2016.021022
7. Wang P, Cao W, Zhou H, et al. Efficacy of median nerve electrical stimulation on the recovery of patients with consciousness disorders: a systematic review and meta-analysis. J Int Med Res. 2022;50(12):030006052211344. doi:10.1177/03000605221134467
8. Ripley D Krese K Rosenow J Patil V Schuele S Pacheco M Roth E Kletzel S Livengood S Aaronson A Herrold A Blabas B Bhaumik R Guernon A Burress Kestner C Walsh E Bhaumik D Bender Pape T (in press) Seizure risk associated with the use of transcranial magnetic stimulation for coma recovery in individuals with disordered
consciousness after severe traumatic brain injury, J Head Trauma Rehabilitation. (PMID: 39293071)
9. Giacino JT, Katz DI, Schiff ND, et al. Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National
Institute on Disability, Independent Living, and Rehabilitation Research. Neurology. 2018;91(10):450-460. doi:10.1212/WNL.0000000000005926.
Author Bios
Patricia Grady-Dominguez, PhD, a postdoctoral fellow in the Meaningful Measurement for Rehabilitation Research Lab at Colorado State University, holds a Ph.D. in Occupation and Rehabilitation Science. Her research focuses on improving precision of rehabilitation outcome measures and improving utility of assessment tools for evaluating recovery, particularly for severe traumatic brain injury and pediatrics. With expertise in advanced psychometric models, including Rasch analysis, she
has contributed to developing and validating instruments used to measure rehabilitation outcomes ranging from body functions to participation.
Lauren Teague is a Doctor of Occupational Therapy student at Colorado State University. She is originally from Indiana, where she graduated from Purdue University with a Bachelor of Science in Psychological and Brain Sciences. Lauren is a Graduate Research Assistant in the Meaningful Measurement in Rehabilitation
Research Lab (METEOR Lab) at Colorado State University. Her research interests include rehabilitation measures, practitioner-caregiver communication, and neurological disorders.
Jennifer Weaver, PhD, OTR/L, is an Assistant Professor in the Department of Occupational Therapy at Colorado State University (CSU), Director of the Meaningful Measurement in Rehabilitation Research Lab, and Director of Implementation Research for the Translational Neurological Lab located at the CSU Spur campus.
She has over 10 years of experience as an occupational therapist and was a certified brain injury specialist. She is the project lead on advancing outcome measures and implementing evidence-based measurement practices in rehabilitation for patients with disorders of consciousness
