Brain Stimulation 10 (2017) 328e330
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Transcutaneous auricular vagus nerve stimulation in disorders of consciousness monitored by fMRI: The first case report Dear Editor, Over the last 10 years, the mortality of patients with severe traumatic brain injury (TBI) and hypoxic ischemic encephalopathy (HIE) declined significantly with the development of intensive care. However, TBI and HIE survivors are largely suffering from disorders of consciousness (DOC), either temporary or long-lasting. DOC often increase the financial strain on families, impose a burden on medical resources, and raise ethical and legal issues [1]. Therefore, developing intervention for patients with DOC is extremely important. Neuro-stimulation techniques, such as deep brain stimulation (DBS) and spinal cord stimulation (SCS), have been employed to treat DOC. While these techniques show some promises to increase patients' responsiveness, there are still some limitations. For instance, DBS involves a craniotomy, which might increase the risks of intracranial hemorrhage and infection. Additionally, the complexity and costs of these techniques further limited their potential applications. Vagus nerve stimulation (VNS) is one of the neuro-stimulation techniques that can modulate functional brain activity via electrostimulation of the vagus nerve. The afferent vagus branches project to the nucleus of solitary tract connecting to thalamus, amygdala, forebrain, and medullary reticular formation. A recent prospective pilot clinical trial conducted by Chen et al. found that VNS improved outcomes in patients with severe brain injury [2]. However, VNS also presents certain limitations, such as the need for a surgery, perioperative risks, potentially adverse effects and high costs. Anatomical studies have shown that the vagus nerve has a branch of afferent projections at the auricular concha [3]. A direct electrostimulation of the branch may produce an effect similar to classic VNS without the potential risks associated with surgery. Based on the rationale, we developed the transcutaneous auricular VNS (taVNS) years ago, and found that this novel non-invasive stimulation was comparable in efficacy to classic VNS for epilepsy and depression [4,5]. Here, we report the first case of taVNS treatment for a patient with DOC. As part of the clinical trial, we recruited patients to test the efficacy of taVNS for DOC (clinical trial number: ChiCTR-INR16008745) in June 2016. A 73 years old female patient was hospitalized with the chief complaint of 50 days of DOC after cardiopulmonary resuscitation. On day one, the patient suffered a respiratory and cardiac arrest, and was immediately rescued with cardiopulmonary resuscitation. She was transferred into the intensive care unit and diagnosed as
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being in the vegetative state (VS). No improvement of consciousness was made in the following fifty days and the patient's relatives gave consent to the taVNS treatment. TaVNS was applied to the patient's bilateral ear concha twice daily for 30 minutes each in four consecutive weeks, with an intensity of 4e6 mA, at a frequency of 20 Hz (less than1ms wave width). The patient's consciousness level was assessed by using the JFK Coma Recovery Scale-Revised (CRS-R), which was designed to differentiate VS from the minimally conscious state (MCS) [6]. Three physicians, who were not in charge of the taVNS treatment, individually assessed the consciousness level of the patient in waken state. The average of two closest scores was recorded as the final score. Brain fMRI was performed prior and posterior to the 4-week taVNS treatment using a 3.0T MR scanner (HD750, General Electrics Co., USA) for 7 min each time (TR ¼ 2000 ms, TE ¼ 30 ms, slice thickness of 4.0mm with an inter-slice gap of 0.6 mm). The scan did not show any cerebral structural abnormality. A seed-based correlation method was employed to identify functional connectivity (FC) changes of the default mode network (DMN) in the patient after the taVNS treatment (sofeware: SPM8, http://www.fil.ion.ucl.ac. uk/spm). The seed region was located in the posterior cingulate cortex (PCC) with a radius of 6 mm. We compared the PCC-based correlation maps prior and posterior to the taVNS treatment. Brain regions beyond a given threshold level (0.4) were considered having significant FC changes. Regarding the consciousness state, the patient presented a CRSR of 6 on June 16th, 2016. On August 4th, 2016, the patient showed eye-opening without stimulation and a clear sleep-wake cycle. Yet the CRS-R remained unchanged at 6, with the patient exhibiting behaviors consistent with a VS diagnosis. The taVNS treatment started on August 5th. Four weeks later, the patient presented a CRS-R of 13, demonstrating new behaviors in both motor and oromotor function, which was consistent with a diagnosis of MCS. As the seed region, the PCC forms a central node in the DMN of the brain [7]. TaVNS increased the FC between posterior cingulate/ precuneus and hypothalamus, thalamus, ventral medial prefrontal cortex (vmPFC), superior temporal gyrus, yet decreased the FC between posterior cingulate/precuneus and the cerebellum (Fig. 1). It is worth mentioning that in these brain regions, both the posterior cingulate/precuneus, known as the pivot for conscious information processing [8], and the thalamus, which played an important role in arousal and awareness [9], were activated by the taVNS. DOC patients exhibit functional impairments in DMN which is critical in the genesis of awareness. It should be noted that the FC
Y.-t. Yu et al. / Brain Stimulation 10 (2017) 328e330
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Fig. 1. Using the posterior cingulate gyrus (PCC) as the seed region, this figure shows the changes of the patient's default mode network (DMN) connectivity before and after taVNS treatment. (A) FC mode before taVNS treatment, (B) FC mode after taVNS treatment, (C) The difference chart between the data after and before taVNS treatment. From the figure, the FC between posterior cingulate/precuneus and hypothalamus, thalamus, ventral medial prefrontal cortex (vmPFC), superior temporal gyrus increased respectively, yet the FC between posterior cingulate/precuneus and cerebellum decreased.
of DMN is decreased in brain-damaged patients, with a severity in proportion to the degree of consciousness impairment. The outcome of this case suggests that taVNS induced enhanced FC of DMN in this patient, which might be the main cause of improved brain function [1]. Our previous study supports the results [4]. According to a previous study, before the taVNS treatment, this patient can be classified as being in the persistent vegetative state with very little hope of natural arousal [10]. For this reason, we consider that the improvement of the patient is closely related to the taVNS treatment, though the possibility of spontaneous coincidental recovery cannot be excluded. To our knowledge, this is the first case of taVNS in a patient with DOC, and the first report of encouraging results from clinical condition and brain functional network. Further studies are needed to confirm the important finding. Acknowledgment This paper is supported by the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ16012), China Postdoctoral Science Foundation (2016M590185), National Natural Science Foundation of China (81600919, 81273674), Beijing Natural Science Foundation (7164302), Beijing Municipal Science & Technology Commission (Z141107002514111, Z161100000516165, Z161100002616003) and Military Medical Science and Technology Fund (15QNP006). There are no conflicts of interest. We thank Dr. Li-jun Bai, Dr. Shu-xing Wang, Dr. Yong Liu, Dr. Wen-cong Li, Dr. Jing Ling and Miss Qiu-li Zhang for their excellent revising opinions to this manuscript. We thank Dr. Bing Zhu for his irreplaceable guidance to this work.
[2] Shi C, Flanagan SR, Samadani U. Vagus nerve stimulation to augment recovery from severe traumatic brain injury impeding consciousness: a prospective pilot clinical trial. Neurol. Res 2013;35(3):263e76. [3] He W, Wang X, Shi H, Shang H, Li L, Jing X, et al. Auricular acupuncture and vagal regulation. Evidence-based Complement. Altern Med eCAM 2012;2012:786839. [4] Fang J, Rong P, Hong Y, Fan Y, Liu J, Wang H, et al. Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder. Biol psychiatry 2016;79(4):266e73. [5] Rong P, Liu A, Zhang J, Wang Y, He W, Yang A, et al. Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial. Clin Sci 2014:CS20130518. [6] Kalmar K, Giacino JT. The JFK coma recovery scaledrevised. Neuropsychol Rehabil 2005;15(3e4):454e60. [7] Leech R, Braga R, Sharp DJ. Echoes of the brain within the posterior cingulate cortex. J Neurosci 2012;32(1):215e22. [8] Fransson P, Marrelec G. The precuneus/posterior cingulate cortex plays a pivotal role in the default mode network: evidence from a partial correlation network analysis. Neuroimage 2008;42(3):1178e84. s RR. The functional states of the thalamus and the associated [9] Steriade M, Llina neuronal interplay. Physiol Rev 1988;68(3):649e742. [10] Estraneo A, Moretta P, Loreto V, Lanzillo B, Santoro L, Trojano L. Late recovery after traumatic, anoxic, or hemorrhagic long-lasting vegetative state. Neurology 2010;75(3):239e45.
Yu-tian Yu1 Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China Yi Yang1 Department of Neurosurgery, PLA Army General Hospital, Beijing, China Lu-bin Wang Cognitive and Mental Health Research Center, Beijing Institute of Basic Medical Sciences, Beijing, China Ji-liang Fang, Yuan-yuan Chen Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.brs.2016.12.004. References [1] Monti MM, Sannita WG. Brain function and responsiveness in disorders of consciousness. Springer; 2016.
Jiang-hong He** Department of Neurosurgery, PLA Army General Hospital, Beijing, China Pei-jing Rong* Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
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Y.-t. Yu et al. / Brain Stimulation 10 (2017) 328e330
Corresponding author. Department of Neurosurgery, PLA Army General Hospital, Beijing, 100700, China.
E-mail address:
[email protected] (J.-h. He). E-mail address:
[email protected] (P.-j. Rong).
Corresponding author. Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, No16. Dongzhimen Nan Xiao Street, Dongcheng District, Beijing, 100700, China.
20 October 2016 Available online 14 December 2016
1
Yu and Yang contributed equally.
