The Role of Hyperbaric Oxygen and Neuropsychological Therapy in Cognitive Function Following Traumatic Brain Injury

The Role of Hyperbaric Oxygen and Neuropsychological Therapy in Cognitive Function Following Traumatic Brain Injury

The Role of Hyperbaric Oxygen and Neuropsychological Therapy in Cognitive Function Following Traumatic Brain Injury

Traumatic brain injury (TBI) caused by accidents is a very important public health problem in Taiwan. There are many people with brain damage and cognitive dysfunction caused by traumatic brain injury every year. Currently, there is no effective treatment for cognitive dysfunction caused by traumatic brain injury. Evidence from clinical studies in recent years suggests that hyperbaric oxygen therapy may be a treatment for repairing nerves after brain injury. Many studies have shown that oxidative stress and inflammatory responses play an important role in the pathogenesis of the central nervous system. In recent years, our research team has shown that oxidative stress and inflammatory response are significantly associated with the prognosis of patients with traumatic brain injury, cerebral hemorrhage, and stroke patients. More and more evidences also show that oxidative stress and inflammatory response play an important role in the neuropathological changes of mental cognitive sequelae after traumatic brain injury. This injury may be gradual from the time of head trauma. This process begins with the generation of oxidative stress and free radicals. When the cell repair and free radical scavenging system can not effectively overcome the excessive production of free radicals, an oxidative damage reaction will occur, causing a series of inflammatory cells and cytokines to be activated. Studies have also shown that when inhibiting those free radicals that produce oxidative stress, the neurological function and cognitive function of the head after trauma can be significantly improved. It is becoming widely acknowledged that the combined action of hyperoxia and hyperbaric pressure leads to significant improvement in tissue oxygenation while targeting both oxygenand pressure-sensitive genes, resulting in improved mitochondrial metabolism with anti-apoptotic and anti-inflammatory effects. The investigators published an article this year showing that hyperbaric oxygen therapy can improve the prognosis of patients with acute stroke and increase endothelial progenitor cells in the systemic circulation. The investigators plan to conduct this research project through hyperbaric oxygen therapy and neuropsychological therapy, and using scientific tests and neurocognitive function assessments. The investigators hope to answer the following questions: (1) Whether the treatment of hyperbaric oxygen can improve oxidative stress and inflammatory response after brain injury, and observe changes in biomarker concentration; (2) Whether hyperbaric oxygen therapy and neuropsychological therapy can improve cognitive function after brain injury; and (3) which biomarkers are factors that influence cognitive function prognosis.

Research Methodology A prospective cohort study will be conducted. The follow-up periods are 18 weeks. Diagnostic criteria of mild and moderate traumatic brain injury. Diagnostic criteria of traumatic brain injury will be according to (1) American Association of Neurosurgical Surgeons (AANS) Guidelines for The Management of Severe Head Injury; (2) YOUMANS Neurological Surgery Fifth Edition Guidelines for Traumatic Brain Injury. Definitions and classifications Traumatic brain injury is defined as damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile. Consequently to the injury, brain function is temporarily or permanently impaired and structural damage may or may not be detectable with current imaging technology. TBI is usually classified based on severity, anatomical features of the injury, and the cause of the injury. The severity is assessed according to the loss of consciousness (LOC) duration, the post-traumatic amnesia (PTA), and the Glasgow coma scale (GCS) grading of the level of consciousness. Approximately (70-90%) of the TBI in the US are classified as mild TBI (mTBI) or concussion - LOC duration of 0-30 minutes, PTA duration of less than a day and GCS grade of 13-15. Post concussion syndrome (PCS) is a set of symptoms succeeding mTBI in most patients. The PCS symptoms include headache, dizziness, neuropsychiatric symptoms, and cognitive impairments. In most patients, PCS may continue for weeks or months, and up to 25% of the patients may experience prolonged PCS (PPCS) in which the symptoms last for over six months. Such individuals are at high risk for emotional and cognitive dysfunction, culminating in inability to carry out ordinary daily activities, work responsibilities and standard social relationships. Hypotheses and Purpose: In this study, the investigators hypothesize that the hyperbaric oxygen therapy in neurotherapeutics, in light of recent persuasive evidence for hyperbaric oxygen therapy efficacy in brain repair and of new understanding of brain energy management and response to damage. The investigators discuss the optimal timing of treatment, optimal dose-response curve (oxygenpressure levels), suitable candidates and promising future directions. The investigators speculate that these changes of biomarkers correlated with the hyperbaric oxygen therapy efficacy and the progression of neuropsychological testing during the 18 weeks follow-up. The investigators plan to conduct this research project through hyperbaric oxygen therapy and neuropsychological therapy and using scientific tests and neurocognitive function assessments. The scientific tests including flow cytometry to evaluate the fraction of circulating activated platelets, the proportion of leukocytosis apoptosis, Erythrocyte assay of antioxidant enzymes and Enzyme-Linked Immunosorbent Assay (ELISA) for inflammatory markers. Purpose: To evaluate that whether the treatment of hyperbaric oxygen can improve oxidative stress and inflammatory response after brain injury, and observe changes in biomarker concentration. To evaluate that whether hyperbaric oxygen therapy and neuropsychological therapy can improve cognitive function after brain injury. To evaluate that which biomarkers are factors that influence the prognosis of cognitive function.

Traumatic brain injury, hyperbaric oxygen therapy, neuropsychological treatment, cognitive function, biomarkers.

After signing an informed consent form, the patients were invited for baseline evaluation. Included patients were randomized into two groups. The neuropsychological functions were the primary endpoints of the study. Secondary end point included quality of life evaluation. Evaluations were made by medical and neuropsychological practitioners who were blinded to patients' inclusion in the control-crossed or the treated groups. Patients in the treated group were evaluated three - at baseline, after 6 weeks of HBOT and after 6 weeks of neuropsychological treatment or no treatment. Patients in the crossover group were evaluated three times: baseline, after 6 weeks control period of no treatment, and after subsequent 6 weeks of HBOT. The post-HBOT neuropsycological evaluations were performed more than 1 week (1-2 weeks) after the end of the HBOT protocol. The following HBOT protocol was practiced: 30 daily sessions, 5 days/week, 60 minutes each, 100% oxygen at 1.5ATA.

Patients in the treated group were evaluated three - at baseline, after 6 weeks of HBOT and after 6 weeks of neuropsychological treatment or no treatment.

Patients in the crossover group were evaluated three times: baseline, after 6 weeks control period of no treatment, and after subsequent 6 weeks of HBOT

The Hyperbaric Oxygen Therapy (HBOT) patients were placed in a chamber that was pressurized with air to 2.5 ATA during 15 min and were supplied 100% oxygen for 25 mins, followed by a 5-min air break. This cycle was repeated once and followed by 100% oxygen for 10 min, after which time the chamber was depressurized to 1 ATA over 15 min with 100% oxygen for a total treatment time of 100 min.

Subtests included the followings: Information with a measure of general knowledge, digit Span, vocabulary ability to define 35 words, arithmetic, comprehension, similarities, picture completion, picture arrangement, block design, digit symbol, and object assembly. The scores could further subscore into verbal comprehension, perceptual reasoning and working memory index.

includes tests of nine domains of cognitive function (attention, concentration, orientation, short and long-term memory, language ability, visual construction, word list generation, abstraction, and judgment), and the score ranges from 0 (worst) to 100 (best score).

The Mini-Mental State Examination (MMSE) test is a 30-point questionnaire. Any score greater than or equal to 24 points (out of 30) indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment.

The SF-36 taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Scoring the SF-36 is a two-step process. First, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are set at 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores.

Neuropsychological testing- The World Health Organization Quality of Life questionnaire (WHOQOL-BREF)

questionnaire is a 26-item questionnaire that evaluates 4 domains of quality of life (QoL), namely Physical, Psychological, Social Relationships and Environment

The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs used here differ from the original as such: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; and 29-63: severe depression.

by a commercially available kit (Ransod, Randox Lab., Grumlin, UK) based on the method developed by McCord and Fridovich. The SOD activity is then measured by the degree of inhibition of this reaction. The assay will be carried out on washed red blood cells, by diluting the samples to give between 30 and 60% inhibition. Together with the kit, a standard is supplied, which is diluted to provide a range of standards and a calibration curve. A standard curve will be produced by plotting % inhibition for each standard against Log 10. The result will be multiplied by the appropriate dilution factor (100) and expressed in units/litre (U/L) of whole blood.

Erythrocyte GPx activity will be measured using a commercially available kit (Ransel; Randox Lab, Crumlin, U.K.). The result obtained will be expressed in U/L of haemolysate and will be multiplied by the appropriate dilution factor to obtain the result in U/L of whole blood.

Serum MDA will be measured using the thiobarbituric acid reactive substances (TBARS) assay. TBARS reagent (1 ml) will be added to a 0.5 ml aliquot of serum and heated for 20 minutes at 100°C. The antioxidant, butylated hydroxytoluene, will be added before heating the samples. After cooling on ice, samples will be centrifuged at 840 g for 15 mins and absorbance of the supernatant will be read at 532 nm. Blanks for each sample will be prepared and assessed in the same way to correct for the contribution of A532 to the sample. TBARS results will be expressed as MDA equivalents using 1,1,3,3-tetraethoxypropane.

Plasma free thiols will be determined by directly reacting thiols with 5,5-dithiobis 2-nitrobenzoic acid (DTNB) to form 5-thio-2- nitrobenzoic acid (TNB). The amount of thiols in the sample will be calculated from the absorbance determined using extinction coefficient of TNB (A412 = 13,600 M-1cm-1).

by Enzyme-linked immunosorbent assays; The values of intra- and inter-assay coefficients were around 5%. Concentration is expressed as pg/ml

by Enzyme-linked immunosorbent assays; The values of intra- and inter-assay coefficients were around 5%. Concentration is expressed as pg/ml

by Enzyme-linked immunosorbent assays; The values of intra- and inter-assay coefficients were around 5%. Concentration is expressed as ng/ml

by Enzyme-linked immunosorbent assays; The values of intra- and inter-assay coefficients were around 5%. Concentration is expressed as ng/ml

DNA will be extracted from 200μL plasma samples with use of a QIAamp Blood Kit (Qiagen) according to the "blood and body fluid protocol" as recommended by the manufacturer. Plasma DNA will be measured by a real-time quantitative PCR assay for the β-globin gene and ND2 gene. The β-globin gene is present in all nucleated cells of the body while ND2 gene is specific mitochondrial DNA. Expression of β-globin and mtDNA will be measured by quantitative RT-PCR based on continuous measurements of Syber green fluorescent dye that binds to double stranded DNA generated during PCR and a specific primer pair for β-globin-354F (5'-GTG CAC CTG ACT CCT GAG GAG A-3') and β-globin-455R (5'-CCT TGA TAC CAA CCT GCC CAG-3') and ND2 (forward：5'-CAC AGA AGC TGC CAT CAA GTA -3'; reverse：5'-CCG GAG AGT ATA TTG TTG AAG AG -3').

Inclusion Criteria: Traumatic brain injury, mild and moderated. Age between 18 and 65 years old Exclusion Criteria: Penetrating injury, including gunshot injury Combined with other major trauma which had unstable hemodynamics Major systemic disease, such ESRD, liver cirrhosis, CHF, or a malignant disease Evidence for alcoholism or any other addictive disorders, or known affective or other psychiatric disease or use of sedatives or neuroleptic medication Known neurological disorders potentially affecting the central nervous system or severe recent life events that might have interfered with neuropsychological testing.

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