Hyperbaric hydrogen therapy improves secondary brain injury after head trauma.

Background: The pathophysiology of traumatic brain injury (TBI) is caused by the initial physical damage and by the subsequent biochemical damage (secondary brain injury). Oxidative stress is deeply involved in secondary brain injury, so molecular hydrogen therapy may be effective for TBI. Hydrogen gas shows the optimal effect at concentrations of 2% or higher, but can only be used up to 1.3% in the form of a gas cylinder mixed with oxygen gas, which may not be sufficiently effective. The partial pressure of hydrogen increases in proportion to the pressure, so hyperbaric hydrogen therapy (HBH2) is more effective than that at atmospheric pressure. Methods: A total of 120 mice were divided into three groups: TBI + non-treatment group (TBI group; n = 40), TBI + HBH2 group (n = 40), and non-TBI + non-treatment group (sham group; n = 40). The TBI and TBI + HBH2 groups were subjected to moderate cerebral contusion induced by controlled cortical impact. The TBI + HBH2 group received hyperbaric hydrogen therapy at 2 atmospheres for 90 minutes, at 30 minutes after TBI. Brain edema, neuronal cell loss in the injured hippocampus, neurological function, and cognitive function were evaluated. Results: The TBI + HBH2 group showed significantly less cerebral edema (p ≺ 0.05). Residual hippocampal neurons were significantly more numerous in the TBI + HBH2 group on day 28 (p ≺ 0.05). Neurological score and behavioral tests showed that the TBI + HBH2 group had significantly reduced hyperactivity on day 14 (p ≺ 0.01). Conclusion: Hyperbaric hydrogen therapy may be effective for posttraumatic secondary brain injury.

Treatment of pediatric cerebral radiation necrosis using hyperbaric oxygenation.

Introduction: Cerebral radiation necrosis is rarely encountered in pediatric patients. This case report describes a child with cerebral radiation necrosis who was successfully treated using corticosteroids, bevacizumab, and hyperbaric oxygenation. Case report: A 3-year-old boy developed progressive extremity weakness six months after the completion of radiation therapy for the treatment of a neuroepithelial malignancy. Treatment with corticosteroids and bevacizumab was initiated, but his symptoms did not improve, and he was then referred for hyperbaric oxygen therapy. After completing 60 hyperbaric treatments, he experienced significant improvements in mobility, which remained stable over the next year. Discussion: Cerebral radiation necrosis typically presents in children with symptoms of ataxia or headache. Corticosteroids and bevacizumab are common treatments, but hyperbaric oxygen therapy has also been studied as a therapeutic modality for this condition. When considering the use of hyperbaric oxygenation in pediatric patients, careful attention to treatment planning and patient safety can reduce the risks of adverse events such as middle ear barotrauma and confinement anxiety. Conclusion: In addition to other available pharmacologic therapies, hyperbaric oxygenation should be considered for the treatment of pediatric patients with cerebral radiation necrosis.

Identifying the Target Traumatic Brain Injury Population for Hyperbaric Oxygen Therapy.

Traumatic brain injury (TBI) results from direct penetrating and indirect non-penetrating forces that alters brain functions, affecting millions of individuals annually. Primary injury following TBI is exacerbated by secondary brain injury; foremost is the deleterious inflammatory response. One therapeutic intervention being increasingly explored for TBI is hyperbaric oxygen therapy (HBOT), which is already approved clinically for treating open wounds. HBOT consists of 100% oxygen administration, usually between 1.5 and 3 atm and has been found to increase brain oxygenation levels after hypoxia in addition to decreasing levels of inflammation, apoptosis, intracranial pressure, and edema, reducing subsequent secondary injury. The following review examines recent preclinical and clinical studies on HBOT in the context of TBI with a focus on contributing mechanisms and clinical potential. Several preclinical studies have identified pathways, such as TLR4/NF-kB, that are affected by HBOT and contribute to its therapeutic effect. Thus far, the mechanisms mediating HBOT treatment have yet to be fully elucidated and are of interest to researchers. Nonetheless, multiple clinical studies presented in this review have examined the safety of HBOT and demonstrated the improved neurological function of TBI patients after HBOT, deeming it a promising avenue for treatment.

First steps toward a BIG change: A pilot study to implement the Brain Injury Guidelines across a 24-hospital system.

INTRODUCTION: The modified Brain Injury Guidelines (mBIG) support a subset of low-risk patients to be managed without repeat head computed tomography (RHCT), neurosurgical consult (NSC), or hospital transfer/admission. This pilot aimed to assess mBIG implementation at a single facility to inform future systemwide implementation. METHODS: Single cohort pilot trial at a level I trauma center, December 2021-August 2022. Adult patients included if tICH meeting BIG 1 or 2 criteria. BIG 3 patients excluded. RESULTS: No patients required neurosurgical intervention. 72 RHCT and 83 NSC were prevented. 21 isolated BIG 1 were safely discharged home from the ED. No hospital readmissions for tICH. Protocol adherence rate was 92%. CONCLUSION: Implementation of the mBIG at a single trauma center is feasible and optimizes resource utilization. This pilot study will inform an implementation trial of the mBIG across a 24-hospital integrated health system.

Efficacy of acupuncture on repair of glial scars in rats with traumatic brain injury.

OBJECTIVE: To explore the underlying mechanism of acupuncture on nerve repair by investigating its effect on the differentiation of glial cells and the repair of glial scars. METHODS: Sprague-Dawley rats were randomly allocated to three groups: normal group, model group, and acupuncture group. Acupuncture was applied at Renzhong (GV26), Baihui (GV20), Fengfu (GV16), Yamen (GV15) and Hegu (LI4) within 12 h after TBI modeling with a frequency of one session per day for 4 weeks. Neurobehavioral assessment, hematoxylin and eosin staining, immunofluorescence detection, and magnetic resonance imaging scanning were performed on days 3, 7, 14, and 28 after modeling of traumatic brain injury (TBI). RESULTS: Acupuncture promoted the proliferation of glial cells and glial scars at an early stage but inhibited the proliferation of glial cells and glial scars at a late stage. Morphological observations and immunofluorescence histochemistry showed that the morphology of the perilesional cortex in the acupuncture group was improved and the number of neurons was increased when compared with the model group. The lesion size of ipsilateral brain parenchyma in the acupuncture group was smaller than in the model group on days 7, 14, and 28 ( < 0.05) after TBI modeling. CONCLUSIONS: Acupuncture might have a bidirectional regulatory effect on glial scar repair after TBI by promoting the proliferation of glial cells and glial scars to limit the injured area and relieve nerve injury during the early stages, and by inhibiting glial scar hyperplasia to benefit the regeneration and repair of neurons and axons and promote neurological function recovery during the later stages.

Acupuncture use for pain after traumatic brain injury: a NIDILRR Traumatic Brain Injury Model Systems cohort study.

BACKGROUND: Pain after traumatic brain injury (TBI) is common and can become chronic. Acupuncture is an increasingly popular non-pharmacologic option in the United States and is commonly used for pain. OBJECTIVE: We explored demographics, injury characteristics, and pain characteristics of individuals who reported using acupuncture for chronic pain after TBI. METHODS: We analyzed a subset of data collected as part of the Pain After Traumatic Brain Injury collaborative study and identified individuals reporting a history of acupuncture as part of management for chronic pain after TBI. We characterized and compared basic demographic data, pain treatment engagements, pain severity, pain interference, functional independence, and pain locations using descriptive and inferential statistics. RESULTS: Our sample included 1,064 individuals. Acupuncture use (n = 208) was lower proportionally among females, Blacks/African Americans, Asians, less educated, and nonmilitary service members. Insurance type varied between acupuncture and non-acupuncture users. Functional and pain outcomes were similar, but acupuncture users reported a higher number of pain sites. DISCUSSION: Acupuncture is one treatment utilized by individuals with TBI and chronic pain. Further investigation would be helpful to understand the barriers and facilitators of acupuncture use to inform clinical trials to examine the potential benefit of acupuncture on pain outcomes after TBI.

Caring for People with Severe Brain Injuries: Improving Health Care Professional Communication and Practice Through Online Learning.

INTRODUCTION: Severe brain injuries can leave people in prolonged disorder of consciousness resulting in multifaceted medical, nursing, and rehabilitative needs that can be challenging for even the most experienced multidisciplinary team. The complexities of care, communication with families, and best interest decision-making about medical interventions means there is a need for ongoing training in clinical, social, ethical, and legal aspects. METHODS: Using a combination of group discussions, interviews, and questionnaires with learners, this article reports an evaluation of designing and delivering an interprofessional, online work-based course to health care professionals caring for prolonged disorder of consciousness patients. RESULTS: There were challenges for staff uptake because of COVID-19, but engaging with it increased knowledge in defining and diagnosing patients' conditions, understanding multidisciplinary team roles, communicating with families, and navigating legal and ethical issues. Course participation also enhanced critical and reflective thinking skills, provided a sense of connection to other professionals, and generated plans to improve service provision. DISCUSSION: Online learning that enables health care professionals to engage at their own pace and also come together as an interprofessional community can provide invaluable continuing professional development and help to enhance joined up, holistic patient care. However, achieving this requires significant investment in creating research-led, multimedia, learning materials, and courses that include synchronous and asynchronous delivery to combine flexible study with the opportunity for peer networks to form. It also depends on a commitment from organizations to support staff online continuing professional development.

[Implementation of a pediatric unit of acquired brain injury in subacute phase in the public health system. Epidemiological, clinical and initial evolution characteristics of the patients attended]. / Implantación de una unidad pediátrica de daño cerebral adquirido en fase subaguda en el sistema público de salud. Características epidemiológicas, clínicas y de evolución inicial de los pacientes atendidos.

INTRODUCTION: Acquired brain injury (ABI) is defined as a neurological injury, acutely occurred, at some point in life causing impairment or loss of functional capacity. In 2019, a specific document was created by the Ombudsman pointing out the relevance of attention to this entity in the pediatric age. PATIENTS AND METHOD: The process of creation and the casuistry of care of one of the first comprehensive care units for subacute ACD in pediatric age within the public health system is presented. RESULTS: Different clinical guidelines have been prepared on the admission and care process within the unit, both for patients and their relatives. Twenty-four patients ≤18 years old, admitted to the subacute phase ACD unit from November 2019 to July 2021, 12 coming from the Community of Madrid, were attended. The median age was 6.97 years. Traumatic mechanism was the most frequent, with iatrogenic causes predominating, followed by precipitation and vehicle-related accidents. On admission to the unit, 8 maintained a minimally conscious/vegetative state. The collaboration of up to 14 different specialists was required due to the complexity of the patients. The overall evolution was favorable in 23 cases, with sequelae in all of them. CONCLUSION: The creation of units specialized in pediatric ACD care with specific action protocols and coordinated trans- and multidisciplinary work is of vital importance.

Astragaloside IV alleviates stroke-triggered early brain injury by modulating neuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway

Purpose: Stroke is an acute cerebrovascular disease. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with an established therapeutic effect on central nervous system diseases. This study examined the neuroprotective properties and possible mechanisms of AS-IV in stroke-triggered early brain injury (EBI) in a rat transient middle cerebral artery occlusion (MCAO) model. Methods: The neurological scores and brain water content were analyzed. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was utilized to determine the infarct volume, neuroinflammatory cytokine levels, and ferroptosis-related genes and proteins, and neuronal damage and molecular mechanisms were evaluated by terminal deoxynucleotidyl transferase dutp nickend labeling (TUNEL) staining, western blotting, and real-time polymerase chain reaction. Results: AS-IV administration decreased the infarct volume, brain edema, neurological deficits, and inflammatory cytokines TNF-α, interleukin-1ß (IL-1ß), IL-6, and NF-κB, increased the levels of SLC7A11 and glutathione peroxidase 4 (GPX4), decreased lipid reactive oxygen species (ROS) levels, and prevented neuronal ferroptosis. Meanwhile, AS-IV triggered the Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of stroke. Conclusion: Hence, the findings of this research illustrate that AS-IV administration can improve delayed ischemic neurological deficits and decrease neuronal death by modulating nuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.

Dignity of Risk, Reemergent Agency, and the Central Thalamic Stimulation Trial for Moderate to Severe Brain Injury.

This article discusses the utility of Perske's "dignity of risk" as a useful heuristic to explain the consent process for a study to evaluate central thalamic deep brain stimulation as a means to restore cognitive function in moderate to severe brain injury. Narratives of interviews with subjects and their families from a related BRAIN Initiative study reveal discordant views on risk, with subjects being more risk-tolerant than their loved ones. This is a challenge for families who remain protective of subjects who have recovered to the point that they are capable of independent decision-making. While the legal threshold for consent has been met, normative and psychological challenges remain as families accommodate themselves to the reemergent agency of the subject. Dignity of risk is a constructive framework to apprehend how families come to appreciate the primacy of the subject's voice and affirm their reemergent agency following a devastating brain injury.

Clinical efficacy of hyperbaric oxygen combined with different timings of right median-nerve electrical stimulation in patients with brain injury-induced disorders of consciousness.

OBJECTIVE: The objective of this study was to investigate the clinical efficacy of hyperbaric oxygen combined with right median-nerve stimulation (RMNES) in patients with disorders of consciousness caused by brain injury. METHODS: A total of 120 patients with consciousness disorders caused by brain injury were selected. They were randomly divided into three groups, a control group, test group 1 (treated with RMNES after hyperbaric oxygen therapy [HBOT]), and test group 2 (treated with RMNES at the same time as HBOT), with 40 patients in each group. Before and after treatment, the Glasgow coma scale (GCS), brainstem auditory-evoked potential (BAEP), electroencephalogram (EEG), and upper-limb sensory-evoked potential (USEP) were evaluated for the three groups of patients. RESULTS: The GCS score of patients in the three groups significantly improved compared with that before treatment (p < .05). There were significant differences in GCS scores among the three groups (p < .05), and the GCS score for the patients was test group 2>test group 1>control group. The EEG, BAEP, and USEP scores were significantly improved compared with those before treatment (p < .05), and the degree of improvement of patients in the three groups was test group 2>test group 1>control group (p < .05). The clinical efficacy of test group 2 was higher than that of test group 1, and the clinical efficacy of test group 1 was higher than that of the control group (p < .05). CONCLUSION: Hyperbaric oxygen combined with RMNES can improve the state of consciousness and promote the recovery of consciousness for patients with consciousness disorders caused by brain injury, and the effect of RMNES combined with HBOT in the chamber on improving the recovery of consciousness is better than after HBOT outside the chamber.

Clinical and neurophysiological effects of central thalamic deep brain stimulation in the minimally conscious state after severe brain injury.

Deep brain stimulation (DBS) of the central thalamus is an experimental treatment for restoration of impaired consciousness in patients with severe acquired brain injury. Previous results of experimental DBS are heterogeneous, but significant improvements in consciousness have been reported. However, the mechanism of action of DBS remains unknown. We used magnetoencephalography to study the direct effects of DBS of the central thalamus on oscillatory activity and functional connectivity throughout the brain in a patient with a prolonged minimally conscious state. Different DBS settings were used to improve consciousness, including two different stimulation frequencies (50 Hz and 130 Hz) with different effective volumes of tissue activation within the central thalamus. While both types of DBS resulted in a direct increase in arousal, we found that DBS with a lower frequency (50 Hz) and larger volume of tissue activation was associated with a stronger increase in functional connectivity and neural variability throughout the brain. Moreover, this form of DBS was associated with improvements in visual pursuit, a reduction in spasticity, and improvement of swallowing, eight years after loss of consciousness. However, after DBS, all neurophysiological markers remained significantly lower than in healthy controls and objective increases in consciousness remained limited. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of DBS of the central thalamus in humans and suggest that DBS can re-activate dormant functional brain networks, but that the severely injured stimulated brain still lacks the ability to serve cognitive demands.

Effects of animal-assisted psychotherapy incorporating mindfulness and self-compassion in neurorehabilitation: a randomized controlled feasibility trial.

Transdiagnostic psychotherapeutic approaches are increasingly used in neurorehabilitation to address psychological distress. Animal-assistance is thought to increase efficacy. The present study evaluates a psychotherapeutic mindfulness- and self-compassion-based group intervention (MSCBI) with and without animal-assistance for patients with acquired brain injury. Patients (N = 31) were randomly assigned to the 6-week intervention with (n = 14) or without animal-assistance (n = 17). Primary outcome was psychological distress at post- and follow-up treatment, secondary outcomes were changes within-session of patients' emotional states, adherence to treatment and attrition. Psychological distress significantly decreased in both groups from pre- to follow-up treatment with no difference between groups. Patients in the animal-assisted MSCBI group reported significantly higher increases in feeling secure, accepted, comforted, grateful, motivated and at ease during the sessions compared to patients in the MSCBI group without animal-assistance. Adherence to sessions was significantly higher in the animal-assisted MSCBI group. Attrition did not significantly differ between groups. Our results show that both MSCBIs with and without animal-assistance are feasible and effective in reducing psychological distress in patients with acquired brain injury. The significant changes within-sessions mainly in relationship-based emotional states and the higher treatment adherence suggest additional effects of animal-assistance. Animal-assistance might increase acceptability and patients' commitment to psychotherapy.

Evaluation of the hyperbaric oxygen therapy on the flash visual evoked potential P2 in patients with severe traumatic brain injury.

BACKGROUND: Studies have shown that hyperbaric oxygen therapy (HBOT) can improve the extraction rate and latency of cortical evoked potential N20 in patients with severe traumatic brain injury, but there are only a few studies on the effect of flash visual evoked potential. OBJECTIVE: This study investigated the effect of hyperbaric oxygen therapy on the P2 wave of flash visual evoked potentials in patients with severe traumatic brain injury. METHODS: In total, we examined 40 TBI patients who received HBOT, in combination with medication, and 38 TBI patients who received medication alone. The FVEPs apparatus was used to detect the P2 wave extraction rate and the latency of the elicited waveform before and after treatment in both the medicated-only controls and HBOT-treated cohorts. RESULTS: Compared with the control group, the HBOT treatment group showed a higher P2 wave elicitation rate, and the P2 wave latency of the HBOT treatment group was significantly shortened (p < 0.05, all). CONCLUSIONS: HBOT, in combination with drug therapy, can significantly increase the P2 wave extraction rate and shorten P2 latency in patients with TBI.

Language Recovery after Brain Injury: A Structural Network Control Theory Study.

Aphasia recovery after stroke depends on the condition of the remaining, extralesional brain network. Network control theory (NCT) provides a unique, quantitative approach to assess the interaction between brain networks. In this longitudinal, large-scale, whole-brain connectome study, we evaluated whether controllability measures of language-related regions are associated with treated aphasia recovery. Using probabilistic tractography and controlling for the effects of structural lesions, we reconstructed whole-brain diffusion tensor imaging (DTI) connectomes from 68 individuals (20 female, 48 male) with chronic poststroke aphasia who completed a three-week language therapy. Applying principles of NCT, we computed regional (1) average and (2) modal controllability, which decode the ability of a region to (1) spread control input through the brain network and (2) to facilitate brain state transitions. We tested the relationship between pretreatment controllability measures of 20 language-related left hemisphere regions and improvements in naming six months after language therapy using multiple linear regressions and a parsimonious elastic net regression model with cross-validation. Regional controllability of the inferior frontal gyrus (IFG) pars opercularis, pars orbitalis, and the anterior insula were associated with treatment outcomes independently of baseline aphasia severity, lesion volume, age, education, and network size. Modal controllability of the IFG pars opercularis was the strongest predictor of treated aphasia recovery with cross-validation and outperformed traditional graph theory, lesion load, and demographic measures. Regional NCT measures can reflect the status of the residual language network and its interaction with the remaining brain network, being able to predict language recovery after aphasia treatment.SIGNIFICANCE STATEMENT Predicting and understanding language recovery after brain injury remains a challenging, albeit a fundamental aspect of human neurology and neuroscience. In this study, we applied network control theory (NCT) to fully harness the concept of brain networks as dynamic systems and to evaluate their interaction. We studied 68 stroke survivors with aphasia who underwent imaging and longitudinal behavioral assessments coupled with language therapy. We found that the controllability of the inferior frontal regional network significantly predicted recovery in language production six months after treatment. Importantly, controllability outperformed traditional demographic, lesion, and graph-theoretical measures. Our findings shed light on the neurobiological basis of human language and can be translated into personalized rehabilitation approaches.

[Xingnao Kaiqiao acupuncture on promoting wake-up of vegetative state after brain injury].

OBJECTIVE: To observe the clinical effect of Xingnao Kaiqiao acupuncture on promoting wake-up of vegetative state after brain injury on the basis of comprehensive rehabilitation training. METHODS: A total of 100 patients with vegetative state after brain injury were randomly divided into an observation group (50 cases, 2 cases dropped off) and a control group (50 cases). Both groups were treated with routine clinical treatment. The patients in the control group were treated with rehabilitation and hyperbaric oxygen; on the basis of the control group treatment, the patients in the observation group were treated with Xingnao Kaiqiao acupuncture at Neiguan (PC 6), Shuigou (GV 26), Sanyinjiao (SP 6), Chize (LU 5), Weizhong (BL 40), Hegu (LI 4) and Taichong (LR 3). The acupuncture was given once a day, 5 days per week, for continuous 30 days. The Glasgow coma scale (GCS) and coma recovery scale-revised (CRS-R) scores were observed before treatment and 10, 20 and 30 days into treatment. The wake-up rate of the two groups was compared after treatment. RESULTS: On 10, 20 and 30 days into treatment, the GCS and CRS-R scores in the two groups were higher than those before treatment (P<0.01), and the scores in the observation group were higher than those in the control group (P<0.01). After treatment, the wake-up rate was 16.7% (8/48) in the observation group, which was higher than 12.0% (6/50) in the control group (P<0.01). CONCLUSION: On the basis of comprehensive rehabilitation and wake-up promotion therapy, the Xingnao Kaiqiao acupuncture could promote the recovery of consciousness level in patients with vegetative state after brain injury.

Home-based light therapy for fatigue following acquired brain injury: a pilot randomized controlled trial.

BACKGROUND AND OBJECTIVES: Fatigue and sleep disturbance are debilitating problems following brain injury and there are no established treatments. Building on demonstrated efficacy of blue light delivered via a lightbox in reducing fatigue and daytime sleepiness after TBI, this study evaluated the efficacy of a novel in-home light intervention in alleviating fatigue, sleep disturbance, daytime sleepiness and depressive symptoms, and in improving psychomotor vigilance and participation in daily productive activity, following injury METHODS: The impact of exposure to a dynamic light intervention (Treatment) was compared to usual lighting (Control) in a randomized within-subject, crossover trial. Outcomes were fatigue (primary outcome), daytime sleepiness, sleep disturbance, insomnia symptoms, psychomotor vigilance, mood and activity levels. Participants (N = 24, M ± SDage = 44.3 ± 11.4) had mild-severe TBI or stroke > 3 months previously, and self-reported fatigue (Fatigue Severity Scale ≥ 4). Following 2-week baseline, participants completed each condition for 2 months in counter-balanced order, with 1-month follow-up. Treatment comprised daytime blue-enriched white light (CCT > 5000 K) and blue-depleted light (< 3000 K) 3 h prior to sleep. RESULTS: Random-effects mixed-model analysis showed no significantly greater change in fatigue on the Brief Fatigue Inventory during Treatment, but a medium effect size of improvement (p = .33, d = -0.42). There were significantly greater decreases in sleep disturbance (p = .004), insomnia symptoms (p = .036), reaction time (p = .004) and improvements in productive activity (p = .005) at end of Treatment relative to Control, with large effect sizes (d > 0.80). Changes in other outcomes were non-significant. CONCLUSIONS: This pilot study provides preliminary support for in-home dynamic light therapy to address sleep-related symptoms in acquired brain injury. TRIAL REGISTRATION: This trial was registered with the Australian and New Zealand Clinical Trials Registry on 13 June 2017, www.anzctr.org.au , ACTRN12617000866303.

The Effects of Group Art Therapy on the Primary Family Caregivers of Hospitalized Patients with Brain Injuries in South Korea.

This study examined the effects of group art therapy on depression, burden, and self-efficacy in primary family caregivers of patients with brain injuries. This was a quasi-experimental, nonequivalent control group and a pre- and post-test design. This study was carried out in one national rehabilitation hospital targeting 41 primary family caregivers of patients with brain injuries. Group art therapy intervention was carried out three days per week comprising 12 sessions over four consecutive weeks. The experimental group (n = 20) received group art therapy, whereas the control group (n = 21) did not. We used a time difference method to minimize the risk of contaminating the control group by sampling sequentially. For depression, although there was a significant difference after the intervention (t = 3.296, p = 0.004), the mean difference score was not statistically significant between the experimental group and the control group (t = 0.861, p = 0.395). The experimental group showed a significantly greater decrease in burden (t = 2.462, p = 0.020) and significantly greater improvement in self-efficacy (t = -6.270, p < 0.001) than the control group. Group art therapy may be an effective nursing intervention for primary family caregivers of patients with brain injuries.

Therapies for neonatal encephalopathy: Targeting the latent, secondary and tertiary phases of evolving brain injury.

In term and near-term neonates with neonatal encephalopathy, therapeutic hypothermia protocols are well established. The current focus is on how to improve outcomes further and the challenge is to find safe and complementary therapies that confer additional protection, regeneration or repair in addition to cooling. Following hypoxia-ischemia, brain injury evolves over three main phases (latent, secondary and tertiary), each with a different brain energy, perfusion, neurochemical and inflammatory milieu. While therapeutic hypothermia has targeted the latent and secondary phase, we now need therapies that cover the continuum of brain injury that spans hours, days, weeks and months after the initial event. Most agents have several therapeutic actions but can be broadly classified under a predominant action (e.g., free radical scavenging, anti-apoptotic, anti-inflammatory, neuroregeneration, and vascular effects). Promising early/secondary phase therapies include Allopurinol, Azithromycin, Exendin-4, Magnesium, Melatonin, Noble gases and Sildenafil. Tertiary phase agents include Erythropoietin, Stem cells and others. We review a selection of promising therapeutic agents on the translational pipeline and suggest a framework for neuroprotection and neurorestoration that targets the evolving injury.

OTULIN is a new target of EA treatment in the alleviation of brain injury and glial cell activation via suppression of the NF-κB signalling pathway in acute ischaemic stroke rats.

OBJECTIVE: Ovarian tumour domain deubiquitinase with linear linkage specificity (OTULIN) is a potent negative regulator of the nuclear factor-κB (NF-κB) signalling pathway, and it plays a strong neuroprotective role following acute ischemic stroke. Electroacupuncture (EA) is an effective adjuvant treatment for reducing brain injury and neuroinflammation via the inhibition of NF-κB p65 nuclear translocation, but the underlying mechanism is not clear. The present study investigated whether OTULIN was necessary for EA to mitigate brain injury and glial cell activation in a transient middle cerebral artery occlusion (tMCAO) model in rats. METHODS: An acute ischaemic stroke model was established via tMCAO surgery in Sprague-Dawley (SD) rats. EA was performed once daily at "Baihui (GV 20)", "Hegu (LI 4)", and "Taichong (LR 3)" acupoints. The effect of EA on the spatiotemporal expression of OTULIN in the ischaemic penumbra of the cerebral cortex was detected within 7 days after reperfusion. The effects of OTULIN gene silencing on EA neurological deficits, cerebral infarct volume, neuronal damage, the activation of microglia and astrocytes, the contents of tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6), and the expression of p-IκBa, IκBa and nucleus/cytoplasm NF-κB p65 protein were assessed. RESULTS: EA treatment increased endogenous OTULIN expression, which peaked at 48 h. Enhanced OTULIN was primarily located in neurons, but a small amount of OTULIN was detected in microglia. OTULIN silencing obviously reversed EA neuroprotection, which was demonstrated by worsened neurobehavioural performance, cerebral infarct volume and neuronal injury. The inhibitory effect of EA on the NF-κB pathway was also attenuated by enhanced IκBα phosphorylation and NF-κB p65 nuclear translocation. EA partially inhibited the transformation of microglia and astrocytes from resting states to activated states and reduced the secretion of TNF-α, IL-1ß and IL-6. However, these preventive effects were reversed after the silencing of OTULIN expression. CONCLUSIONS: OTULIN provides a new potential therapeutic target for EA to alleviate acute ischaemic stroke-induced brain injury and the activation of glial cells, which are related to suppression of the NF-κB signalling pathway.