Traumatic axonal injury influences the cognitive effect of non-invasive brain stimulation.

Non-invasive brain stimulation has been widely investigated as a potential treatment for a range of neurological and psychiatric conditions, including brain injury. However, the behavioural effects of brain stimulation are variable, for reasons that are poorly understood. This is a particular challenge for traumatic brain injury, where patterns of damage and their clinical effects are heterogeneous. Here we test the hypothesis that the response to transcranial direct current stimulation following traumatic brain injury is dependent on white matter damage within the stimulated network. We used a novel simultaneous stimulation-MRI protocol applying anodal, cathodal and sham stimulation to 24 healthy control subjects and 35 patients with moderate/severe traumatic brain injury. Stimulation was applied to the right inferior frontal gyrus/anterior insula node of the salience network, which was targeted because our previous work had shown its importance to executive function. Stimulation was applied during performance of the Stop Signal Task, which assesses response inhibition, a key component of executive function. Structural MRI was used to assess the extent of brain injury, including diffusion MRI assessment of post-traumatic axonal injury. Functional MRI, which was simultaneously acquired to delivery of stimulation, assessed the effects of stimulation on cognitive network function. Anodal stimulation improved response inhibition in control participants, an effect that was not observed in the patient group. The extent of traumatic axonal injury within the salience network strongly influenced the behavioural response to stimulation. Increasing damage to the tract connecting the stimulated right inferior frontal gyrus/anterior insula to the rest of the salience network was associated with reduced beneficial effects of stimulation. In addition, anodal stimulation normalized default mode network activation in patients with poor response inhibition, suggesting that stimulation modulates communication between the networks involved in supporting cognitive control. These results demonstrate an important principle: that white matter structure of the connections within a stimulated brain network influences the behavioural response to stimulation. This suggests that a personalized approach to non-invasive brain stimulation is likely to be necessary, with structural integrity of the targeted brain networks an important criterion for patient selection and an individualized approach to the selection of stimulation parameters.

Progressive increase in brain glucose metabolism after intrathecal administration of autologous mesenchymal stromal cells in patients with diffuse axonal injury.

BACKGROUND AIMS: Cell therapy in neurological disability after traumatic brain injury (TBI) is in its initial clinical stage. We describe our preliminary clinical experience with three patients with diffuse axonal injury (DAI) who were treated with intrathecal administration of autologous mesenchymal stromal cells (MSCs). METHODS: Three patients with established neurological sequelae due to DAI received intrathecally autologous MSCs. The total number of MSCs administered was 60 × 106 (one patient), 100 × 106 (one patient) and 300 × 106 (one patient). RESULTS: All three patients showed improvement after cell therapy, and subsequent studies with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) showed a diffuse and progressive increase in brain glucose metabolism. CONCLUSION: Our present results suggest benefit of intrathecal administration of MSCs in patients with DAI, as well as a relationship between this type of treatment and increase in brain glucose metabolism. These preliminary findings raise the question of convenience of assessing the potential benefit of intrathecal administration of MSCs for brain diseases in which a decrease in glucose metabolism represents a crucial pathophysiological finding, such as Alzheimer's disease (AD) and other dementias.

Increased CSF concentrations of myelin basic protein after TBI in infants and children: absence of significant effect of therapeutic hypothermia.

BACKGROUND: The objectives of this study were to determine effects of severe traumatic brain injury (TBI) on cerebrospinal fluid (CSF) concentrations of myelin basic protein (MBP) and to assess relationships between clinical variables and CSF MBP concentrations. METHODS: We measured serial CSF MBP concentrations in children enrolled in a randomized controlled trial evaluating therapeutic hypothermia (TH) after severe pediatric TBI. Control CSF was obtained from children evaluated, but found not to be having CNS infection. Generalized estimating equation models and Wilcoxon Rank-Sum test were used for comparisons of MBP concentrations. RESULTS: There were 27 TBI cases and 57 controls. Overall mean (± SEM) TBI case MBP concentrations for 5 days after injury were markedly greater than controls (50.49 ± 6.97 vs. 0.11 ± 0.01 ng/ml, p < 0.01). Mean MBP concentrations were lower in TBI patients <1 year versus >1 year (9.18 ± 1.67 vs. 60.22 ± 8.26 ng/ml, p = 0.03), as well as in cases with abusive head trauma (AHT) versus non-abusive TBI (14.46 ± 3.15 vs. 61.17 ± 8.65 ng/ml, p = 0.03). TH did not affect MBP concentrations. CONCLUSIONS: Mean CSF MBP increases markedly after severe pediatric TBI, but is not affected by TH. Infancy and AHT are associated with low MBP concentrations, suggesting that age-dependent myelination influences MBP concentrations after injury. Given the magnitude of MBP increases, axonal injury likely represents an important therapeutic target in pediatric TBI.

Combination of Neutrophil-to-Lymphocyte Ratio and Admission Glasgow Coma Scale Score Is Independent Predictor of Clinical Outcome in Diffuse Axonal Injury.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is an independent predictor of clinical outcome of different diseases, such as acute ischemic stroke, intracerebral hemorrhage, malignant tumor, and traumatic brain injury. However, the prognostic value of NLR plus admission Glasgow Coma Scale score (NLR-GCS) is still unclear in patients with diffuse axonal injury (DAI). Therefore this study assessed the relationship between the NLR-GCS and 6-month outcome of DAI patients. METHODS: The clinical characteristics of DAI patients admitted to our department between January 2014 and January 2020 were retrospectively analyzed. The candidate risk factors were screened by using univariate analysis, and the independence of resultant risk factors was evaluated by the binary logistic regression analysis and least absolute shrinkage and selection operator regression analysis. The predictive value of NLR-GCS in an unfavorable outcome was assessed by the receiver operating characteristics curve analysis. RESULTS: A total of 93 DAI patients were included. Binary logistic regression analysis and least absolute shrinkage and selection operator regression analysis showed the level of NLR on admission was an independent risk factor of unfavorable outcomes in DAI patients. The ROC curve analysis showed that the predictive capacity of the combination of NLR and admission GCS score and combination of NLR and coma duration outperformed NLR, admission GCS score, and coma duration alone. CONCLUSIONS: The higher NLR level on admission is independently associated with unfavorable outcomes of DAI patients at 6 months. Furthermore, the combination of NLR and admission GCS score provides the superior predictive capacity to either NLR or GCS alone.

Diffuse axonal injury: novel insights into detection and treatment.

Diffuse axonal injury (DAI) is one of the most common and important pathologic features of traumatic brain injury. The definitive diagnosis of DAI, especially in its early stage, is difficult. In addition, most therapeutic agents for patients with DAI are non-specific. The CT scan is widely used to identify signs of DAI. Although its sensitivity is limited to moderate to severe DAI, it remains a useful first-line imaging tool that may also identify co-morbid injuries such as intracerebral hemorrhage. Recently, investigations have sought to apply advanced imaging techniques and laboratory techniques to detect DAI. Meanwhile, some potential specific treatments that may protect injured axons or stimulate axonal regeneration have been developed. We review some new diagnostic technologies and specific therapeutic strategies for DAI.

Severe traumatic brain injury: outcome in patients with diffuse axonal injury managed conservatively in Hospital Sultanah Aminah, Johor Bahru--an observational study.

Patients with isolated severe head injury with diffuse axonal injury and without any surgical lesion may be treated safely without cerebral resuscitation and intracranial pressure (ICP) monitoring. Seventy two patients were divided into three groups of patients receiving treatment based on ICP-CPP-targeted, or conservative methods either with or without ventilation support. The characteristics of these three groups were compared based on age, gender, Glasgow Coma Scale (GCS), pupillary reaction to light, computerized tomography scanning according to the Marshall classification, duration of intensive care unit (ICU) stays, Glasgow Outcome Score (GOS) and possible complications. There were higher risk of mortality (p < 0.001), worse GCS improvement upon discharge (p < 0.001) and longer ICU stays (p = 0.016) in ICP group compared to Intubation group. There were no significant statistical differences of GOS at 3rd and 6th months between all three groups.

Cerebral atrophy after traumatic white matter injury: correlation with acute neuroimaging and outcome.

Traumatic brain injury (TBI) is a pathologically heterogeneous disease, including injury to both neuronal cell bodies and axonal processes. Global atrophy of both gray and white matter is common after TBI. This study was designed to determine the relationship between neuroimaging markers of acute diffuse axonal injury (DAI) and cerebral atrophy months later. We performed high-resolution magnetic resonance imaging (MRI) at 3 Tesla (T) in 20 patients who suffered non-penetrating TBI, during the acute (within 1 month after the injury) and chronic stage (at least 6 months after the injury). Volume of abnormal fluid-attenuated inversion-recovery (FLAIR) signal seen in white matter in both acute and follow-up scans was quantified. White and gray matter volumes were also quantified. Functional outcome was measured using the Functional Status Examination (FSE) at the time of the chronic scan. Change in brain volumes, including whole brain volume (WBV), white matter volume (WMV), and gray matter volume (GMV), correlates significantly with acute DAI volume (r = -0.69, -0.59, -0.58, respectively; p <0.01 for all). Volume of acute FLAIR hyperintensities correlates with volume of decreased FLAIR signal in the follow-up scans (r = -0.86, p < 0.001). FSE performance correlates with acute hyperintensity volume and chronic cerebral atrophy (r = 0.53, p = 0.02; r = -0.45, p = 0.03, respectively). Acute axonal lesions measured by FLAIR imaging are strongly predictive of post-traumatic cerebral atrophy. Our findings suggest that axonal pathology measured as white matter lesions following TBI can be identified using MRI, and may be a useful measure for DAI-directed therapies.

[Acupuncture treatment for a patient with diffuse axonal injury].

Acupuncture has been used as a therapeutic technique in China, Japan and East Asia. Recently, it is used to treat neural injuries. We describe a 6-year-old boy with consciousness disturbance and heavy muscle spasticity of extremities due to severe diffuse axonal injury (DAI) in whom acupuncture treatment for 6 months alleviated these symptoms remarkably. Acupuncture treatment may be effective to improve consciousness disturbance and heavy spasticity of DAI.

[Acupuncture treatment for a patient with diffuse axonal injury--report no. 2].

Acupuncture has been applied as a therapeutic technique in China, Japan and East Asia. Recently, its application is extended to treat neural injuries. We describe a 26-year-old man with consciousness disturbance and intense muscle spasticity of extremities due to severe diffuse axonal injury (DAI) in whom acupuncture treatment for 1 month was effective to alleviate these symptoms remarkably. We also investigated the cerebral blood flow two times by 123I-IMP SPECT in acupuncture period. Acupuncture treatment may be effective to improve consciousness disturbance and intense spasticity of DAI and to modulate cerebral blood flow.

Lack of improvement in cerebral metabolism after hyperoxia in severe head injury: a microdialysis study.

OBJECT: The authors investigated the effects of hyperoxia on brain tissue PO2 and on glucose metabolism in cerebral and adipose tissue after traumatic brain injury (TBI). METHODS: After 3 hours of ventilation with pure O2, 18 tests were performed on different days in eight comatose patients with TBI. Lactate, pyruvate, glucose, glutamate, and brain tissue PO2 were measured in the cerebral extracellular fluid (ECF) by using microdialysis. Analytes were also measured in the ECF of abdominal adipose tissue. After 3 hours of increase in the fraction of inspired O2, brain tissue PO2 rose from the baseline value of 32.7 +/- 18 to 122.6 +/- 45.2 mm Hg (p < 0.0001), whereas brain lactate dropped from its baseline (3.21 +/- 2.77 mmol/L), reaching its lowest value (2.90 +/- 2.58 mmol/L) after 3 hours of hyperoxia (p < 0.01). Pyruvate dropped as well, from 153 +/- 56 to 141 +/- 56 micromol/L (p < 0.05), so the lactate/pyruvate ratio did not change. No significant changes were observed in glucose and glutamate. The arteriovenous difference in O2 content dropped, although not significantly, from a baseline of 4.52 +/- 1.22 to 4.15 +/- 0.76 m/100 ml. The mean concentration of lactate in adipose tissue fell significantly as well (p < 0.01), but the lactate/pyruvate ratio did not change. CONCLUSIONS: Hyperoxia slightly reduced lactate levels in brain tissue after TBI. The estimated redox status of the cells, however, did not change and cerebral O2 extraction seemed to be reduced. These data indicate that oxidation of glucose was not improved by hyperoxia in cerebral and adipose tissue, and might even be impaired.

Hypoflow and hyperflow in diffuse axonal injury. Prognostic and therapeutic implications of transcranial Doppler sonography evaluation.

BACKGROUND: In the present report we describe the results of a study aimed at evaluating the cerebral haemodynamics and the neuroradiological findings observ-ed in 7 consecutive patients, 4 adults and 3 children (6, 8 and 10 years old), affected by diffuse axonal injury (DAI). METHODS: All the patients were admitted to the Paediatric or Adult Intensive Care Unit with GCS scores less than 8 after a severe brain injury. Serial head CT scan and trans-cranial Doppler sonography (TCD) examinations were carried out in all patients; MRI was carried out in the paediatric patients only. TCD of the middle cerebral arteries was performed through the temporal bone window. In 6 cases (2 paediatric) diuretic osmotic therapy was immediately administered and in 6 cases (3 paediatric) barbiturates and hyperventilation were also used. RESULTS: Hyperflow, variably responsive to barbiturate therapy of vasoparalysis, was observed in all paediatric patients and in 3 adult subjects (85.7%: 6 out of 7 pa-tients) by means of TCD. CONCLUSIONS: Observation of these phenomena allowed us to modify the pharmacological treatment and/or perform external cerebrospinal fluid (CSF) drainage (4 cases). Compartimental hyperflow TCD pattern was evident in 1 patient. Although the limited number of patients in our series does not allow definitive conclusions, we strongly believe that TCD monitoring is an useful tool in planning surgical strategy in patients with DAI.

Successful treatment by spinal cord stimulation for gait disturbance in a patient with diffuse axonal injury.

The authors present a case of diffuse axonal injury (DAI) treated by cervical spinal cord stimulation (C-SCS) for gait disturbance. The patient had right hemiparesis of moderate degree, mild ataxia, ideational apraxia and gait disturbance, when admitted to our hospital for rehabilitation. He could not walk by himself, nevertheless neurorehabilitation was done for four months. Xenon-CT was examined by C-SCS loading and the changes of regional cerebral blood flow were significantly increased in both hemispheres, especially in the thalamus. C-SCS was performed continuously on condition of 25 Hz, 200 microsec and 0.5 V, daily for a month. Neurological deficits, especially gait disturbance due to ideational apraxia, were gradually improved after initiation of C-SCS, and the patient could walk by himself. We speculate that C-SCS played a role in triggering improvement of gait disturbance at the chronic stage in our case, and SCS may be helpful for neurorehabilitation of focal symptoms after DAI.

Ultrastructural observation of effect of moderate hypothermia on axonal damage in an animal model of diffuse axonal injury.

OBJECTIVE: To investigate the effect of moderate hypothermia on responses of axonal cytoskeleton to axonal injury in the acute stage of injury. METHODS: Of fifteen adult guinea pigs, twelve animals were subjected to stretch injury to the right optic nerves and divided into the normothermic group (n = 6) in which the animal's core temperature was maintained at 36.0-37.5 degrees C and the hypothermia group (n = 6) in which the core temperature was reduced to 32.0-32.5 degrees C after stretch injury. Remaining three animals sustained no injury to the right optic nerves and served as control group. Half of injured animals (n = 3) of either normothermic group or hypothermic group were killed at either 2 hours or 4 hours after injury. The ultrastructural changes of axonal cytoskeleton of the right optic nerve fibers from the animals were examined under a transmission electron microscope and analyzed by quantitative analysis with a computer image analysis system. RESULTS: At 2 hours after stretch injury, there was a significant reduction in the mean number of microtubules (P < 0.001), and a significant increase in the mean intermicrotubule spacing (P < 0.05 or P < 0.01) in axons of all sizes in normothermic animals. The mean number of neurofilaments also decreased statistically (P < 0.01) in large and medium subgroups of axons in the same experimental group at 2 hours. By 4 hours, the large subgroup of axons in normothermic animals still demonstrated a significant decline in the mean number of microtubules (P < 0.01) and an increase in the mean intermicrotubule spacing (P < 0.05), while the medium and small subgroups of axons displayed a significant increase in the mean number of neurofilaments (P < 0.05) and reduction in the mean interneurofilament spacing (P < 0.05). On the contrary, either the mean number of microtubules and the mean intermicrotubule spacing, or the mean number of neurofilaments and interneurofilament spacing in axons of all sizes in hypothermic stretch-injured animals was not significant different from the mean values of sham-operated animals. CONCLUSIONS: Posttraumatic moderate hypothermia induced immediately after axonal injury results in substantial protection of axonal cytoskeleton and ameliorates axonal damage.

Transcranial magnetic stimulation in brain injury.

OBJECTIVES: Transcranial magnetic stimulations (TMS) have been used for many years as a diagnostic tool to explore changes in cortical excitability, and more recently as a tool for therapeutic neuromodulation. We are interested in their applications following brain injury: stroke, traumatic and anoxic brain injury. DATA SYNTHESIS: Following brain injury, there is decreased cortical excitability and changes in interhemispheric interactions depending on the type, the severity, and the time-lapse between the injury and the treatment implemented. rTMS (repetitive TMS) is a therapeutic neuromodulation tool which restores the interhemispheric interactions following stroke by inhibiting the healthy cortex with frequencies ≤1Hz, or by exciting the lesioned cortex with frequencies between 3 and 50Hz. Results in motor recovery are promising and those in improving aphasia or visuospatial neglect are also encouraging. Finally, the use of TMS is mainly limited by the risk of seizure, and is therefore contraindicated for many patients. CONCLUSION: TMS is a useful non-invasive brain stimulation tool to diagnose the effects of brain injury, to study the mechanisms of recovery and a non-invasive neuromodulation promising tool to influence the post-lesional recovery.

Evaluation of TGF ß1, IL-8 and nitric oxide in the serum of diffuse axonal injury patients and its association with clinical status and outcome.

AIM: The aim was to evaluate the level of interleukin 8 (IL-8), transforming growth factor ß1 (TGF ß1) and Nitric oxide (NO) in diffuse axonal injury (DAI) and its association to the outcome and clinical status. MATERIAL AND METHODS: This cross-sectional study was conducted on 20 patients with DAI and 20 patients with multiple traumas without head injury and 20 healthy subjects as controls. Blood levels of IL-8, TGF ß1 and nitric oxide in the 1st, 2nd, 3rd and 7th days of injury were measured. Glasgow coma scale (GCS) of patients was recorded. The patients' outcome was evaluated by Glasgow Outcome Scale (GOS). RESULTS: The level of TGF ß1 was increasing during the admission and had the maximum level at the 7th day. In the DAI group, there was significant correlation between GOS score and serum IL-8 at 7th day of admission (r=-0.68, p= 0.002). In this group the GCS was found to be significantly correlated with the IL-8 concentration at 7th day of admission (p= 0.026, r=-0.55). CONCLUSION: IL-8 has negative correlation with GCS and GOS. TGF ß1 could protect the brain from cytotoxics, hypoxia and acidosis so its level comes down in brain injuries as a result of its overuse.

Significance of differences between brain temperature and core temperature (δ T) during mild hypothermia in patients with diffuse axonal injury.

The differences between brain and bladder temperature (delta T), and the relationship of delta T to cerebral perfusion pressure (CPP) and jugular venous oxygen saturation (SjO(2)) were studied during hypothermia in 11 patients with severe traumatic brain injury, of whom 5 underwent conservative treatment for diffuse axonal injury (DAI) (DAI group) and 6 who underwent decompressive craniectomy for hematoma (SDH group). All patients underwent hypothermia treatment. Brain temperature was monitored via an intraparenchymal catheter. Bladder temperature was used as the core temperature. SjO(2) was measured continuously. The outcome of all patients was evaluated at discharge using the Glasgow Outcome Scale. Delta T in the SDH group was significantly lower than that in the DAI group. No relationship was found between delta T and CPP during the investigation period. A significant correlation between delta T and SjO(2) was seen in the DAI group, but not in the SDH group. Decompressive craniectomy affects the brain temperature through external environmental factors. Measurement of brain temperature may be a reliable indicator of cerebral blood flow and brain metabolism in patients with DAI and closed cranium during hypothermia. Further experience is required to test this proposal.