IL-6 Inhibition Reduces Neuronal Injury in a Murine Model of Ventilator-induced Lung Injury.

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.

Eyebrow supraorbital keyhole craniotomy for olfactory groove meningiomas with endoscope assistance: case series and systematic review of extent of resection, quantification of postoperative frontal lobe injury, anosmia, and recurrence.

BACKGROUND: Olfactory groove meningiomas (OGMs) are commonly treated with open craniotomy. Endonasal approaches have also been described. OBJECTIVE: To present clinical and radiographic outcomes for the minimally invasive eyebrow incision supraorbital keyhole approach with endoscopic assistance for OGMs. METHODS: We performed a retrospective single-center cohort study and a systematic literature review. RESULTS: Fifteen patients were identified, all with Grade I meningiomas. Radiographic gross total resection of enhancing tumor was achieved in all patients. Mean frontal lobe fluid-attenuated inversion recovery volume decreased from 11.1 ± 18.3 cm3 preoperatively to 9.9 ± 11.4 cm3 immediately postoperatively, and there was minimal new restricted diffusion (3.2 ± 2.2 cm3; max 7.5 cm3). Median length of stay was 3 days (range 2-8). Vision was improved in 4 (80%) and stable in 1 (20%) of 5 patients with a preoperative deficit. New postoperative anosmia occurred in 3 (23%) of 13 patients with any preoperative olfaction. All patients were satisfied with their cosmetic result at 3 months. After a median follow-up of 32.2 months, there were 2 (13.3%) asymptomatic radiographic recurrences, 1 treated with radiosurgery and the other with endoscopic endonasal approach (EEA). No patients required further craniotomy. Systematic review revealed the present series to be the largest to date reporting disaggregated outcomes for the eyebrow approach to OGM. CONCLUSION: The eyebrow incision supraorbital keyhole craniotomy with endoscopic assistance is a safe and effective approach to OGM with tumor control rates similar to more invasive open approaches and better than the endonasal approach. Rates of frontal lobe injury, CSF leak and anosmia are comparatively low.

Delayed Brain Cyst Formation After Gamma Knife Anterior Capsulotomy.

BACKGROUND: Gamma Knife ventral anterior capsulotomy is an effective option to treat refractory obsessive-compulsive disorder. Although well tolerated, complications can develop years after radiosurgery. We describe a case in which abnormal complications induced by very high doses of radiation evolved. CASE DESCRIPTION: A 55-year-old man with refractory obsessive-compulsive disorder was treated with Gamma Knife ventral anterior capsulotomy using a dose of 180 Gy. His obsessive-compulsive symptoms improved, but his condition evolved with a manic episode, cognitive memory changes, visual hallucinations, confabulation, and frontal lobe symptoms. Magnetic resonance imaging showed brain edema in the left hemisphere and a 6-mm brain cyst in the right hemisphere at postoperative month 20. CONCLUSIONS: This case shows the consequences of affecting more fibers related to the anterior frontal region than intended with a radiosurgical procedure and illustrates the importance of careful clinical and imaging follow-up after Gamma Knife ventral anterior capsulotomy.

TBI weight-drop model with variable impact heights differentially perturbs hippocampus-cerebellum specific transcriptomic profile.

The degree of brain injury is the governing factor for the magnitude of the patient's psycho- and physiological deficits post-injury, and the associated long-term consequences. The present scaling method used to segregate the patients among mild, moderate and severe phases of traumatic brain injury (TBI) has major limitations; however, a more continuous stratification of TBI is still elusive. With the anticipation that differentiating molecular markers could be the backbone of a robust method to triage TBI, we used a modified closed-head injury (CHI) Marmarou model with two impact heights (IH). By definition, IH directly correlates with the impact force causing TBI. In our modified CHI model, the rat skull was fitted with a helmet to permit a diffuse axonal injury. With the frontal cortex as the focal point of injury, the adjacent brain regions (hippocampus, HC and cerebellum, CB) were susceptible to diffuse secondary shock injury. At 8 days post injury (po.i.), rats impacted by 120 cm IH (IH120) took a longer time to find an escape route in the Barnes maze as compared to those impacted by 100 cm IH (IH100). Using a time-resolved interrogation of the transcriptomic landscape of HC and CB tissues, we mined those genes that altered their regulations in correlation with the variable IHs. At 14 days po.i., when all rats demonstrated nearly normal visuomotor performance, the bio-functional analysis suggested an advanced healing mechanism in the HC of IH100 group. In contrast, the HC of IH120 group displayed a delayed healing with evidence of active cell death networks. Combining whole genome rat microarrays with behavioral analysis provided the insight of neuroprotective signals that could be the foundation of the next generation triage for TBI patients.

Overexpression of Mfsd2a attenuates blood brain barrier dysfunction via Cav-1/Keap-1/Nrf-2/HO-1 pathway in a rat model of surgical brain injury.

INTRODUCTION: Disruption of the blood brain barrier (BBB) and subsequent cerebral edema formation is one of the major adverse effects of brain surgery, leading to postoperative neurological dysfunction. Recently, Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions. In this study, we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury (SBI) in rats. MATERIALS AND METHODS: Rats were subjected to SBI by partial resection of the right frontal lobe. To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI, Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids, respectively. The potential mechanism of Mfsd2a-mediated BBB protection through the cav-1/Nrf-2/HO-1 signaling pathway was evaluated. RESULTS: Mfsd2a levels were significantly decreased while cav-1, Nrf-2 and HO-1 levels were increased in the right frontal perisurgical area following SBI. When overexpressed, Mfsd2a attenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI. The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav-1, increased Keap-1/Nrf-2 dissociation and further augmented levels of Nrf-2 and HO-1 in the right frontal perisurgical area, leading to enhanced levels of tight junction proteins following SBI. The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf-2 and HO-1. CONCLUSIONS: Mfsd2a attenuates BBB disruption through cav-1/Nrf-2/HO-1 signaling pathway in rats subjected to experimental SBI.

Fasciculation and Elongation Protein Zeta-1 Expression in Reactive Astrocytes in a Rat Model of Frontal Lobe Injury.

There are reports that depression induced by frontal lobe injury (FLI) has a devastating effect on human mental health. We previously reported that fasciculation and elongation protein zeta-1 (FEZ1) was essential for astrocytic protection of dopamine neurons. Studies of glutamate-glutamine cycle in mental illness have been reported, whereas not from the perspective of astrocytes. This study was designed to investigate the roles of astrocytic FEZ1 and glutamate-glutamine cycle after FLI. A model of FLI was established by inserting a blade into the right frontal lobe of rats. Behavioral tests were used to observe the behavioral changes of FLI rats. Neuropathologic examinations, including immunohistochemistry, were conducted. Behavioral tests showed that FLI decreased exploratory activity. Western blot analysis revealed that the expression of astroglial proteins overall decreased in the initial injury stage, as well as FEZ1. Immunohistochemistry showed a shift of FEZ1 localization from neurons in sham-lesioned rats to astrocytes in FLI rats, and showed the expression profile of glutamate transporter 1 and glutamine synthetase (GS) was consistent with Western blot observation. Our results indicate that astrocytic FEZ1 and glutamate-glutamine cycle dysfunction may be involved in the pathogenesis of depression after FLI.

The functions of the frontal lobes: Evidence from patients with focal brain damage.

Patients with focal frontal lobe damage have long been a crucial source of information about the role of this region in human behavior. This method remains the only means to provide inferentially powerful loss-of-function evidence for many regions within the human frontal lobes. This chapter demonstrates modern focal lesion research methods, focusing on specific subregions within prefrontal cortex, and their contributions to widely studied aspects of executive function and decision-making. Examples of such studies are reviewed in detail, to demonstrate the strengths, limitations, and logic of lesion methods. The evidence provided by such studies is considered in relation to converging evidence from other cognitive neuroscience methods. The tensions between modular and network views of prefrontal function are also addressed. Lesion studies straddle fundamental and clinical neuroscience, allowing basic advances in this area to be readily translated to psychiatric and neurologic disorders. This unique position, as well as the ability to test causal claims, explains the staying power of this classic approach to understanding the brain basis of behavior.

Tau progression in single severe frontal traumatic brain injury in human brains.

The neuropathological features of chronic traumatic encephalopathy (CTE), caused by repeated traumatic brain injury (TBI), include abnormal accumulations of hyper-phosphorylated tau (p-tau) protein in neurons, neurites and astrocytes, considered to progress via neuronal circuits in brains. Some previous reports suggest that a single severe TBI (sTBI) can also induce CTE and p-tau accumulation, but it is not clear whether the pathology is the same as that of repetitive TBI (rTBI). Since prefrontal leucotomy could be regarded as a model of sTBI, in this study we evaluated two autopsied schizophrenia with this procedure. Histopathologically, gliosis and neuronal loss were found not only in the primary ablated prefrontal region, but also in secondary affected areas, i.e., cingulate gyrus, medial nucleus of the thalamus, and nucleus accumbens, which are connected to prefrontal areas. Accumulation of p-tau was mostly seen in neurons, neurites and glias around small blood vessels in the leucotomized prefrontal region. In addition, secondary regions showed some p-tau-positive neurons/glias, as well as many axonal spheroids. Regions of neuronal/glial p-tau pathology showed immunoreactivity to both 3R/4R tau antibodies. Immunoblot analyses of sarkosyl-insoluble tau from frozen brains showed an AD-type tau banding pattern with strong immunoreactivities. sTBI patients showed limited comorbidities, such as TDP-43, alpha-synuclein or AD pathology, whereas rTBI patients have high frequencies of them. The findings suggest that p-tau in the primary affected lesion might progress to connected regions via neuronal circuits over time, and a single severe axonal injury might lead to CTE pathology different from that caused by rTBI.

Implicit learning of artificial grammatical structures after inferior frontal cortex lesions.

OBJECTIVE: Previous research associated the left inferior frontal cortex with implicit structure learning. The present study tested patients with lesions encompassing the left inferior frontal gyrus (LIFG; including Brodmann areas 44 and 45) to further investigate this cognitive function, notably by using non-verbal material, implicit investigation methods, and by enhancing potential remaining function via dynamic attending. Patients and healthy matched controls were exposed to an artificial pitch grammar in an implicit learning paradigm to circumvent the potential influence of impaired language processing. METHODS: Patients and healthy controls listened to pitch sequences generated within a finite-state grammar (exposure phase) and then performed a categorization task on new pitch sequences (test phase). Participants were not informed about the underlying grammar in either the exposure phase or the test phase. Furthermore, the pitch structures were presented in a highly regular temporal context as the beneficial impact of temporal regularity (e.g. meter) in learning and perception has been previously reported. Based on the Dynamic Attending Theory (DAT), we hypothesized that a temporally regular context helps developing temporal expectations that, in turn, facilitate event perception, and thus benefit artificial grammar learning. RESULTS: Electroencephalography results suggest preserved artificial grammar learning of pitch structures in patients and healthy controls. For both groups, analyses of event-related potentials revealed a larger early negativity (100-200 msec post-stimulus onset) in response to ungrammatical than grammatical pitch sequence events. CONCLUSIONS: These findings suggest that (i) the LIFG does not play an exclusive role in the implicit learning of artificial pitch grammars, and (ii) the use of non-verbal material and an implicit task reveals cognitive capacities that remain intact despite lesions to the LIFG. These results provide grounds for training and rehabilitation, that is, learning of non-verbal grammars that may impact the relearning of verbal grammars.

Childhood Transorbital Skull Base Penetrating Injury: Report of 2 Cases and Review of Literature.

BACKGROUND: A foreign object penetrating the brain via orbit is a rare occurrence. Accurate diagnosis and immediate intervention is essential to prevent ophthalmic or neurological deficits and to reduce chances of infection or hemorrhage. CASE DESCRIPTION: We report 2 cases of transorbital orbitocranial penetrating injury of metal objects in children. Computed tomography scan was obtained to assess the extent of the injury and to locate the objects. According to the trajectory, the best craniotomy approach was performed, and the objects were safely removed without any complication. Our cases are unique because of the absence of any neurological deficit on admission, before and after the removal. CONCLUSIONS: The importance of transorbital orbitocranial penetrating injury cannot be neglected because of possible orbital and intracranial damage. Therefore, in this report we aim to heighten awareness of the complexity and severity of transorbital penetrating brain injury.

Death Related to Elective Nasal Polypectomy: Case Report.

The investigation of deaths that are suspected to be related to medical therapy present several challenges for a forensic pathologist. We present a case of an otherwise healthy 58-year-old woman with multiple nasal polyps who underwent nasal polypectomy. The operation was initially considered successful. However, the patient had never recovered from general anesthesia and was declared deceased 24 hours after the surgery.The autopsy revealed a basilar subarachnoid hemorrhage. The examination of the basilar skull showed a perforation of approximately 15 by 7 mm in the right cribriform plate. Above the bone perforation, there was a disruption of the dura and a 20-mm-long penetrating wound within the right frontal lobe parenchyma of the brain, with associated intraventricular hemorrhage. The subsequent sectioning of the formalin-fixed brain revealed extensive parenchymal destruction. The cause of death was certified as complications of nasal/sinus surgery, with a perforation of the skull base with hemorrhagic tissue destruction, whereas the manner of death was considered accidental.Common nasal surgical procedures and known complications are discussed.

Synergistic Role of Oxidative Stress and Blood-Brain Barrier Permeability as Injury Mechanisms in the Acute Pathophysiology of Blast-induced Neurotrauma.

Blast-induced traumatic brain injury (bTBI) has been recognized as the common mode of neurotrauma amongst military and civilian personnel due to an increased insurgent activity domestically and abroad. Previous studies from our laboratory have identified enhanced blood-brain barrier (BBB) permeability as a significant, sub-acute (four hours post-blast) pathological change in bTBI. We also found that NADPH oxidase (NOX)-mediated oxidative stress occurs at the same time post-blast when the BBB permeability changes. We therefore hypothesized that oxidative stress is a major causative factor in the BBB breakdown in the sub-acute stages. This work therefore examined the role of NOX1 and its downstream effects on BBB permeability in the frontal cortex (a region previously shown to be the most vulnerable) immediately and four hours post-blast exposure. Rats were injured by primary blast waves in a compressed gas-driven shock tube at 180 kPa and the BBB integrity was assessed by extravasation of Evans blue and changes in tight junction proteins (TJPs) as well as translocation of macromolecules from blood to brain and vice versa. NOX1 abundance was also assessed in neurovascular endothelial cells. Blast injury resulted in increased extravasation and reduced levels of TJPs in tissues consistent with our previous observations. NOX1 levels were significantly increased in endothelial cells followed by increased superoxide production within 4 hours of blast. Blast injury also increased the levels/activation of matrix metalloproteinase 3 and 9. To test the role of oxidative stress, rats were administered apocynin, which is known to inhibit the assembly of NOX subunits and arrests its function. We found apocynin completely inhibited dye extravasation as well as restored TJP levels to that of controls and reduced matrix metalloproteinase activation in the sub-acute stages following blast. Together these data strongly suggest that NOX-mediated oxidative stress contributes to enhanced BBB permeability in bTBI through a pathway involving increased matrix metalloproteinase activation.

Craniofacial penetration by a wooden stick.

INTRODUCTION: Penetrating craniofacial injuries caused by stick-like foreign bodies occur as a result of accidents particularly in children, and often lead to significant morbidity. CASE SUMMARY: We describe a 5-year-old boy who sustained facial trauma after falling on a wooden stick which penetrated his left cheek. At the initial visit, his vital and neurological signs were normal. However, the stick had penetrated the frontal lobe to a depth of 3cm via the orbital cavity and the anterior skull base. The stick was successfully removed while visualizing the anterior skull base in an endoscopic transethmoidal approach. A follow-up examination one year after the accident demonstrated normal visual acuity and ocular motility, with no diplopia, tearing or pain. DISCUSSION: Penetrating facial injuries caused by stick-like objects carry a significantly higher risk of serious neurological involvement. Even if penetrating facial injuries sometimes appear trivial, the external injury site is often insufficient to determine the position of the object within the head. Although the cheek is a rare entry site for intracranial injuries, the extent of damage should be assessed fully before attempting removal.

The bridge between cognition and behavior in acquired brain injury: A graph theoretical approach.

BACKGROUND: The assumption is that executive dysfunctions (EF), associated with frontal lobe injury, are responsible for behavioral disturbances. Some studies do not find a relationship between EF and behavior following frontal lobe lesions. Our main goal of this study was to use a novel statistical method, graph theory, to analyze this relationship in different brain injury groups; frontal lobe damage, non-frontal lobe damage, and controls. Within the frontal group, we expect to find a pattern of executive nodes that are highly interconnected. METHODS: For each group, we modeled the relationship between executive functions and behavior as a network of interdependent variables. The cognitive tests and the behavioral questionnaire are the "nodes" in the network, while the relationships between the nodes were modeled as the correlations between two nodes corrected for the correlation with all other nodes in the network. Sparse networks were estimated within each group using graphical LASSO. We analyzed the relative importance of the nodes within a network (centrality) and the clustering (modularity) of the different nodes. RESULTS: Network analysis showed distinct patterns of relationships between EF and behavior in the three subgroups. The performance on the verbal learning test is the most central node in all the networks. In the frontal group, verbal memory forms a community with working memory and fluency. The behavioral nodes do not differentiate between groups or form clusters with cognitive nodes. No other communities were found for cognitive and behavioral nodes. CONCLUSION: The cognitive phenotype of the frontal lobe damaged group, with its stability and proportion, might be theoretically interpreted as a potential "buffer" for possible cognitive executive deficits. This might explain some of the ambiguity found in the literature. This alternative approach on cognitive test scores provides a different and possibly complimentary perspective of the neuropsychology of brain-injured patients.

Activation of the Nrf2-ARE signal pathway after blast induced traumatic brain injury in mice.

Background: Treatment of blast-induced traumatic brain injury (bTBI) has been hindered. Previous studies have demonstrated that oxidative stress may contribute to the pathophysiological process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway exhibits a protective effect after traumatic brain injury (TBI). This study explored whether the Nrf2-ARE pathway was activated in a modified bTBI mouse model. Method: Mice were randomly divided into six groups: the 6 h, 1 d, 3 d, 7 d and 14 d after bTBI groups and a sham group. The protein levels of nuclear Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) were detected using western blot, and HO-1 and NQO1 mRNA levels were determined by real-time quantitative polymerase chain reaction. Moreover, HO-1 and Nrf2 were localized using histological staining. Results: The protein level of the Nrf2-ARE pathway in the frontal lobe increased significantly in the 3 d after bTBI. The HO-1 and NQO1 mRNA levels also reached a peak in the frontal lobe 3 d after bTBI. The histological staining demonstrated higher expression of HO-1 in the frontal lobe and hippocampus 3 d after bTBI, when nuclear import of Nrf2 reached a peak in the frontal lobe. Conclusions: bTBI activated the Nrf2-ARE signaling pathway in the brain. The peak activation time in the frontal lobe may be 3 d after injury, and activating the Nrf2 pathway could be a new direction for treatment.

Penetrating head injury due to angle grinder: an occupational hazard.

Penetrating head injury is a life threatening condition. In the workplace, these are mostly non missile type, low velocity civilian injuries caused by sharp objects. Angle grinders are used to cut stones, metal etc, and cause penetrating head injuries due to shattered rotating discs from the grinder at home and workplaces. We report a series of three cases of penetrating head injuries due to unsafe use of angle grinders. The relevant literature is reviewed and management of such cases is discussed.

Full Recovery After a Bihemispheric Gunshot Wound to the Head: Case Report, Clinical Management, and Literature Review.

BACKGROUND: Nearly 33,600 people die each year in the United States as a result of gunshot wounds (GSWs). Penetrating craniocerebral GSWs are often fatal with a nearly 70% death rate at the scene of the trauma. Overall combined mortality rate for patients who die at the scene or at the hospital is almost 91%. Poor outcome is associated with initial low Glasgow Coma Scale score and bihemispheric and transventricular gunshot trajectory. We summarize current understanding in management, prognostic factors, and survival outcomes in patients with a penetrating GSWs to the head. We report a patient with return to full function despite bihemispheric, multilobar involvement. Full function is defined here as ability to return to previous work and perform activities of daily living. CASE DESCRIPTION: A 33-year-old man sustained a GSW to the head under unknown circumstances. On initial presentation, he had a Glasgow Coma Scale score of 15. He was verbalizing and communicating but was amnestic for the event. From a left frontal entry wound, the bullet traversed both frontal lobes of the brain reaching the right frontal-parietal junction. Physical examination and vital signs were normal. Appropriate surgical and medical management resulted in complete recovery. CONCLUSIONS: Craniocerebral GSWs have a high mortality rate and usually require aggressive management. Evaluation of most GSWs requires appropriate imaging studies followed by proactive treatment against infection, seizure, and increased intracranial pressure. Surgical intervention is often necessary and ranges from local wound débridement to craniectomy, decompression, and wound exploration.