Sequelae Of Traumatic Brain Injury Research Articles

Bioenergetic restoration and neuroprotection after therapeutic targeting of mitoNEET: New mechanism of pioglitazone following traumatic brain injury

Mitochondrial dysfunction is a pivotal event in many neurodegenerative disease states including traumatic brain injury (TBI) and spinal cord injury (SCI). One possible mechanism driving mitochondrial dysfunction is glutamate excitotoxicity leading to Ca2+-overload in neuronal or glial mitochondria. Therapies that reduce calcium overload and enhance bioenergetics have been shown to improve neurological outcomes. Pioglitazone, an FDA approved compound, has shown neuroprotective properties following TBI and SCI, but the underlying mechanism(s) are unknown. We hypothesized that the interaction between pioglitazone and a novel mitochondrial protein called mitoNEET was the basis for neuroprotection following CNS injury. We discovered that mitoNEET is an important mediator of Ca2+-mediated mitochondrial dysfunction and show that binding mitoNEET with pioglitazone can prevent Ca2+-induced dysfunction. By utilizing wild-type (WT) and mitoNEET null mice, we show that pioglitazone mitigates mitochondrial dysfunction and provides neuroprotection in WT mice, though produces no restorative effects in mitoNEET null mice. We also show that NL-1, a novel mitoNEET ligand, is neuroprotective following TBI in both mice and rats. These results support the crucial role of mitoNEET for mitochondrial bioenergetics, its importance in the neuropathological sequelae of TBI and the necessity of mitoNEET for pioglitazone-mediated neuroprotection. Since mitochondrial dysfunction is a pathobiological complication seen in other diseases such as diabetes, motor neuron disease and cancer, targeting mitoNEET may provide a novel mitoceutical target and therapeutic intervention for diseases that expand beyond TBI.

Acute administration of perampanel, an AMPA receptor antagonist, reduces cognitive impairments after traumatic brain injury in rats

Traumatic brain injury (TBI) is a major cause of death and physical as well as cognitive disability for which an effective treatment option remains to be identified. Evidence in preclinical models has indicated that antagonists of the α-amino-3-hydroxy-5-methyl-4-isozazole propionate (AMPA) receptor exert neuroprotective effects after mechanical injury in vitro and in vivo. In particular, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate (perampanel), a selective AMPA receptor antagonist with good bioavailability, was recently shown to therapeutically protect against the sequelae of TBI in the rodent controlled cortical impact model. However, this model induces a largely focal injury and is less representative of diffuse injury components that occur in TBI resulting from acceleration/deceleration forces. Here, we investigated the neuroprotective effects of perampanel in the rodent lateral fluid percussion injury model (LFPI), which produces both focal and diffuse injury. Pre- or post-injury administration of perampanel in male adult rats attenuated the injury-induced increase in the pro-apoptotic bax/bcl-xL ratio in the hippocampus; reduced impairments in learning and memory, assessed by the Morris water maze test; and reduced impairments in reward-seeking behavior, assessed by a female encounter test. Although additional studies are needed to determine the sex-related differences in the neuroprotective effects, these results provide support for the therapeutic potential of perampanel in TBI.

Prognosis of prolonged disorders of consciousness outcome based on the determination of certain hormones and natriuretic peptide

Introduction: Changes in hormonal status in patients with prolonged disorders of consciousness (PDC) remain poorly understood. There are no studies devoted to the investigation of prognostic value of hormonal changes to predict the outcome which is primarily due to a relatively small number of patients, different variants of structural brain disorders in vegetative state (VS) patients, concomitant somatic pathology including typical complications.The objective: to study the correlation between outcomes in VS patients with hormonal status and the level of natriuretic peptide. Subjects and methods. 275 patients in VS were examined for the time period from 2007 to 2017. 152 patients had sequela of traumatic brain injury (TBI) and 123 patients suffered from hypoxic brain damage. All patients matched the international criteria of VS diagnosis. In all patients, blood samples were collected during the first week after admission to ICU to test hormones and natriuretic peptide levels. ACTH, cortisol, TSH, free T3 and T4 , STH, prolactin and natriuretic peptide were tested in the period from 2 to 4 months of staying in VS. In men, the level of total testosterone, LH and FSH was additionally tested. The obtained data were compared with VS outcome.Results. The tested hormones were stably insufficient only in few VS patients. None of the tested hormones of the hypothalamic-pituitary-adrenal axis made a reliable criterion for predicting VS outcome. The tendency of disrupted rhythm of cortisol secretion was found to be most frequent and consistent, with higher rates in the evening hours. The average value of STH was higher in men with sequela of traumatic brain injury who had recovered consciousness versus those who remained in VS. A significant decrease in testosterone levels, regardless of age, was found in the patients with TBI sequela. Mean levels of LH were higher in patients with TBI sequela and hypoxia who remained unconscious versus patients who later restored consciousness. The average level of FSH was higher in patients who had recovered consciousness compared to those who remained in chronic VS. The increased level of natriuretic peptide was observed both in patients who remained in chronic VS and in those who restored consciousness.Conclusions. When investigating levels of certain hormones, no specific endocrine background characterizing this category of patients was found. Abnormal rhythms of some hormones secretion, in particular cortisol, can be considered typical of VS patients especially patients with TBI sequela.

Injury of the dentatorubrothalamic tract in patients with post-traumatic tremor following mild traumatic brain injury: a case-control study.

Post-traumatic movement disorder is one of the sequelae of traumatic brain injury. The dentatorubrothalamic tract (DRTT) is reported to be involved in the control of movement. Therefore, injury of the DRTT can be accompanied by abnormal movements, including ataxia, tremor, or dystonia. We investigated DRTT injuries in 27 patients who showed post-traumatic tremor in at least one of four extremities following mild traumatic brain injury. We classified DRTT injuries based on diffusion tensor tractography parameters and configuration: type A: the DRTT showed narrowing, type B: the DRTT showed partial tearing, and type C: the DRTT showed discontinuation. Fractional anisotropy and fiber number of the DRTT were significantly decreased in patients compared with the healthy controls. Based on our DRTT injury classification, among the 54 hemispheres of the 27 patients, type A injury occurred in 22 hemispheres (40.7%) of 17 patients, type B injury was present in 15 hemispheres (27.7%) of 10 patients, and type C injury was observed in 8 hemispheres (14.8%) of 6 patients. Our results suggest that diffusion tensor tractography-based evaluation of the DRTT would be useful when determining cause of post-traumatic tremor in patients with mild traumatic brain injury. The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital (YUMC-2018-09-007) on September 5, 2018.

Surgical Outcomes in Post-Traumatic Epilepsy: A Single Institutional Experience.

Post-traumatic epilepsy (PTE) is a debilitating sequela of traumatic brain injury (TBI), occurring in up to 20% of severe cases. This entity is generally thought to be more difficult to treat with surgical intervention. To detail our experience with the surgical treatment of PTE. Patients with a history of head injury undergoing surgical treatment for epilepsy were retrospectively enrolled. Engel classification at the last follow-up was used to assess outcome of patients that underwent surgical resection of an epileptic focus. Reduction in seizure frequency was assessed for patients who underwent vagal nerve stimulator (VNS) or responsive neurostimulator (RNS) implantation. A total of 23 patients met inclusion criteria. Nineteen (82.6%) had mesial temporal sclerosis, 3 had lesional neocortical epilepsy (13.0%), and 1 had nonlesional neocortical epilepsy (4.3%). Fourteen patients (60.9%) underwent temporal lobectomy (TL), 2 underwent resection of a cortical focus (8.7%), and 7 underwent VNS implantation (30.4%). Three patients underwent RNS implantation after VNS failed to reduce seizure frequency more than 50%. In the patients treated with resection, 11 (68.8%) were Engel I, 3 (18.8%) were Engel II, and 2 (12.5%) were Engel III at follow-up. Average seizure frequency reduction in the VNS group was 30.6%±25.6%. RNS patients had reduction of seizure severity but seizure frequency was only reduced 9.6%±13.6%. Surgical outcomes of PTE patients treated with TL were similar to reported surgical outcomes of patients with nontraumatic epilepsy treated with TL. Patients who were not candidates for resection demonstrated variable response rates to VNS or RNS implantation.

Prognostic factors and profile in traumatic brain injury in the paediatric age

Traumatic brain injury (TBI) is a common cause of death and disability in the paediatric population, although the literature on the Spanish population is scarce. From the perspective of early vulnerability, recent research findings suggest that early brain injury has worse sequelae and a higher risk of impact. To analyse the intelligence profile, executive functions and behaviour, and examine the association between age at the time of the injury, severity of the TBI and environmental factors for cognitive and behavioural outcomes. Seventy-one participants with moderate to severe TBI, from 6 to 16 years of age, were assessed with measures of intelligence (intelligence quotient), executive functions and behaviour. Children with TBI are at increased risk of disability in all aspects of intelligence, executive functions and behaviour. Children who suffered a traumatic brain injury in infancy and the preschool period had more overall effects on intelligence quotient and some aspects of the executive functions. Socioeconomic and cultural factors are the best predictors for intelligence quotient and behaviour. These findings contribute to a better understanding of the sequelae of TBI in children, which will help in rehabilitation planning and re-adaptation to functional life.

Observer‐perceived light aversion behaviour in photophobic subjects with traumatic brain injury

BackgroundPhotophobia is a common sequela of traumatic brain injury (TBI). Diagnostic tools for this debilitating condition are lacking. This investigation sought to determine whether masked observers can distinguish subjects with TBI‐associated photophobia from matched controls based on video recordings of their ocular responses to light stimulation.MethodsCohorts of students (n = 20), photophobic TBI subjects (n = 28) and their matched control subjects (n = 12) were recruited. A custom pupillometer delivered bright (1013–1014 photons/s/cm2), flashing (0.10-Hz) red (625-nm) and blue (470-nm) light stimuli to subjects, and consensual pupil light responses were recorded. Using a five‐point scale, masked observers later graded light aversion behaviour in the pupil video recordings obtained from the student cohort based on observed blinking, tearing and squinting. A grading scale was developed and used by masked observers to grade light aversion behaviour in videos obtained from subjects with post‐TBI photophobia and the matched controls. These subjects also scored their perceived discomfort during each light pulse using a five‐point scale.ResultsThe subjects in the TBI cohort scored both the blue and red flashing stimuli as evoking more discomfort, relative to control subjects, consistent with their reported photophobia. There was strong agreement among the masked observers for their grades of light aversion behaviour in the videos of ocular light stimulation (interclass correlation co‐efficient = 0.78; 29 per cent perfect concordance). However, the median grades for the videos obtained from the TBI subject cohort were not significantly different from those for the control group.ConclusionsClinicians cannot diagnose TBI‐related photophobia based solely on video recordings of ocular responses to light. The need remains for an objective test to diagnose and manage this prevalent post‐TBI symptom.

Postconcussive, posttraumatic stress and depressive symptoms in recently deployed U.S. Army soldiers with traumatic brain injury.

Prior studies raise questions about whether persistent postconcussive symptoms (PCS) are differentiable from mental health sequelae of traumatic brain injury (TBI). To investigate whether PCS represented a distinct symptom domain, we evaluated the structure of post-concussive and psychological symptoms using data from The Army STARRS Pre/Post Deployment Study, a panel survey of three U.S. Army Brigade Combat Teams that deployed to Afghanistan. Data from 1229 participants who sustained probable TBI during deployment completed ratings of past-30-day post-concussive, posttraumatic stress, and depressive symptoms three months after their return. Exploratory factor analysis (EFA; n = 300) and confirmatory factor analysis (CFA; n = 929) of symptom ratings were performed in independent subsamples. EFA suggested a model with 3 correlated factors resembling PCS, posttraumatic stress, and depression. CFA confirmed adequate fit of the 3-factor model (CFI = .964, RMSEA = .073 [.070, .075]), contingent upon allowing theoretically defensible cross-loadings. Bifactor CFA indicated that variance in all symptoms was explained by a general factor (λ = .36-.93), but also provided evidence of domain factors defined by (a) reexperiencing/hyperarousal, (b) cognitive/somatic symptoms, and (c) depressed mood/anhedonia. Soldiers with more severe TBI had higher cognitive/somatic scores, whereas soldiers with more deployment stress had higher general and reexperiencing/hyperarousal scores. Thus, variance in PCS is attributable to both a specific cognitive/somatic symptom factor and a general factor that also explains variance in posttraumatic stress and depression. Measurement of specific domains representing cognitive/somatic symptoms, reexperiencing/hyperarousal, and depressed mood/anhedonia may help clarify the relative severity of PCS, posttraumatic stress, and depression among individuals with recent TBI. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Blast Exposure and Risk of Recurrent Occupational Overpressure Exposure Predict Deployment TBIs.

Traumatic brain injury (TBI) has been the leading cause of morbidity and mortality in recent military conflicts and deployment-related TBIs are most commonly caused by blast. However, knowledge of risk factors that increase susceptibility to TBI following an acute, high-level blast is limited. We hypothesized that recurrent occupational overpressure exposure (ROPE) may be one factor that increases susceptibility to mild TBI (mTBI) following blast. Using military occupational specialty as a proxy, we examined the effects of high versus low ROPE on mTBI following blast exposure. Initial analyses included 111,641 active-duty-enlisted U.S. Marines who completed the 2003 or 2008 version of the Post-Deployment Health Assessment. Final analyses examined probable mTBI screens among Marines with at least one qualifying exposure as a function of whether the exposure was a blast and level of ROPE (N=12,929). This study was approved by the Institutional Review Board at the Naval Health Research Center. Blast and ROPE were both independently and jointly associated with a probable mTBI. Marines who experienced a blast (vs other qualifying exposure) and those in high (vs low) risk occupations were 1.07 and 1.23 times more likely to sustain a probable mTBI, respectively. Furthermore, among those who experienced a blast during deployment, those in high-risk occupations were 1.45 times more likely than those in low-risk occupations to sustain a probable mTBI. Blast exposure and ROPE were independently associated with mTBIs, and Marines with both blast exposure during deployment and ROPE were especially likely to sustain an mTBI. This suggests that ROPE heightens the risk of mTBI following blast. Ongoing research is examining the severity, symptomology, and sequelae of TBIs as a function of ROPE.

Amyotrophic Lateral Sclerosis Among Veterans Deployed in Support of Post-9/11 U.S. Conflicts.

Amyotrophic lateral sclerosis (ALS) is a recognized military service-connected condition. Prior prevalence studies of ALS among U.S. war Veterans were not able to address concerns related to neurodegenerative sequelae of traumatic brain injury (TBI) and disregarded risk heterogeneity from occupational categories within service branches. We identified the prevalence of definite and possible ALS and cumulative incidence of definite ALS among Post-9/11 U.S. Veterans deployed in support of Post-9/11 conflicts (mean age 36.3) who received care in the Veterans Health Administration during fiscal years 2002-2015. Using a case-control study design, we also evaluated the association of TBI and major military occupation groups with ALS adjusting for demographics and comorbidities. The prevalence of ALS was 19.7 per 100,000 over 14 years. Both prevalence and cumulative incidence of definite ALS were significantly higher among Air Force personnel compared to other service branches and among tactical operation officers and health care workers compared to general and administrative officers. Neither TBI nor younger age (<45 years) was associated with ALS. Depression, cardiac disease, cerebrovascular disease, high blood pressure, and obstructive sleep apnea were clinical comorbidities significantly associated with ALS in this population of Veterans. This study among a cohort of relatively young Veterans showed a high ALS prevalence, suggesting an early onset of ALS among deployed military service members. The higher prevalence among some military specific occupations highlights the need to determine which occupational exposures specific to these occupations (particularly, Air Force personnel, tactical operations officers, and health care workers) might be associated with early onset ALS.

Sluggish cognitive tempo in children with traumatic brain injuries

This exploratory study is the first to investigate whether the construct of sluggish-cognitive tempo (SCT) is related to slowed processing speed in children with traumatic brain injury (TBI), while also considering pre-morbid and injury variables. The study evaluated SCT, as measured by the Child Behavior Checklist (CBCL), and processing speed, as assessed with the Wechsler Intelligence Scale for Children—Fourth Edition (WISC–IV Processing Speed Index), in children who sustained TBI with a wide range of injury severity. Injury variables examined included the length of coma, presence of neuroimaging findings, and time between injury and assessment. Children’s cognitive reserve, as estimated by parental level of education, was a non-injury variable. The participants included 50 children, ages 6–16 years, without co-morbid neurological or psychiatric conditions who underwent a neuropsychological evaluation within 1–12 months after injury. Results indicated no significant correlations between SCT and any of the WISC–IV index scores. Children with a moderate-severe TBI did not differ from those with uncomplicated mild TBI on SCT but they had statistically significant lower WISC–IV Processing Speed. Although parents of children with uncomplicated mild TBI had higher levels of education as compared to parents of children with moderate-severe TBI, there was no statistically significant relationship between the level of parental education and either SCT or Processing Speed. This study suggests that SCT, as measured by the CBCL, is not a sensitive measure of sequelae of pediatric TBI.

THE SIGNIFICANCE OF ΝО GAS TRANSMITTER AND NUCLEASES IN SHAPING THE SEQUELAE OF TRAUMATIC BRAIN INJURY

Traumatic brain injuries are at present remaining an important worldwide medical problem due to substantial percentages of incapacitation and lethality, especially among people of working age. All therapeutic interventions in TBI and their timeliness and efficacy depend on timely and quality diagnosis of patient’s condition, including laboratory parameters of blood and urine. The aim: To assess for peculiar patterns in changes of NO gas transmitter levels in patients with severe traumatic brain injury during the treatment period and to investigate into its relationship with nuclease enzymes in the context of various treatment outcomes. This research work has used clinical data, history and diagnostic tests obtained in 72 patients with severe traumatic brain injury, age 18 to 76 years (mean age 42.26±15.02 years), who six months later have been divided into the following four groups according to Glasgow outcome scale: “Death”, “Severe disability”, “Moderate disability” and “Recovery”. Biochemical assessments in patients with severe traumatic brain injury have shown supranormal levels of urinary nitric oxide and serum DNAses. Going forward, nitric oxide levels significantly decreased over the time of treatment in subjects with favorable outcomes (“Moderate disability” and “Recovery” groups) and increased with treatment time in subjects with unfavorable outcomes (“Severe disability” and “Death” groups). The diagnostic markers of further unfavorable survival outcomes may be present at the onset of treatment (Day 1) and may include urinary levels of nitric oxide below 1.1 μmol/L and DNAse levels below 26 μU/mL. A positive diagnostic sign of favorable survival and health outcomes may include DNAse І levels over 30.0 μU/mL from Day 7 of treatment. The findings of this work can be used when making a diagnosis/selecting an optimal treatment schedule and predicting the sequelae of traumatic brain injury in a patient, which may cumulatively minimize the impact of the injury.

What determines a good outcome from traumatic brain injury

Cognitive impairments are the principal clinical manifestations of traumatic brain injury (TBI) from injury onset throughout the early and late post-injury periods. The functional effects of posttraumatic cognitive impairments and associated neuropsychiatric disturbances present substantial challenges to patients and their families and for clinicians providing their rehabilitative care. In this lecture, a neuropsychiatrically-informed approach to the evaluation and management of the cognitive and non-cognitive neuropsychiatric sequelae of TBI is offered, with the aim of improving TBI outcomes for affected individuals and their families. In the service of meeting that aim, the epidemiology and natural history of cognitive recovery after TBI is reviewed. The differential diagnosis of cognitive problems among people with TBI is considered within the context of acute traumatic encephalopathy, and expectations for long-term outcomes associated with mild versus moderate-to-severe TBI are described. The evidence base for pharmacologic and cognitive rehabilitative interventions for persons with persistent posttraumatic cognitive impairments then are considered and recommendations for evidence-informed treatments are offered.

Biomarkers for paediatric traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide with a substantial health and socioeconomic impact.1,2 The potential long-term sequelae of mild TBI are becoming increasingly apparent.2–4 Tools to assess injury severity, monitor patients for early signs of clinical deterioration, and improve prognosis are being investigated. For these reasons, brain biomarkers have attracted increasing interest, with more than 90 different biomarkers studied in paediatric patients with TBI to date.

Low-Field Magnetic Stimulation Restores Cognitive and Motor Functions in the Mouse Model of Repeated Traumatic Brain Injury: Role of Cellular Prion Protein.

Traumatic brain injury (TBI)/concussion is a growing epidemic throughout the world. Memory and neurobehavioral dysfunctions are among the sequelae of TBI. Dislodgement of cellular prion protein (PrPc) and disruption of circadian rhythm have been linked to TBI. Low-field magnetic stimulation (LFMS) is a new noninvasive repetitive transcranial magnetic stimulation (rTMS) technique that generates diffused and low-intensity magnetic stimulation to deep cortical and subcortical areas. The role of LFMS on PrPc, proteins related to the circadian rhythm, and behavior alterations in a repeated TBI mouse model were studied in the present study. TBI was induced to the mice (right hemisphere) using weight-drop method, once daily for 3 days. LFMS treatment was given for 20 min once daily for 4 days (immediately after each TBI induction). The results showed that LFMS-treated TBI mice significantly improved cognitive and motor function as evidenced by open field exploration, rotarod, and novel location recognition tasks. In addition, a significant increase in PrPc and decreased glial fibrillary acidic protein levels were observed in cortical and hippocampal regions of LFMS-treated TBI mice brain compared with sham-treated TBI mice, while neuronal nuclei level was significantly increased in cortical region. In LFMS-treated mice, a decrease in proteins related to circadian rhythm were observed, compared with sham-treated TBI mice. The results obtained from the study demonstrated the neuroprotective effect of LFMS, which may be through regulating PrPc and/or proteins related to circadian rhythm. Thus, the present study suggests that LFMS may improve the subject's neurological condition following TBI.

Improving Military Readiness and Reducing Suicide Risk: The Role Between Positive TBI Screens, Severe Insomnia, and Suicidal Outcomes

This study examined how insomnia severity and a positive traumatic brain injury (TBI) screen relate to suicidal outcomes across military branches. Data were compiled from 1,635 participants across seven studies. A series of analyses were conducted by military branch to identify which significantly differed on the variables of interest. A series of multiple regression analyses were conducted to explore whether insomnia severity and a positive TBI screen predicted suicidal outcomes and whether the effect varied as a function of military branch. Insomnia severity and a positive TBI screen each had independent relationships with the suicide risk outcomes. The relationship between insomnia and suicide risk varied by military branch. However, a positive TBI screen had a significant effect on suicidal behavior and thoughts and the effect was similar across the four groups. Efforts to identify and intervene on insomnia and TBI sequelae may improve quality of care for service members at risk of suicide. Insomnia and post-TBI symptoms are important targets of intervention as they are often less stigmatized and can be easily assessed by brief self-report measures.

The Beehive Theory: Role of microorganisms in late sequelae of traumatic brain injury and chronic traumatic encephalopathy

Traumatic brain injury and chronic traumatic encephalopathy are both major health problems, well-publicized for the severe delayed effects attributed to them, including cognitive decline, psychiatric disorders, seizures, impaired motor function, and personality changes. For convenience, the two afflictions are considered together under the rubric traumatic brain injury. Despite the need for neuroprotective agents, no substances have shown efficacy in clinical studies. Thus, a deeper understanding of the neuropathological mechanism of such injury is still needed. Proposed here is a theory that microorganisms from within the brain and elsewhere in the body contribute to the long-term neurological deterioration characteristic of traumatic brain injury. The label, “The Beehive Theory”, is drawn from the well-known fact that disturbing a tranquil beehive with a blow can cause a swarm of angry bees to exit their dwelling place and attack nearby humans. Similarly, an impact to the head can initiate dislocations and disruptions in the microbiota present in the brain and body. First, since the normal human brain is not sterile, but is host to a variety of microorganisms, blows to the skull may dislodge them from their accustomed local environments, in which they have been living in quiet equilibrium with neighboring brain cells. Deleterious substances may be released by the displaced microbes, including metabolic products and antigens. Second, upon impact commensal microbes already resident on surfaces of the nose, mouth, and eyes, and potentially harmful organisms from the environment, may gain access to the brain through the distal ends of the olfactory and optic nerves or even a disrupted blood-brain barrier. Third, microbes dwelling in more distant parts of the body may be propelled through the walls of local blood vessels into the bloodstream, and then leak out into damaged areas of the brain that have increased blood-brain barrier permeability. Fourth, the impact may cause dysbiosis in the gastrointestinal microbiome, thereby disrupting signaling via the gut-brain axis. Possible preventatives or therapeutics that would address the adverse contributions of microbes to the late sequelae of traumatic brain injury include anti-inflammatories, antibacterials, antivirals, and probiotics.

Low-Frequency Right Repetitive Transcranial Magnetic Stimulation for the Treatment of Depression After Traumatic Brain Injury: A Randomized Sham-Controlled Pilot Study.

Major depression is the most common psychiatric sequela of traumatic brain injury (TBI), but effective treatment continues to be a challenge, with few studies providing guidance. In a pilot study, the authors evaluated the effect size of low-frequency right-sided (LFR) repetitive transcranial magnetic stimulation (rTMS), compared with sham treatment, over the right dorsolateral prefrontal cortex (DLPFC) in patients (N=30) with TBI depression and co-occurring neuropsychiatric symptoms, including suicidal thoughts, anxiety, posttraumatic stress disorder, sleep disturbance, behavioral problems, and cognitive dysfunction. Exploratory analyses of diffusion tensor imaging pre- and postintervention were performed to determine the effect size of LFR rTMS on white matter integrity. Small (Hedge's g=0.19) and highly variable effects of LRF rTMS over right DLPFC in TBI depression were observed. Similarly, the effect of LFR rTMS for treatment of comorbid neuropsychiatric symptoms varied from small to moderate. These findings suggest that the observed effects of LFR rTMS over the right DLPFC in TBI depression and co-occurring neuropsychiatric symptoms are small, at best, and, preliminarily, that low-frequency right DLPFC stimulation has limited potential in this patient population. However, studies employing different rTMS parameters (e.g., type, location, frequency, duration) or other participant characteristics (e.g., TBI severity, chronicity, comorbidity, concurrent treatment) may potentially yield different responses.

Doctrine of head injury sequelae

In this article, we provide the definitions of “sequelae” and “complications” of traumatic brain injury (TBI). We have developed the classification principles for TBI consequences and described their clinical forms and morphological substrates. We also provide a radiological grading for assessing the severity of sequelae of focal and diffuse brain injuries. The article covers conceptual approaches, technologies, and results of their application related to leading surgically significant consequences of TBI, including carotid cavernous fistulas, chronic subdural hematomas, post-traumatic hydrocephalus, long-term basal liquorrhea, and skull defects. We have developed the doctrine of sequelae of TBI.

Increased Cortical Interleukin‐1 Receptor Signaling Following Blast‐Induced Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a leading cause of disability in the United States resulting in an estimated annual economic cost of over $75 billion. Furthermore, there is a lack of any FDA approved medications aimed at ameliorating the effects of acute injury or the chronic comorbidities of TBI. Those affected are often left with profound chronic neurologic deficits such as major depressive disorder (MDD), anxiety, sleep disturbances, and/or post‐traumatic epilepsy. Neuroinflammation is a hallmark of TBI, although whether neuroinflammatory signaling contributes to the etiology of neuropsychiatric complications following various forms of neurotrauma is not well characterized. We hypothesize that following TBI, interleukin‐1 alpha (IL‐1α) and interleukin‐1 beta (IL‐1β) signaling through functional type 1 interleukin‐1 receptors (IL‐1R1) acts to orchestrate molecular signaling that contributes to the generation of neuropsychiatric sequelae. To test this hypothesis, the current study aimed to characterize alterations in interleukin‐1 (IL‐1) signaling elicited by blast‐induced TBI in murine subjects. Moderate blast‐induced TBI (≈ 20 psi) resulted in an acute increase in righting reflex time (RRT) and a transient decrease in total locomotor activity 3 hrs post‐injury. Rapid increases in il‐1β, il‐1α and tnf‐α mRNA expression occurred in cortical and hippocampal samples ipsilateral to injury in TBI subjects as compared to their sham counterparts, indicating increased CNS production of proinflammatory cytokines. Elevated levels of il‐1r1 mRNA were found in the ipsilateral cortex following injury, however no changes were found in interleukin‐1 receptor associated kinase‐4 (irak‐4) mRNA expression, providing evidence of increased cortical IL‐1R1‐mediated signaling in TBI subjects. Further, TBI resulted in increased mRNA expression and immunoreactivity of the astrocytic marker glial fibrillary acidic protein (GFAP) in the ipsilateral cortex as compared to sham subjects 24 and 72 hrs post‐injury, respectively, indicative of significant reactive astrogliosis. One‐week post‐injury, TBI increased despair‐like behavior as compared to sham treatments as determined by the Porsolt forced swim test (FST). Importantly, no concomitant alterations in general locomotor activity were found in TBI subjects one‐week post‐injury. Future studies will utilize murine models, affording the conditional elimination and restoration of IL‐1R1 in conjunction with blast‐induced TBI to ascertain the cell‐specific contributions of IL‐1R1‐mediated signaling to injury‐induced neuroinflammation and functional outcomes post‐injury. Systematic characterization of IL‐1R1 signaling post‐injury will lead to a better understanding of how neuroinflammatory signaling contributes to the acute and chronic neurologic sequelae of TBI and may lead to viable pharmacotherapeutic targets aimed at ameliorating these deficits.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.