Association of Cavum Septum Pellucidum and Cavum Vergae With Cognition, Mood, and Brain Volumes in Professional Fighters.

Importance: Many studies have investigated the imaging findings showing sequelae of repetitive head trauma, with mixed results. Objective: To determine whether fighters (boxers and mixed martial arts fighters) with cavum septum pellucidum (CSP) and cavum vergae (CV) have reduced volumes in various brain structures or worse clinical outcomes on cognitive and mood testing. Design, Setting, and Participants: This cohort study assessed participants from the Professional Fighters Brain Health Study. Data were collected from April 14, 2011, to January 17, 2018, and were analyzed from September 1, 2018, to May 23, 2019. This study involved a referred sample of 476 active and retired professional fighters. Eligible participants were at least 18 years of age and had at least a fourth-grade reading level. Healthy age-matched controls with no history of trauma were also enrolled. Exposures: Presence of CSP, CV, and their total (additive) length (CSPV length). Main Outcomes and Measures: Information regarding depression, impulsivity, and sleepiness among study participants was obtained using the Patient Health Questionnaire depression scale, Barrett Impulsiveness Scale, and the Epworth Sleepiness Scale. Cognition was assessed using raw scores from CNS Vital Signs. Volumes of various brain structures were measured via magnetic resonance imaging. Results: A total of 476 fighters (440 men, 36 women; mean [SD] age, 30.0 [8.2] years [range, 18-72 years]) and 63 control participants (57 men, 6 women; mean [SD] age, 30.8 [9.6] years [range, 18-58 years]) were enrolled in the study. Compared with fighters without CV, fighters with CV had significantly lower mean psychomotor speed (estimated difference, -11.3; 95% CI, -17.4 to -5.2; P = .004) and lower mean volumes in the supratentorium (estimated difference, -31 191 mm3; 95% CI, -61 903 to -479 mm3; P = .05) and other structures. Longer CSPV length was associated with lower processing speed (slope, -0.39; 95% CI, -0.49 to -0.28; P < .001), psychomotor speed (slope, -0.43; 95% CI, -0.53 to -0.32; P < .001), and lower brain volumes in the supratentorium (slope, -1072 mm3 for every 1-mm increase in CSPV length; 95% CI, -1655 to -489 mm3; P < .001) and other structures. Conclusions and Relevance: This study suggests that the presence of CSP and CV is associated with lower regional brain volumes and cognitive performance in a cohort exposed to repetitive head trauma.

Age at First Exposure to Repetitive Head Impacts Is Associated with Smaller Thalamic Volumes in Former Professional American Football Players.

Thalamic atrophy has been associated with exposure to repetitive head impacts (RHI) in professional fighters. The aim of this study is to investigate whether or not age at first exposure (AFE) to RHI is associated with thalamic volume in symptomatic former National Football League (NFL) players at risk for chronic traumatic encephalopathy (CTE). Eighty-six symptomatic former NFL players (mean age = 54.9 ± 7.9 years) were included. T1-weighted data were acquired on a 3T magnetic resonance imager, and thalamic volumes were derived using FreeSurfer. Mood and behavior, psychomotor speed, and visual and verbal memory were assessed. The association between thalamic volume and AFE to playing football and to number of years playing was calculated. Decreased thalamic volume was associated with more years of play (left: p = 0.03; right: p = 0.03). Younger AFE was associated with decreased right thalamic volume (p = 0.014). This association remained significant after adjusting for total years of play. Decreased left thalamic volume was associated with worse visual memory (p = 0.014), whereas increased right thalamic volume was associated with fewer mood and behavior symptoms (p = 0.003). In our sample of symptomatic former NFL players at risk for CTE, total years of play and AFE were associated with decreased thalamic volume. The effect of AFE on right thalamic volume was almost twice as strong as the effect of total years of play. Our findings confirm previous reports of an association between thalamic volume and exposure to RHI. They suggest further that younger AFE may result in smaller thalamic volume later in life.

Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat.

The role of microglia in the pathophysiology of injury to the developing brain has been extensively studied. In children under the age of 4 who have sustained a traumatic brain injury (TBI), markers of microglial/macrophage activation were increased in the cerebrospinal fluid and were associated with worse neurologic outcome. Minocycline is an antibiotic that decreases microglial/macrophage activation following hypoxic-ischemia in neonatal rodents and TBI in adult rodents thereby reducing neurodegeneration and behavioral deficits. In study 1, 11-day-old rats received an impact to the intact skull and were treated for 3days with minocycline. Immediately following termination of minocycline administration, microglial reactivity was reduced in the cortex and hippocampus (p<0.001) and was accompanied by an increase in the number of fluoro-Jade B profiles (p<0.001) suggestive of a reduced clearance of degenerating cells; however, this effect was not sustained at 7days post-injury. Although microglial reactivity was reduced in the white matter tracts (p<0.001), minocycline treatment did not reduce axonal injury or degeneration. In the thalamus, minocycline treatment did not affect microglial reactivity, axonal injury and degeneration, and neurodegeneration. Injury-induced spatial learning and memory deficits were also not affected by minocycline. In study 2, to test whether extended dosing of minocycline may be necessary to reduce the ongoing pathologic alterations, a separate group of animals received minocycline for 9days. Immediately following termination of treatment, microglial reactivity and neurodegeneration in all regions examined were exacerbated in minocycline-treated brain-injured animals compared to brain-injured animals that received vehicle (p<0.001), an effect that was only sustained in the cortex and hippocampus up to 15days post-injury (p<0.001). Whereas injury-induced spatial learning deficits remained unaffected by minocycline treatment, memory deficits appeared to be significantly worse (p<0.05). Sex had minimal effects on either injury-induced alterations or the efficacy of minocycline treatment. Collectively, these data demonstrate the differential effects of minocycline in the immature brain following impact trauma and suggest that minocycline may not be an effective therapeutic strategy for TBI in the immature brain.

Low-level laser therapy effectively prevents secondary brain injury induced by immediate early responsive gene X-1 deficiency.

A mild insult to the brain can sometimes trigger secondary brain injury, causing severe postconcussion syndrome, but the underlying mechanism is ill understood. We show here that secondary brain injury occurs consistently in mice lacking immediate early responsive gene X-1 (IEX-1), after a gentle impact to the head, which closely simulates mild traumatic brain injury in humans. The pathologic lesion was characterized by extensive cell death, widespread leukocyte infiltrates, and severe tissue loss. On the contrary, a similar insult did not induce any secondary injury in wild-type mice. Strikingly, noninvasive exposure of the injured head to a low-level laser at 4 hours after injury almost completely prevented the secondary brain injury in IEX-1 knockout mice. The low-level laser therapy (LLLT) suppressed proinflammatory cytokine expression like interleukin (IL)-1ß and IL-6 but upregulated TNF-α. Moreover, although lack of IEX-1 compromised ATP synthesis, LLLT elevated its production in injured brain. The protective effect of LLLT may be ascribed to enhanced ATP production and selective modulation of proinflammatory mediators. This new closed head injury model provides an excellent tool to investigate the pathogenesis of secondary brain injury as well as the mechanism underlying the beneficial effect of LLLT.

Low-level laser therapy for closed-head traumatic brain injury in mice: effect of different wavelengths.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) affects millions worldwide and is without effective treatment. One area that is attracting growing interest is the use of transcranial low-level laser therapy (LLLT) to treat TBI. The fact that near-infrared light can penetrate into the brain would allow non-invasive treatment to be carried out with a low likelihood of treatment-related adverse events. LLLT may treat TBI by increasing respiration in the mitochondria, causing activation of transcription factors, reducing inflammatory mediators and oxidative stress, and inhibiting apoptosis. STUDY DESIGN/MATERIALS AND METHODS: We tested LLLT in a mouse model of closed-head TBI produced by a controlled weight drop onto the skull. Mice received a single treatment with continuous-wave 665, 730, 810, or 980 nm lasers (36 J/cm(2) delivered at 150 mW/cm(2)) 4-hour post-TBI and were followed up by neurological performance testing for 4 weeks. RESULTS: Mice with moderate-to-severe TBI treated with 665 and 810 nm laser (but not with 730 or 980 nm) had a significant improvement in Neurological Severity Score that increased over the course of the follow-up compared to sham-treated controls. Morphometry of brain sections showed a reduction in small deficits in 665 and 810 nm laser treated mouse brains at 28 days. CONCLUSIONS: The effectiveness of 810 nm agrees with previous publications, and together with the effectiveness of 660 nm and non-effectiveness of 730 and 980 nm can be explained by the absorption spectrum of cytochrome oxidase, the candidate mitochondrial chromophore in transcranial LLLT.

Analysis of pituitary lesions in fatal closed head injury.

We analyzed forensic autopsy findings of 66 consecutive patients with fatal closed head injury who survived up to 48 days after trauma to ascertain the causal factors and the time course of development of posttraumatic pituitary lesions. Pituitary lesions were identified in 27 patients. In patients with pituitary lesions, posterior lobe hemorrhage was observed in 21 patients, followed by anterior lobe hemorrhage in 10 patients and anterior lobe infarct in 7 patients. Comparisons between patients with and without pituitary lesions showed that falls and subdural hematoma were significantly frequent in patients with pituitary lesions. Immunohistochemistry of neurophysin showed increased immunoreactivity in the hypothalamus of patients with pituitary lesions and brain edema, providing morphologic evidence of pituitary dysfunction. Hemorrhage in the anterior or posterior lobe was identifiable in patients with short survival periods, whereas infarct in the anterior lobe appeared in patients surviving at least 14 hours. These data further our understanding of the mechanisms of pituitary dysfunctions and help in the estimation of the survival period after head trauma.

When backyard fun turns to trauma: risk assessment of blunt ballistic impact trauma due to potato cannons.

Although potato cannons are an area of great interest among internet users, they are almost completely unknown in the medical community. These simple ballistic devices are made from plastic plumbing pipes and are powered with propellant gas from aerosol cans. By combustion of the gas-oxygen mixture, a high pressure is produced which propels the potato chunks through the barrel. It is the aim of this study to investigate the hazardous potential of these shooting devices. Test shots were performed using three illegally manufactured potato cannons that were confiscated by police authorities. Velocity, impulse, kinetic energy, and energy density were calculated. The risk of head and chest injuries was investigated by using Sturdivan's Blunt Criterion (BC), an energy based five parametric trauma model assessing the vulnerability to blunt weapons, projectile impacts, and behind-body-armor exposures. The probability of lethality due to blunt impact trauma to the chest was assessed using Sturdivan's lethality model. For potential head impacts, all test shots far exceeded the critical BC (head) value which corresponds to a 50% risk of skull fracture. The risk of injury with regard to chest impacts was similar. All but two test shots far exceeded the critical BC (chest) value corresponding to a 50% risk of sustaining a thoracic skeletal injury of Abbreviated Injury Scale 2 or 3. The probability of a lethal injury due to blunt chest impact was as high as 20%. To conclude, this work demonstrates that potato cannons should be considered dangerous weapons rather than as toys used by adventurous adolescents.

Possible relationship of cranial traumatic injuries with violence in the south-east Iberian Peninsula from the Neolithic to the Bronze Age.

The main aim of this study was to analyze the presence and distribution of cranial trauma, as possible evidence of violence, in remains from the Neolithic to Bronze Age from the SE Iberian Peninsula. The sample contains skulls, crania, and cranial vaults belonging to 410 prehistoric individuals. We also studied 267 crania from medieval and modern times for comparative purposes. All lesions in the prehistoric crania are healed and none of them can be attributed to a specific weapon. In all studied populations, injuries were more frequent in adults than in subadults and also in males than in females, denoting a sexual division in the risk of suffering accidents or intentional violence. According to the archeological record, the development of societies in the SE Iberian Peninsula during these periods must have entailed an increase in conflict. However, a high frequency of cranial traumatic injuries was observed in the Neolithic series, theoretically a less conflictive time, and the lowest frequency was in crania from the 3rd millennium B.C. (Copper Age), which is characterized by the archeologists as a period of increasing violence. The relatively large size and the high rate of injuries in Neolithic crania and the practice of cannibalism are strongly suggestive of episodes of interpersonal or intergroup conflict. The number and distribution of injuries in Bronze Age is consistent with the increase in violence at that time described by most archeologists.

Minimal traumatic brain injury induce apoptotic cell death in mice.

In the United States, 1.4 million people suffer from traumatic brain injury (TBI) each year because of traffic, sports, or war-related injuries. The majority of TBI victims suffer mild to minimal TBI (mTBI), but most are released undiagnosed. Detailed pathologies are poorly understood. We characterized the microscopic changes of neurons of closed-head mTBI mice after increased unilateral trauma using hematoxylin and eosin (H&E) stain, and correlated it with the expression of the apoptotic proteins c-jun, p53, and BCL-2. Minimal damage to the brain increases the number of pyknotic appearing neurons and activates the apoptotic proteins in both hemispheres. Although minimal, increased impact was positively correlated with the increased number of damaged neurons. These results may explain the wide variety of behavioral and cognitive deficits closed-head mTBI causes in mice. Our cumulative results point to the pathological origin of post-concussion syndrome and may aid in the development of future neuroprotective strategies for the disease.

Selective deficit of mental visual imagery with intact primary visual cortex and visual perception.

There is a vigorous debate as to whether visual perception and imagery share the same neuronal networks, whether the primary visual cortex is necessarily involved in visual imagery, and whether visual imagery functions are lateralized in the brain. Two patients with brain damage from closed head injury were submitted to tests of mental imagery in the visual, tactile, auditory, gustatory, olfactory and motor domains, as well as to an extensive testing of cognitive functions. A computerized mapping procedure was used to localize the site and to assess the extent of the lesions. One patient showed pure visual mental imagery deficits in the absence of imagery deficits in other sensory domains as well as in the motor domain, while the other patient showed both visual and tactile imagery deficits. Perceptual, language, and memory deficits were conspicuously absent. Computerized analysis of the lesions showed a massive involvement of the left temporal lobe in both patients and a bilateral parietal lesion in one patient. In both patients the calcarine cortex with the primary visual area was bilaterally intact. Our study indicates that: (i) visual imagery deficits can occur independently from deficits of visual perception; (ii) visual imagery deficits can occur when the primary visual cortex is intact and (iii) the left temporal lobe plays an important role in visual mental imagery.

Structure and function in acquired prosopagnosia: lessons from a series of 10 patients with brain damage.

Acquired prosopagnosia varies in both behavioural manifestations and the location and extent of underlying lesions. We studied 10 patients with adult-onset lesions on a battery of face-processing tests. Using signal detection methods, we found that discriminative power for the familiarity of famous faces was most reduced by bilateral occipitotemporal lesions that involved the fusiform gyri, and better preserved with unilateral right-sided lesions. Tests of perception of facial structural configuration showed severe deficits with lesions that included the right fusiform gyrus, whether unilateral or bilateral. This deficit was most consistent for eye configuration, with some patients performing normally for mouth configuration. Patients with anterior temporal lesions had better configuration perception, though at least one patient showed a more subtle failure to integrate configural data from different facial regions. Facial imagery, an index of facial memories, was severely impaired by bilateral lesions that included the right anterior temporal lobe and marginally impaired by fusiform lesions alone; unilateral right fusiform lesions tended to spare imagery for facial features. These findings suggest that (I) prosopagnosia is more severe with bilateral than unilateral lesions, indicating a minor contribution of the left hemisphere to face recognition, (2) perception of facial configuration critically involves the right fusiform gyrus and (3) access to facial memories is most disrupted by bilateral lesions that also include the right anterior temporal lobe. This supports assertions that more apperceptive variants of prosopagnosia are linked to fusiform damage, whereas more associative variants are linked to anterior temporal damage. Next, we found that behavioural indices of covert recognition correlated with measures of overt familiarity, consistent with theories that covert behaviour emerges from the output of damaged neural networks, rather than alternative pathways. Finally, to probe the face specificity of the prosopagnosic defect, we tested recognition of fruits and vegetables: While face specificity was not found in most of our patients, the data of one patient suggested that this may be possible with more focal lesions of the right fusiform gyrus.

low-level laser therapy applied transcranially to mice following traumatic brain injury significantly reduces long-term neurological deficits.

Low-level laser therapy (LLLT) has been evaluated in this study as a potential therapy for traumatic brain injury (TBI). LLLT has been found to modulate various biological processes. Following TBI in mice, we assessed the hypothesis that LLLT might have a beneficial effect on their neurobehavioral and histological outcome. TBI was induced by a weight-drop device, and motor function was assessed 1 h post-trauma using a neurological severity score (NSS). Mice were then divided into three groups of eight mice each: one control group that received a sham LLLT procedure and was not irradiated; and two groups that received LLLT at two different doses (10 and 20 mW/cm(2) ) transcranially. An 808-nm Ga-As diode laser was employed transcranially 4 h post-trauma to illuminate the entire cortex of the brain. Motor function was assessed up to 4 weeks, and lesion volume was measured. There were no significant changes in NSS at 24 and 48 h between the laser-treated and non-treated mice. Yet, from 5 days and up to 28 days, the NSS of the laser-treated mice were significantly lower (p < 0.05) than the traumatized control mice that were not treated with the laser. The lesion volume of the laser treated mice was significantly lower (1.4%) than the non-treated group (12.1%). Our data suggest that a non-invasive transcranial application of LLLT given 4 h following TBI provides a significant long-term functional neurological benefit. Further confirmatory trials are warranted.

[Expression of caspase-8 after brain injury from fluid percussion in rats].

OBJECTIVE: To provide the evidence of the relationship between brain injury and the time of injury. METHODS: Rats were contused on brain by fluid percussion, then were killed after injury for 15 min, 30 min, 1,3,6,12 h, and 1,4,7,14 d respectively. The expression of caspase-8 were detected by immunohistochemical technology on rat brain section and the results were assessed by image analysis system in the cerebral cortex, thalamus, and hippocampus. RESULTS: The expression of caspase-8 in cortex and hippocampus could be detected in 30 min after injury, increased significantly in 3h, reached apex in 1d after injury, remained 4d before decreased. In addition, the expression of caspase-8 can be detected in 1h after injury and reached apex in 1d after injury, and remained 4d then reduced. CONCLUSION: It seems that the expression of caspase-8 should be a useful target for diagnosis of early brain injury.

Expression of caspase-8 after brain injury from fluid percussion in rats / 法医学杂志

OBJECTIVE@#To provide the evidence of the relationship between brain injury and the time of injury.@*METHODS@#Rats were contused on brain by fluid percussion, then were killed after injury for 15 min, 30 min, 1,3,6,12 h, and 1,4,7,14 d respectively. The expression of caspase-8 were detected by immunohistochemical technology on rat brain section and the results were assessed by image analysis system in the cerebral cortex, thalamus, and hippocampus.@*RESULTS@#The expression of caspase-8 in cortex and hippocampus could be detected in 30 min after injury, increased significantly in 3h, reached apex in 1d after injury, remained 4d before decreased. In addition, the expression of caspase-8 can be detected in 1h after injury and reached apex in 1d after injury, and remained 4d then reduced.@*CONCLUSION@#It seems that the expression of caspase-8 should be a useful target for diagnosis of early brain injury.

Tumor necrosis factor alpha expression and protein levels after fluid percussion injury in rats: the effect of injury severity and brain temperature.

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) is elevated in some models of traumatic brain injury (TBI). However, it is unclear how TNFalpha messenger ribonucleic acid (mRNA) expression and protein levels are affected by injury severity and posttraumatic temperature modification. This study determined the regional and temporal profile of TNFalpha levels after moderate and severe TBI and assessed the effects of posttraumatic hypothermia or hyperthermia on this proinflammatory cytokine. METHODS: Adult male Sprague-Dawley rats were subjected to sham procedures (no injury), moderate fluid-percussion TBI (1.8-2.2 atm), or severe fluid-percussion TBI (2.4-2.6 atm). After 1 to 72 hours of survival, animals were killed, and brain samples, cerebrospinal fluid, and serum were harvested for enzyme-linked immunosorbent assay quantification of TNFalpha levels. In a subsequent study, a 3-hour period of posttraumatic hypothermia (33 degrees C) or hyperthermia (39.5 degrees C) was applied, followed by immediate killing and cytokine assay. Another group was subjected to moderate TBI (1.8-2.2 atm), followed by killing at 15 minutes or at 1, 3, or 24 hours for TNFalpha reverse transcriptase-polymerase chain reaction analysis. RESULTS: A significant increase in TNFalpha mRNA and protein levels in cellular lysates of injured cortex and ipsilateral hippocampus was noted by 1 hour after TBI; it was sustained to 3 hours, followed by a rapid decline. Increased injury severity was associated with increased protein levels at remote injury sites and in the injured cerebral cortex at 72 hours. Posttraumatic hypothermia significantly reduced TNFalpha mRNA expression in the hippocampus compared with that in normothermic rats. In contrast, no temperature effects on TNFalpha protein levels were documented. CONCLUSION: Rapid and marked increase in TNFalpha mRNA expression and protein levels follows moderate and severe TBI. Injury severity and posttraumatic temperature play a modest but significant role on TNFalpha expression and protein levels. These findings suggest that the effects of posttraumatic temperature on histopathological and behavioral outcome primarily may involve secondary mediators that do not operate directly through their effect on TNFalpha.

Fast vigilance decrement in closed head injury patients as reflected by the mismatch negativity (MMN).

Event-related potentials (ERPs) were measured from 24 chronic closed head injury (CHI) patients and 18 age- and education-matched controls. The oddball paradigm was applied while subjects were watching a silent movie. The standard (p=0.8) sound of 75 ms duration had a basic frequency of 500 Hz with harmonic partials of 1000 Hz and 1500 Hz, whereas these frequencies for the pitch deviant were each 10% higher. The frequencies of the duration deviant matched with those of the standard but was 25 ms in duration. The MMN (mismatch negativity), generated by the brain's automatic auditory change-detector mechanism, was elicited by both deviants. No significant differences in the MMN latency or amplitude for either pitch or duration deviants were found between the groups. However, the MMN amplitude for the pitch deviant decreased in the patient group during the experiment considerably faster than in controls, suggesting a faster vigilance decrement in the patients.

Neuroimaging variables related to development of Secondary Attention Deficit Hyperactivity Disorder after closed head injury in children and adolescents.

OBJECTIVE: To characterize children who develop Secondary Attention Deficit Hyperactivity Disorder (S-ADHD) after severe and moderate closed head injury (CHI) according to neuroimaging variables. METHOD: Ninety-nine children from 4-19 years who suffered severe and moderate CHI were prospectively followed for a year after injury. Premorbid psychiatric status was determined by administration to the parent of a structured psychiatric interview. This interview was readministered 1 year after injury to determine the presence of post-closed head injury S-ADHD. An MRI was performed 3 months after injury to define lesion locations and volumes. RESULTS: A set of multiple logistic regression models determined that the odds of developing S-ADHD were 3.64 times higher among children with thalamus injury, and 3.15 times higher among children with basal ganglia injury. There was no significant difference in lesion volumes in any of the locations of interest between the group who developed S-ADHD and the group who did not develop S-ADHD. CONCLUSION: The data support an association between S-ADHD and injury in either or both the thalamus and basal ganglia, but they do not definitively demonstrate whether injury in either structure has an effect on S-ADHD in the absence of injury in the other.