Acute neuroendocrine changes after traumatic brain injury.

Introduction: Post-traumatic hypopituitarism (PTHP) is a significant, but often neglected consequence of traumatic brain injury (TBI). Research question: We aimed to provide a comprehensive overview of epidemiology, pathophysiology, clinical features and diagnostic approaches of PTHP. Materials and methods: MEDLINE, EMBASE, Cochrane Library and Web of Science were searched. 45 articles of human studies evaluating acute endocrine changes following mild, moderate and severe TBI were selected. Results: Severity of TBI seems to be the most important risk factor of PTHP. Adrenal insufficiency (AI) was present in 10% of TBI patients (prevalence can be as high as 50% after severe TBI), and hypocortisolemia is a predictor of mortality and long-term hypopituitarism. Suppression of the thyroid axis in 2-33% of TBI patients may be an independent predictor of adverse neurological outcome, as well. 9-36% of patients with severe TBI exhibit decreased function of the somatotrophic axis with a divergent effect on the central nervous system. Arginine-Vasopressin (AVP) deficiency is present in 15-51% of patients, associated with increased mortality and unfavorable outcome. Due to shear and injury of the stalk hyperprolactinemia is relatively common (2-50%), but it bears little clinical significance. Sex hormone levels remain within normal values. Discussion and conclusion: PTHP occurs frequently after TBI, affecting various axis and determining patients' outcome. However, evidence is scarce regarding exact epidemiology, diagnosis, and effective clinical application of hormone substitution. Future studies are needed to identify patients at-risk, determine the optimal timing for endocrine testing, and refine diagnostic and treatment approaches to improve outcome.

Artificial intelligence-based screening for amblyopia and its risk factors: comparison with four classic stereovision tests.

Introduction: The development of costs-effective and sensitive screening solutions to prevent amblyopia and identify its risk factors (strabismus, refractive problems or mixed) is a significant priority of pediatric ophthalmology. The main objective of our study was to compare the classification performance of various vision screening tests, including classic, stereoacuity-based tests (Lang II, TNO, Stereo Fly, and Frisby), and non-stereoacuity-based, low-density static, dynamic, and noisy anaglyphic random dot stereograms. We determined whether the combination of non-stereoacuity-based tests integrated in the simplest artificial intelligence (AI) model could be an alternative method for vision screening. Methods: Our study, conducted in Spain and Hungary, is a non-experimental, cross-sectional diagnostic test assessment focused on pediatric eye conditions. Using convenience sampling, we enrolled 423 children aged 3.6-14 years, diagnosed with amblyopia, strabismus, or refractive errors, and compared them to age-matched emmetropic controls. Comprehensive pediatric ophthalmologic examinations ascertained diagnoses. Participants used filter glasses for stereovision tests and red-green goggles for an AI-based test over their prescribed glasses. Sensitivity, specificity, and the area under the ROC curve (AUC) were our metrics, with sensitivity being the primary endpoint. AUCs were analyzed using DeLong's method, and binary classifications (pathologic vs. normal) were evaluated using McNemar's matched pair and Fisher's nonparametric tests. Results: Four non-overlapping groups were studied: (1) amblyopia (n = 46), (2) amblyogenic (n = 55), (3) non-amblyogenic (n = 128), and (4) emmetropic (n = 194), and a fifth group that was a combination of the amblyopia and amblyogenic groups. Based on AUCs, the AI combination of non-stereoacuity-based tests showed significantly better performance 0.908, 95% CI: (0.829-0.958) for detecting amblyopia and its risk factors than most classical tests: Lang II: 0.704, (0.648-0.755), Stereo Fly: 0.780, (0.714-0.837), Frisby: 0.754 (0.688-0.812), p < 0.02, n = 91, DeLong's method). At the optimum ROC point, McNemar's test indicated significantly higher sensitivity in accord with AUCs. Moreover, the AI solution had significantly higher sensitivity than TNO (p = 0.046, N = 134, Fisher's test), as well, while the specificity did not differ. Discussion: The combination of multiple tests utilizing anaglyphic random dot stereograms with varying parameters (density, noise, dynamism) in AI leads to the most advanced and sensitive screening test for identifying amblyopia and amblyogenic conditions compared to all the other tests studied.

Age-related decline in circulating IGF-1 associates with impaired neurovascular coupling responses in older adults.

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) to the increased oxygen and energy requirements of active brain regions via neurovascular coupling (NVC) contributes to the genesis of age-related cognitive impairment. Aging is associated with marked deficiency in the vasoprotective hormone insulin-like growth factor-1 (IGF-1). Preclinical studies on animal models of aging suggest that circulating IGF-1 deficiency is causally linked to impairment of NVC responses. The present study was designed to test the hypotheses that decreases in circulating IGF-1 levels in older adults also predict the magnitude of age-related decline of NVC responses. In a single-center cross-sectional study, we enrolled healthy young (n = 31, 11 female, 20 male, mean age: 28.4 + / - 4.2 years) and aged volunteers (n = 32, 18 female, 14 male, mean age: 67.9 + / - 4.1 years). Serum IGF-1 level, basal CBF (phase contrast magnetic resonance imaging (MRI)), and NVC responses during the trail making task (with transcranial Doppler sonography) were assessed. We found that circulating IGF-1 levels were significantly decreased with age and associated with decreased basal CBF. Age-related decline in IGF-1 levels predicted the magnitude of age-related decline in NVC responses. In conclusion, our study provides additional evidence in support of the concept that age-related circulating IGF-1 deficiency contributes to neurovascular aging, impairing CBF and functional hyperemia in older adults.

The Effect of Mild Traumatic Brain Injury on Cerebral Microbleeds in Aging.

A traumatic brain injury (TBI) induces the formation of cerebral microbleeds (CMBs), which are associated with cognitive impairments, psychiatric disorders, and gait dysfunctions in patients. Elderly people frequently suffer TBIs, especially mild brain trauma (mTBI). Interestingly, aging is also an independent risk factor for the development of CMBs. However, how TBI and aging may interact to promote the development of CMBs is not well established. In order to test the hypothesis that an mTBI exacerbates the development of CMBs in the elderly, we compared the number and cerebral distribution of CMBs and assessed them by analysing susceptibility weighted (SW) MRI in young (25 ± 10 years old, n = 18) and elder (72 ± 7 years old, n = 17) patients after an mTBI and in age-matched healthy subjects (young: 25 ± 6 years old, n = 20; aged: 68 ± 5 years old, n = 23). We found significantly more CMBs in elder patients after an mTBI compared with young patients; however, we did not observe a significant difference in the number of cerebral microhemorrhages between aged and aged patients with mTBI. The majority of CMBs were found supratentorially (lobar and basal ganglion). The lobar distribution of supratentorial CMBs showed that aging enhances the formation of parietal and occipital CMBs after mTBIs. This suggests that aging and mTBIs do not synergize in the induction of the development of CMBs, and that the different distribution of mTBI-induced CMBs in aged patients may lead to specific age-related clinical characteristics of mTBIs.

Errors and Consequences of Inaccurate Estimation of Mean Blood Flow Velocity in Cerebral Arteries.

Many transcranial Doppler ultrasonography devices estimate the mean flow velocity (FVm) by using the traditional formula (FVsystolic + 2 × FVdiastolic)/3 instead of a more accurate formula calculating it as the time integral of the current flow velocities divided by the integration period. We retrospectively analyzed flow velocity and intracranial pressure signals containing plateau waves (transient intracranial hypertension), which were collected from 14 patients with a traumatic brain injury. The differences in FVm and its derivative pulsatility index (PI) calculated with the two different methods were determined. We found that during plateau waves, when the intracranial pressure (ICP) rose, the error in FVm and PI increased significantly from the baseline to the plateau (from 4.6 ± 2.4 to 9.8 ± 4.9 cm/s, P < 0.05). Similarly, the error in PI also increased during plateau waves (from 0.11 ± 0.07 to 0.44 ± 0.24, P < 0.005). These effects were most likely due to changes in the pulse waveform during increased ICP, which alter the relationship between systolic, diastolic, and mean flow velocities. If a change in the mean ICP is expected, then calculation of FVm with the traditional formula is not recommended.

Cerebrovascular Consequences of Elevated Intracranial Pressure After Traumatic Brain Injury.

We compared various descriptors of cerebral hemodynamics in 517 patients with traumatic brain injury (TBI) who had, on average, elevated (>23 mmHg) or normal (<15 mmHg) intracranial pressure (ICP). In a subsample of 193 of those patients, transcranial Doppler ultrasound (TCD) recordings were made. Arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), cerebral autoregulation indices based on TCD (the mean flow index (Mx; the coefficient of correlation between the the cerebral perfusion pressure CPP and flow velocity) and the autoregulation index (ARI)), and the pressure reactivity index (PRx) were compared between groups. We also analyzed the TCD-based cerebral blood flow (CBF) index (diastolic CBFV/mean CBFV), the spectral pulsatility index (sPI), and the critical closing pressure (CrCP). Finally, we also looked at brain tissue oxygenation (cerebral oxygen partial tension (PbtO2)) in 109 patients. The mean cerebral perfusion pressure (CPP) was lower in the group with elevated ICP (p < 0.01), despite a higher mean arterial pressure (MAP) (p < 0.005) and worse autoregulation (as assessed with the Mx, ARI, and PRx indices), greater CrCP, a lower CBF index, and a higher sPI (all with p values of <0.001). Neither the mean CBFV nor PbtO2 reached significant differences between groups. Mortality in the group with elevated ICP was almost three times greater than that in the group with normal ICP (45% versus 17%). Elevated ICP affects cerebral autoregulation. When autoregulation is not working properly, the brain is exposed to ischemic insults whenever CPP falls.

Usability of Noninvasive Counterparts of Traditional Autoregulation Indices in Traumatic Brain Injury.

The pressure reactivity index (PRx) and the pulse amplitude index (PAx) are invasively determined parameters that are commonly used to describe autoregulation following traumatic brain injury (TBI). Using a transcranial Doppler ultrasound (TCD) technique, it is possible to approximate cerebral arterial blood volume (CaBV) solely from cerebral blood flow velocities, and further, to calculate non-invasive markers of autoregulation. In this brief study, we aimed to investigate whether the estimation of relative CaBV with different models could describe the cerebrovascular reactivity of TBI patients. PRx, PAx and their non-invasive counterparts (nPRx and nPAx) were calculated retrospectively from data collected during the monitoring of TBI patients. CaBV, an essential parameter for the calculation of nPRx and nPAx, was determined with both a continuous flow forward (CFF) model-considering a non-pulsatile blood outflow from the brain-and a pulsatile flow forward (PFF) model, presuming a pulsatile outflow. We found that the estimated CaBV demonstrates good coherence with ICP and that nPRx and nPAx can describe cerebrovascular reactivity similarly to PRx and PAx. Continuous monitoring with TCD is difficult, so the usability of PRx and PAx is limited. However, they might become useful for clinicians in the near future owing to rapid advances in these technologies.

Optimal Cerebral Perfusion Pressure Assessed with a Multi-Window Weighted Approach Adapted for Prospective Use: A Validation Study.

BACKGROUND: Pressure reactivity index (PRx)-cerebral perfusion pressure (CPP) relationships over a given time period can be used to detect a value of CPP at which PRx shows the best autoregulation (optimal CPP, or CPPopt). Algorithms for continuous assessment of CPPopt in traumatic brain injury (TBI) patients reached the desired high yield with a multi-window approach (CPPopt_MA). However, the calculations were tested on retrospective manually cleaned datasets. Moreover, CPPopt false-positive values can be generated from non-physiological variations of intracranial pressure (ICP) and arterial blood pressure (ABP). Therefore, the algorithm robustness was improved, making it suitable for prospective bedside application (COGiTATE trial). OBJECTIVE: To validate the CPPopt revised algorithm in a large single-centre retrospective cohort of TBI patients. METHODS: 840 TBI patients were included. CPPopt yield, stability and ability to discriminate outcome groups were compared to CPPopt_MA and the Brain Trauma Foundation (BTF) guideline reference. RESULTS: CPPopt yield was lower than CPPopt_MA yield (85% and 90%, p < 0.001), but, importantly, with increased stability (p < 0.0001). The ∆(CPP-CPPopt) could distinguish the mortality and survival outcome (t = -6.7, p < 0.0001) with a statistical significance higher than the ∆CPP calculated with the guideline reference (CPP-60) (t = -4.5, p < 0.0001). CONCLUSION: This study validates, on a large cohort of patients, the new algorithm proposed for prospective use of CPPopt as a CPP target at bedside.

Methodological Consideration on Monitoring Refractory Intracranial Hypertension and Autonomic Nervous System Activity.

Refractory intracranial hypertension (RIH) refers to a dramatic increase in intracranial pressure (ICP) that cannot be controlled by treatment and leads to patient death. Detrimental sequelae of raised ICP in acute brain injury (ABI) are unclear because the underlying physiopathological mechanisms of raised ICP have not been sufficiently investigated. Recent reports have shown that autonomic activity is altered during changes in ICP. The aim of our study was to evaluate the feasibility of assessing autonomic activity during RIH with our adopted methodology. We selected 24 ABI patients for retrospective review who developed RIH. They were monitored based on ICP, arterial blood pressure, and electrocardiogram using ICM+ software. Secondary parameters reflecting autonomic activity were computed in time and frequency domains through the continuous measurement of heart rate variability and baroreflex sensitivity. The results of the analysis will be presented later in a full paper. This preliminary analysis shows the feasibility of the adopted methodology.

Effect of Growth Hormone on Neuropsychological Outcomes and Quality of Life of Patients with Traumatic Brain Injury: A Systematic Review.

One of the most devastating chronic consequences of traumatic brain injury (TBI) is cognitive impairment. One of the possible underlying causes is growth hormone deficiency (GHD) caused by TBI-induced hypopituitarism. Currently, TBI patients are not routinely screened for pituitary function, and there are no standard therapies when GHD is diagnosed. Further, the possible positive effects of GH replacement on cognitive function and quality of life after TBI are not well established. We aimed to assess the current knowledge regarding the effect of GH therapy on cognitive function and quality of life after TBI. We performed a literature search in PubMed, Embase, and Central® databases from inception to October 2019. We extracted data on each term of severity (mild-moderate-severe) of TBI with and without GHD, time since injury, parameters of growth hormone treatment (dosing, length), and cognitive outcomes in terms of verbal and non-verbal memory, and executive, emotional, and motor functions, and performed a meta-analysis on the results of a digit span test assessing working memory. We identified 12 studies (containing two randomized controlled trials) with 264 mild-to-moderate-to-severe TBI patients (Glasgow Coma Score [GCS] varied between 6 and 15) with (n = 255) or without (n = 9) GHD who received GH therapy. GH was administered subcutaneously in gradually increasing doses, monitoring serum insulin-like growth factor-I (IGF-I) level. After TBI, regardless of GCS, 6-12 months of GH therapy, started in the chronic phase post-TBI, induced a moderate improvement in processing speed and memory capacities, decreased the severity of depression, and led to a marked improvement in quality of life. Limitations include the relatively low number of patients involved and the divergent neuropsychological tests used. These results indicate the need for further multi-centric controlled studies to substantiate the use of GH replacement therapy as a potential tool to alleviate TBI-related cognitive impairment and improve quality of life.

Autonomic Nervous System Activity during Refractory Rise in Intracranial Pressure.

Refractory intracranial hypertension (RIH) is a dramatic increase in intracranial pressure (ICP) that cannot be controlled by treatment. Recent reports suggest that the autonomic nervous system (ANS) activity may be altered during changes in ICP. Our study aimed to assess ANS activity during RIH and the causal relationship between rising in ICP and autonomic activity. We reviewed retrospectively 24 multicenter (Cambridge, Tromso, Berlin) patients in whom RIH developed as a pre-terminal event after acute brain injury (ABI). They were monitored with ICP, arterial blood pressure (ABP), and electrocardiography (ECG) using ICM+ software. Parameters reflecting autonomic activity were computed in time and frequency domain through the measurement of heart rate variability (HRV) and baroreflex sensitivity (BRS). Our results demonstrated that a rise in ICP was associated to a significant rise in HRV and BRS with a higher significance level in the high-frequency HRV (p < 0.001). This increase was followed by a significant decrease in HRV and BRS above the upper-breakpoint of ICP where ICP pulse-amplitude starts to decrease whereas the mean ICP continues to rise. Temporality measured with a Granger test suggests a causal relationship from ICP to ANS. The above results suggest that a rise in ICP interacts with ANS activity, mainly interfacing with the parasympathetic-system. The ANS seems to react to the rise in ICP with a response possibly focused on maintaining the cerebrovascular homeostasis. This happens until the critical threshold of ICP is reached above which the ANS variables collapse, probably because of low perfusion of the brain and the central autonomic network.

Traumatic brain injury-induced cerebral microbleeds in the elderly.

Traumatic brain injury (TBI) was shown to lead to the development of cerebral microbleeds (CMBs), which are associated with long term cognitive decline and gait disturbances in patients. The elderly is one of the most vulnerable parts of the population to suffer TBI. Importantly, ageing is known to exacerbate microvascular fragility and to promote the formation of CMBs. In this overview, the effect of ageing is discussed on the development and characteristics of TBI-related CMBs, with special emphasis on CMBs associated with mild TBI. Four cases of TBI-related CMBs are described to illustrate the concept that ageing exacerbates the deleterious microvascular effects of TBI and that similar brain trauma may induce more CMBs in old patients than in young ones. Recommendations are made for future prospective studies to establish the mechanistic effects of ageing on the formation of CMBs after TBI, and to determine long-term consequences of CMBs on clinically relevant outcome measures including cognitive performance, gait and balance function.

Circulating Brain Injury Exosomal Proteins following Moderate-To-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications.

Brain injury exosomal proteins are promising blood biomarker candidates in traumatic brain injury (TBI). A better understanding of their role in the diagnosis, characterization, and management of TBI is essential for upcoming clinical implementation. In the current investigation, we aimed to explore longitudinal trajectories of brain injury exosomal proteins in blood of patients with moderate-to-severe TBI, and to evaluate the relation with the free-circulating counterpart and patient imaging and clinical parameters. Exosomal levels of glial (glial fibrillary acidic protein (GFAP)) and neuronal/axonal (ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light chain (NFL), and total-tau (t-tau)) proteins were measured in serum of 21 patients for up 5 days after injury using single molecule array (Simoa) technology. Group-based trajectory analysis was used to generate distinct temporal exosomal biomarker profiles. We found altered profiles of serum brain injury exosomal proteins following injury. The dynamics and levels of exosomal and related free-circulating markers, although correlated, showed differences. Patients with diffuse injury displayed higher acute exosomal NFL and GFAP concentrations in serum than those with focal lesions. Exosomal UCH-L1 profile characterized by acutely elevated values and a secondary steep rise was associated with early mortality (n = 2) with a sensitivity and specificity of 100%. Serum brain injury exosomal proteins yielded important diagnostic and prognostic information and represent a novel means to unveil underlying pathophysiology in patients with moderate-to-severe TBI. Our findings support their utility as potential tools to improve patient phenotyping in clinical practice and therapeutic trials.

Prostaglandin E2, a postulated mediator of neurovascular coupling, at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles.

There is considerable controversy regarding the vasoactive action of prostaglandin E2 (PGE2). On the one hand, indirect evidence implicates that astrocytic release of PGE2 contributes to neurovascular coupling responses mediating functional hyperemia in the brain. On the other hand, overproduction of PGE2 was also reported to contribute to cerebral vasospasm associated with subarachnoid hemorrhage. The present study was conducted to resolve this controversy by determining the direct vasoactive effects of PGE2 in resistance-sized human cerebral parenchymal arterioles. To achieve this goal PGE2-induced isotonic vasomotor responses were assessed in parenchymal arterioles isolated from fronto-temporo-parietal cortical tissues surgically removed from patients and expression of PGE2 receptors were examined. In functionally intact parenchymal arterioles lower concentrations of PGE2 (from 10-8 to 10-6 mol/l) caused significant, endothelium-independent vasorelaxation, which was inhibited by the EP4 receptor blocker BGC201531. In contrast, higher concentrations of PGE2 evoked significant EP1-dependent vasoconstriction, which could not be reversed by the EP4 receptor agonist CAY10598. We also confirmed previous observations that PGE2 primarily evokes constriction in intracerebral arterioles isolated from R. norvegicus. Importantly, vascular mRNA and protein expression of vasodilator EP4 receptors was significantly higher than that of vasoconstrictor EP1 receptors in human cerebral arterioles. PGE2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles. This bimodal vasomotor response is consistent with both the proposed vasodilator role of PGE2 during functional hyperemia and its putative role in cerebral vasospasm associated with subarachnoid hemorrhage in human patients.

Validation of non-invasive cerebrovascular pressure reactivity and pulse amplitude reactivity indices in traumatic brain injury.

BACKGROUND: Two transcranial Doppler (TCD) estimators of cerebral arterial blood volume (CaBV) coexist: continuous outflow of arterial blood outside the cranium through a low-pulsatile venous system (continuous flow forward, CFF) and pulsatile outflow through regulating arterioles (pulsatile flow forward, PFF). We calculated non-invasive equivalents of the pressure reactivity index (PRx) and the pulse amplitude index PAx with slow waves of mean CaBV and its pulse amplitude. METHODS: About 273 individual TBI patients were retrospectively reviewed. PRx is the correlation coefficient between 30 samples of 10-second averages of ICP and mean ABP. PAx is the correlation coefficient between 30 samples of 10-second averages of the amplitude of ICP (AMP, derived from Fourier analysis of the raw full waveform ICP tracing) and mean ABP. nPRx is calculated with CaBV instead of ICP and nPAx with the pulse amplitude of CaBV instead of AMP (calculated using both the CFF and PFF models). All reactivity indices were additionally compared with Glasgow Outcome Score (GOS) to verify potential outcome-predictive strength. RESULTS: When correlated, slow waves of ICP demonstrated good coherence between slow waves in CaBV (>0.75); slow waves of AMP showed good coherence with slow waves of the pulse amplitude of CaBV (>0.67) in both the CFF and PFF models. nPRx was moderately correlated with PRx (R = 0.42 for CFF and R = 0.38 for PFF; p < 0.0001). nPAx correlated with PAx with slightly better strength (R = 0.56 for CFF and R = 0.41 for PFF; p < 0.0001). nPAx_CFF showed the strongest association with outcomes. CONCLUSIONS: Non-invasive estimators (nPRx and nPAx) are associated with their invasive counterparts and can provide meaningful associations with outcome after TBI. The CFF model is slightly superior to the PFF model.

Hypertension Exacerbates Cerebrovascular Oxidative Stress Induced by Mild Traumatic Brain Injury: Protective Effects of the Mitochondria-Targeted Antioxidative Peptide SS-31.

Traumatic brain injury (TBI) induces cerebrovascular oxidative stress, which is associated with neurovascular uncoupling, autoregulatory dysfunction, and persisting cognitive decline in both pre-clinical models and patients. However, single mild TBI (mTBI), the most frequent form of brain trauma, increases cerebral generation of reactive oxygen species (ROS) only transiently. We hypothesized that comorbid conditions might exacerbate long-term ROS generation in cerebral arteries after mTBI. Because hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive and spontaneously hypertensive rats (SHR) and assessed changes in cytoplasmic and mitochondrial superoxide (O2-) production by confocal microscopy in isolated middle cerebral arteries (MCA) 2 weeks after mTBI using dihydroethidine (DHE) and the mitochondria-targeted redox-sensitive fluorescent indicator dye MitoSox. We found that mTBI induced a significant increase in long-term cytoplasmic and mitochondrial O2- production in MCAs of SHRs and increased expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit Nox4, which were reversed to the normal level by treating the animals with the cell-permeable, mitochondria-targeted antioxidant peptide SS-31 (5.7 mg kg-1 day-1, i.p.). Persistent mTBI-induced oxidative stress in MCAs of SHRs was significantly decreased by inhibiting vascular NADPH oxidase (apocyinin). We propose that hypertension- and mTBI-induced cerebrovascular oxidative stress likely lead to persistent dysregulation of cerebral blood flow (CBF) and cognitive dysfunction, which might be reversed by SS-31 treatment.

Single Mild Traumatic Brain Injury Induces Persistent Disruption of the Blood-Brain Barrier, Neuroinflammation and Cognitive Decline in Hypertensive Rats.

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1ß and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI.

Validation of dynamic random dot stereotests in pediatric vision screening.

PURPOSE: Stereo vision tests are widely used in the clinical practice for screening amblyopia and amblyogenic conditions. According to literature, none of these tests seems to be suitable to be used alone as a simple and reliable tool. There has been a growing interest in developing new types of stereo vision tests, with sufficient sensitivity to detect amblyopia. This new generation of assessment tools should be computer based, and their reliability must be statistically warranted. The present study reports the clinical evaluation of a screening system based on random dot stereograms using a tablet as display. Specifically, a dynamic random dot stereotest with binocularly detectable Snellen-E optotype (DRDSE) was used and compared with the Lang II stereotest. METHODS: A total of 141 children (aged 4-14, mean age 8.9) were examined in a field study at the Department of Ophthalmology, Pécs, Hungary. Inclusion criteria consisted of diagnoses of amblyopia, anisometropia, convergent strabismus, and hyperopia. Children with no ophthalmic pathologies were also enrolled as controls. All subjects went through a regular pediatric ophthalmological examination before proceeding to the DRDSE and Lang II tests. RESULTS: DRDSE and Lang II tests were compared in terms of sensitivity and specificity for different conditions. DRDSE had a 100% sensitivity both for amblyopia (n = 11) and convergent strabismus (n = 21), as well as a 75% sensitivity for hyperopia (n = 36). However, the performance of DRDSE was not statistically significant when screening for anisometropia. On the other hand, Lang II proved to have 81.8% sensitivity for amblyopia, 80.9% for strabismus, and only 52.8% for hyperopia. The specificity of DRDSE was 61.2% for amblyopia, 67.3% for strabismus, and 68.6% for hyperopia, respectively. Conversely, Lang II showed about 10% better specificity, 73.8% for amblyopia, 79.2% for strabismus, and 77.9% for hyperopia. CONCLUSIONS: The DRDSE test has a better sensitivity for the detection of conditions such as amblyopia or convergent strabismus compared with Lang II, although with slightly lower specificity. If the specificity could be further improved by optimization of the stimulus parameters, while keeping the sensitivity high, DRDSE would be a promising stereo vision test for screening of amblyopia.

Correction: Simple reaction times to cyclopean stimuli reveal that the binocular system is tuned to react faster to near than to far objects.

[This corrects the article DOI: 10.1371/journal.pone.0188895.].