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Neuroimaging biomarkers that can detect white matter (WM) pathology after mild traumatic brain injury (mTBI) and predict long-term outcome are needed to improve care and develop therapies. We used diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate WM microstructure cross-sectionally and longitudinally after mTBI and correlate these with neuropsychological performance. Cross-sectionally, early decreases of fractional anisotropy and increases of mean diffusivity corresponded to WM regions with elevated free water fraction on NODDI. This elevated free water was more extensive in the patient subgroup reporting more early postconcussive symptoms. The longer-term longitudinal WM changes consisted of declining neurite density on NODDI, suggesting axonal degeneration from diffuse axonal injury for which NODDI is more sensitive than DTI. Therefore, NODDI is a more sensitive and specific biomarker than DTI for WM microstructural changes due to mTBI that merits further study for mTBI diagnosis, prognosis, and treatment monitoring.

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BACKGROUND AND PURPOSE: In blunt traumatic brain injury with isolated falcotentorial subdural hematoma not amenable to neurosurgical intervention, the routinely performed, nonvalidated practice of serial head CT scans frequently necessitates increased hospital resources and exposure to ionizing radiation. The study goal was to evaluate clinical and imaging features of isolated falcotentorial subdural hematoma at presentation and short-term follow-up. MATERIALS AND METHODS: We performed a retrospective analysis of patients presenting to a level 1 trauma center from January 2013 to March 2015 undergoing initial and short-term follow-up CT with initial findings positive for isolated subdural hematoma along the falx and/or tentorium. Patients with penetrating trauma, other sites of intracranial hemorrhage, or depressed skull fractures were excluded. Patient sex, age, Glasgow Coma Scale score, and anticoagulation history were obtained through review of the electronic medical records. RESULTS: Eighty patients met the inclusion criteria (53 males; 27 females; median age, 61 years). Of subdural hematomas, 57.1% were falcine, 33.8% were tentorial, and 9.1% were mixed. The mean initial Glasgow Coma Scale score was 14.2 (range, 6-15). Isolated falcotentorial subdural hematomas were small (mean, 2.8 mm; range, 1-8 mm) without mass effect and significant change on follow-up CT (mean, 2.7 mm; range, 0-8 mm; P = .06), with an average follow-up time of 10.3 hours (range, 3.9-192 hours). All repeat CTs demonstrated no change or decreased size of the initial subdural hematoma. No new intracranial hemorrhages were seen on follow-up CT. CONCLUSIONS: Isolated falcotentorial subdural hematomas in blunt traumatic brain injury average 2.8 mm in thickness and do not increase in size on short-term follow-up CT. Present data suggest that repeat CT in patients with mild traumatic brain injury with isolated falcotentorial subdural hematoma may not be necessary.

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BACKGROUND AND PURPOSE: Acute markers of spinal cord injury are essential for both diagnostic and prognostic purposes. The goal of this study was to assess the relationship between early MR imaging biomarkers after acute cervical spinal cord injury and to evaluate their predictive validity of neurologic impairment. MATERIALS AND METHODS: We performed a retrospective cohort study of 95 patients with acute spinal cord injury and preoperative MR imaging within 24 hours of injury. The American Spinal Injury Association Impairment Scale was used as our primary outcome measure to define neurologic impairment. We assessed several MR imaging features of injury, including axial grade (Brain and Spinal Injury Center score), sagittal grade, length of injury, maximum canal compromise, and maximum spinal cord compression. Data-driven nonlinear principal component analysis was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment. RESULTS: Nonlinear principal component analysis identified 2 clusters of MR imaging variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MR imaging measures of intrinsic cord signal abnormality, with axial grade representing the most accurate predictor of short-term impairment, even when correcting for surgical decompression and degree of cord compression. CONCLUSIONS: This study demonstrates the utility of applying nonlinear principal component analysis for defining the relationship between MR imaging biomarkers in a complex clinical syndrome of cervical spinal cord injury. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute spinal cord injury, highlighting the value of axial T2 MR imaging.

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BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) may be a useful index of microstructural changes implicated in diffuse axonal injury (DAI) linked to persistent postconcussive symptoms, especially in mild traumatic brain injury (TBI), for which conventional MR imaging techniques may lack sensitivity. We hypothesized that for mild TBI, DTI measures of DAI would correlate with impairments in reaction time, whereas the number of focal lesions on conventional 3T MR imaging would not. MATERIALS AND METHODS: Thirty-four adult patients with mild TBI with persistent symptoms were assessed for DAI by quantifying traumatic microhemorrhages detected on a conventional set of T2*-weighted gradient-echo images and by DTI measures of fractional anisotropy (FA) within a set of a priori regions of interest. FA values 2.5 SDs below the region average, based on a group of 26 healthy control adults, were coded as exhibiting DAI. RESULTS: DTI measures revealed several predominant regions of damage including the anterior corona radiata (41% of the patients), uncinate fasciculus (29%), genu of the corpus callosum (21%), inferior longitudinal fasciculus (21%), and cingulum bundle (18%). The number of damaged white matter structures as quantified by DTI was significantly correlated with mean reaction time on a simple cognitive task (r = 0.49, P = .012). In contradistinction, the number of traumatic microhemorrhages was uncorrelated with reaction time (r = -0.08, P = .71). CONCLUSION: Microstructural white matter lesions detected by DTI correlate with persistent cognitive deficits in mild TBI, even in populations in which conventional measures do not. DTI measures may thus contribute additional diagnostic information related to DAI.

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Aquaporins are intrinsic membrane proteins involved in water transport in fluid-transporting tissues. In the brain, aquaporin-4 (AQP4) is expressed widely by glial cells, but its function is unclear. Extensive basic and clinical studies indicate that osmolarity affects seizure susceptibility, and in our previous studies we found that AQP4 -/- mice have an elevated seizure threshold in response to the chemoconvulsant pentylenetetrazol. In this study, we examined the seizure phenotype of AQP4 -/- mice in greater detail using in vivo electroencephalographic recording. AQP4 -/- mice were found to have dramatically longer stimulation-evoked seizures following hippocampal stimulation as well as a higher seizure threshold. These results implicate AQP4 in water and potassium regulation associated with neuronal activity and seizures.

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Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain and spinal cord suggests a role in water transport under normal and pathological conditions. Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role of AQP4 in cerebral water balance and neural signal transduction. Primary cultures of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability compared with wild-type astrocytes, indicating that AQP4 is the principal water channel in these cells. AQP4-null mice have reduced brain swelling and improved neurological outcome following water intoxication and focal cerebral ischemia, establishing a role of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem response potentials and significantly increased seizure threshold in response to chemical convulsants, implicating AQP4 in modulation of neural signal transduction. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the CNS associated with altered brain water balance.

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Despite their diverse histological types, most brain tumours cause brain oedema, which is a significant cause of patient morbidity and mortality. Brain tumour oedema occurs when plasma-like fluid enters the brain extracellular space through impaired capillary endothelial tight junctions in tumours. Under-expression of the tight junction proteins occludin, claudin-1 and claudin-5 are key molecular abnormalities responsible for the increased permeability of tumour endothelial tight junctions. Recent evidence suggests that the membrane water channel protein aquaporin-4 (AQP4) also plays a role in brain tumour oedema. AQP4-deficient mice show remarkably altered brain water balance after various insults, including brain tumour implantation. AQP4 expression is strongly upregulated around malignant human brain tumours in association with reduced extracellular volume, which may restrict the flow of extracellular fluid from the tumour bed into the brain parenchyma. Elimination of excess fluid leaking into brain parenchyma requires passage across three AQP4-rich barriers: a) the glia limitans externa, b) the glia limitans interna/ependyma, and c) the blood-brain barrier. Modulation of the expression and/or function of endothelial tight junction proteins and aquaporins may provide novel therapeutic options for reducing brain tumour oedema.

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Aquaporins (AQPs) are membrane proteins involved in water transport in many fluid-transporting tissues. Aquaporins AQP1, AQP4, and AQP9 have been identified in brain and hypothesized to participate in brain water homeostasis. Here we use reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry to describe the expression and immunolocalization of AQPs in adult mouse spinal cord. AQP4 was expressed in glial cells, predominantly in gray matter, and in astrocytic end-feet surrounding capillaries in spinal cord white matter. AQP9 expression extensively co-localized with glial fibrillary acidic protein-immunoreactive astrocytes, located predominantly in the white matter. AQP5 was detected by RT-PCR but not by immunohistochemical analysis. Interestingly, AQP8 was detected primarily in ependymal cells lining the fluid-filled central canal. The aquaporin expression pattern in spinal cord suggests involvement in water homeostasis and diseases associated with abnormal water fluxes such as spinal cord injury and syringomyelia.

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Aquaporins are membrane proteins involved in water transport in many fluid-transporting tissues. The objective of this study was to investigate the expression of aquaporins in malignant glial tumors associated with cerebral edema. Eighteen human glial tumors were obtained from the UCSF Neurosurgery Tissue Bank. Aquaporin-1 (AQP1) expression was evaluated via Western blot and immunohistochemistry. Intense upregulation of AQP1 expression was found in all glioblastomas. The robust expression of aquaporins in glioblastomas suggests a pathologic role for these membrane water channels, and raises the possibility that selective AQP inhibition might offer a new therapeutic option for tumor-associated cerebral edema.

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Aquaporin-1 (AQP1) is a water channel that is strongly expressed at the ventricular-facing surface of choroid plexus epithelium. Using wildtype and AQP1 null mice, we developed novel methods to compare the water permeability in isolated choroid plexus, and cerebrospinal fluid (CSF) production in living mice. Osmotically-induced water transport was rapid in freshly isolated choroid plexus from wildtype mice as measured by a spatial-filtering optical method, and reduced by 5-fold by AQP1 deletion. CSF production, an isosmolar fluid secretion process, was measured by a dye dilution method involving fluid collections using a second microneedle introduced into the cisterna magna. CSF production in wildtype mice was (in microl/min) 0.37 +/- 0.04 microl/min (control), 0.16 +/- 0.03 microl/min (acetazolamide-treated) and 1.14 +/- 0.15 microl/min (forskolin-treated), and reduced by up to 25% in AQP1 null mice. The impaired CSF production in AQP1 null mice provides direct functional evidence for the involvement of AQP1 in CSF formation.

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BACKGROUND: Retrospective studies have suggested an association between systemic hypotension and hypoxia and worsened outcome from traumatic brain injury. Little is known, however, about the frequency and duration of these potentially preventable causes of secondary brain injury. HYPOTHESIS: Early episodes of hypoxia and hypotension occurring during initial resuscitation will have a significant impact on outcome following traumatic brain injury. DESIGN: Prospective cohort study. SETTING: Urban level I trauma center. PATIENTS: Patients with a traumatic brain injury who had a Glasgow Coma Score of 12 or less within the first 24 hours of admission to the hospital and computed tomographic scan results demonstrating intracranial pathologic features. Patients who died in the emergency department were excluded from the study. MAIN OUTCOME MEASURES: Automated blood pressure and pulse oximetry readings were collected prospectively from the time of arrival through initial resuscitation. The number and duration of hypotensive (systolic blood pressure, < or =90 mm Hg) and hypoxic (oxygen saturation, < or =92%) events were analyzed for their association with mortality and neurological outcome. RESULTS: One hundred seven patients met the enrollment criteria (median Glasgow Coma Score, 7). Overall mortality was 43%. Twenty-six patients (24%) had hypotension while in the emergency department, with an average of 1.5 episodes per patient (mean duration, 9.1 minutes). Of these 26 patients with hypotension, 17 (65%) died (P =.01). When the number of hypotensive episodes increased from 1 to 2 or more, the odds ratio for death increased from 2.1 to 8.1. Forty-one patients (38%) had hypoxia, with an average of 2.1 episodes per patient (mean duration, 8.7 minutes). Of these 41 patients with hypoxia, 18 (44%) died (P =.68). CONCLUSIONS: Hypotension, but not hypoxia, occurring in the initial phase of resuscitation is significantly (P =.009) associated with increased mortality following brain injury, even when episodes are relatively short. These prospective data reinforce the need for early continuous monitoring and improved treatment of hypotension in brain-injured patients.

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The last two decades have produced a great deal of evidence that in the mammalian organ of Corti outer hair cells undergo active shape changes that are part of a "cochlear amplifier" mechanism that increases sensitivity and frequency selectivity of the hearing epithelium. However, many signs of active processes have also been found in nonmammals, raising the question as to the ancestry and commonality of these mechanisms. Active movements would be advantageous in all kinds of sensory hair cells because they help signal detection at levels near those of thermal noise and also help to overcome fluid viscosity. Such active mechanisms therefore presumably arose in the earliest kinds of hair cells that were part of the lateral line system of fish. These cells were embedded in a firm epithelium and responded to relative motion between the hair bundle and the hair cell, making it highly likely that the first active motor mechanism was localized in the hair-cell bundle. In terrestrial nonmammals, there are many auditory phenomena that are best explained by the presence of a cochlear amplifier, indicating that in this respect the mammalian ear is not unique. The latest evidence supports siting the active process in nonmammals in the hair-cell bundle and in intimate association with the transduction process.

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PURPOSE: To compare the efficacy of a vaginal insert administering continuous dinoprostone with vaginal suppositories containing two different doses of misoprostol for cervical ripening and induction of labor. STUDY DESIGN: In this prospective, randomized, double-blinded study, 118 patients with indications for induction of labor and an unfavorable Bishop score were randomly assigned to receive either continuous dinoprostone, misoprostol 35-microg suppositories, or misoprostol 50-microg suppositories. RESULTS: No significant differences were noted among the three groups in the change of Bishop score, induction of active labor or the time from initial treatment to delivery. Active labor occurred in roughly two-thirds of the patients in an average of about 5.7-6.7 h regardless of treatment assignment. When the two misoprostol groups were combined, a shorter interval from insertion to vaginal delivery was observed in the nulliparous women receiving misoprostol than those receiving continuous dinoprostone (21.3 vs. 27.2 h, p = 0.019). Except for the significantly lower incidence of tachysystole observed in the combined misoprostol group (3.8% vs. 15.4%, p = 0.036), there were no other significant differences between the groups in mode of delivery or in adverse maternal, fetal, or neonatal effects. CONCLUSION: Misoprostol suppositories appeared to be as effective and safe as continuous dinoprostone in inducing cervical ripening in this sample.

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BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) constitutes 10% to 15% of all strokes and remains without a treatment of proven benefit. Despite several existing outcome prediction models for ICH, there is no standard clinical grading scale for ICH analogous to those for traumatic brain injury, subarachnoid hemorrhage, or ischemic stroke. METHODS: Records of all patients with acute ICH presenting to the University of California, San Francisco during 1997-1998 were reviewed. Independent predictors of 30-day mortality were identified by logistic regression. A risk stratification scale (the ICH Score) was developed with weighting of independent predictors based on strength of association. RESULTS: Factors independently associated with 30-day mortality were Glasgow Coma Scale score (P<0.001), age >/=80 years (P=0.001), infratentorial origin of ICH (P=0.03), ICH volume (P=0.047), and presence of intraventricular hemorrhage (P=0.052). The ICH Score was the sum of individual points assigned as follows: GCS score 3 to 4 (=2 points), 5 to 12 (=1), 13 to 15 (=0); age >/=80 years yes (=1), no (=0); infratentorial origin yes (=1), no (=0); ICH volume >/=30 cm(3) (=1), <30 cm(3) (=0); and intraventricular hemorrhage yes (=1), no (=0). All 26 patients with an ICH Score of 0 survived, and all 6 patients with an ICH Score of 5 died. Thirty-day mortality increased steadily with ICH Score (P<0.005). CONCLUSIONS: The ICH Score is a simple clinical grading scale that allows risk stratification on presentation with ICH. The use of a scale such as the ICH Score could improve standardization of clinical treatment protocols and clinical research studies in ICH.

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OBJECTIVE: To describe the normal relationships between brain tissue oxygen tension (PbrO2) and physiological parameters of systemic blood pressure and CO2 concentrations. METHODS: Licox Clark-type oxygen probes (GMS mbH, Kiel, Germany) were inserted in the frontal white matter of 12 swine maintained under general anesthesia with a 1.0 fraction of inspired oxygen (FiO2). In seven swine, alterations in end-tidal carbon dioxide (ET-CO2) concentration (range, 13-72 mm Hg) were induced via hyperventilation or instillation of CO2 into the ventilation circuit. In nine swine, mean arterial pressure (MAP) (range, 33-200 mm Hg) was altered; phenylephrine was used to induce hypertension, and a nitroprusside-esmolol combination or systemic hemorrhage was used for hypotension. Quantitative cerebral blood flow (CBF) was measured in two animals by using a thermal diffusion probe. RESULTS: Mean baseline PbrO2 was 41.9 +/- 11.3 mm Hg. PbrO2 varied linearly with changes in ET-CO2, ranging from 20 to 60 mm Hg (r2 = 0.70). The minimum PbrO2 with hypocarbia was 5.9 mm Hg, and the maximum PbrO2 with hypercarbia was 132.4 mm Hg. PbrO2 varied with MAP in a sigmoid fashion suggestive of pressure autoregulation between 60 and 150 mm Hg (r2 = 0.72). The minimum PbrO2 with hypotension was 1.4 mm Hg, and the maximum PbrO2 with hypertension was 97.2 mm Hg. In addition, CBF correlated linearly with PbrO2 during CO2 reactivity testing (r2 = 0.84). CONCLUSION: In the uninjured brain, PbrO2 exhibits CO2 reactivity and pressure autoregulation. The relationship of PbrO2 with ET-CO2 and MAP appears to be similar to those historically established for CBF with ET-CO2 and MAP. This suggests that, under normal conditions, PbrO2 is strongly influenced by factors that regulate CBF.

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Vertebrate sensory hair cells achieve high sensitivity and frequency selectivity by adding self-generated mechanical energy to low-level signals. This allows them to detect signals that are smaller than thermal molecular motion and to achieve significant resonance amplitudes and frequency selectivity despite the viscosity of the surrounding fluid. In nonmammals, a great deal of in vitro evidence indicates that the active process responsible for this amplification is intimately associated with the hair cells' transduction channels in the stereovillar bundle. Here, we provide in vivo evidence of hair-cell bundle involvement in active processes. Electrical stimulation of the inner ear of a lizard at frequencies typical for this hearing organ induced low-level otoacoustic emissions that could be modulated by low-frequency sound. The unique modulation pattern permitted the tracing of the active process involved to the stereovillar bundles of the sensory hair cells. This supports the notion that, in nonmammals, the cochlear amplifier in the hair cells is driven by a bundle motor system.

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The frog inner ear contains two hearing organs: the amphibian and the basilar papilla. The amphibian papilla is sensitive to low- and mid-frequency stimuli (0.1--0.5 and 0.5--1.3 kHz, respectively, in Hyla cinerea), while the basilar papilla is sensitive to high-frequency stimuli (2.8--3.9 kHz in H. cinerea). Distortion product otoacoustic emissions (DPOAE) were recorded from the ear of the tree frog H. cinerea. In each of six ears investigated, a cubic distortion product (DP) at 2f(1)--f(2) was present when the primary frequencies f(1) and f(2) and the DP frequency were close to either the mid- or the high-frequency range. At frequencies between the sensitive ranges of both papillae, no emissions were observed. For the basilar papilla, the dependence of DP level on the primary tone frequency ratio f(2)/f(1) showed a pattern characteristic of the response of a single nonlinear resonator. Thus, in agreement with neural data, DPOAE from the basilar papilla reflect the contribution of a single auditory filter to emission generation.

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The hearing organ of the inner ear was the last of the paired sense organs of amniotes to undergo formative evolution. As a mechanical sensory organ, the inner-ear hearing organ's function depends highly on its physical structure. Comparative studies suggest that the hearing organ of the earliest amniote vertebrates was small and simple, but possessed hair cells with a cochlear amplifier mechanism, electrical frequency tuning, and incipient micromechanical tuning. The separation of the different groups of amniotes from the stem reptiles occurred relatively early, with the ancestors of the mammals branching off first, approximately 320 million years ago. The evolution of the hearing organ in the three major lines of the descendents of the stem reptiles (e.g., mammals, birds-crocodiles, and lizards-snakes) thus occurred independently over long periods of time. Dramatic and parallel improvements in the middle ear initiated papillar elongation in all lineages, accompanied by increased numbers of sensory cells with enhanced micromechanical tuning and group-specific hair-cell specializations that resulted in unique morphological configurations. This review aims not only to compare structure and function across classification boundaries (the comparative approach), but also to assess how and to what extent fundamental mechanisms were influenced by selection pressures in times past (the phylogenetic viewpoint).

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Over the past year, much progress has been achieved in the study of both the peripheral and the central auditory systems of birds. Significant advances have been made in the study of hair cells, including elucidation of the mechanisms of selectivity for sound frequency, functional differentiation, efferent innervation, and regeneration. Most of the studies of central auditory neurones have concerned the developmental and physiological correlates of vocal learning in songbirds and sound localisation in owls.

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OBJECTIVES: Prophylactic hyperventilation of patients with head injuries worsens outcome, presumably by exacerbating tissue hypoxia. Oxygen tension in brain tissue (PbrO2) provides a direct measurement of cerebral metabolic substrate delivery and varies with changing end-tidal carbon dioxide tension (ETCO2) and mean arterial pressure. However, the effects of hyperventilation and hypoventilation on PbrO2 during hemorrhagic shock are not known. The aim of this study was to examine the effects of alteration in ventilation on PbrO2 in hemorrhaged swine. METHODS: Clark-type polarographic probes were inserted into the brain tissue of seven swine to measure PbrO2 directly. To examine the effects of alterations in ventilation on hemorrhage-induced hypotension, swine were hemorrhaged to 50% estimated blood volume and PbrO2 was monitored during hyperventilation (RR = 30) and hypoventilation (RR = 4). RESULTS: After the 50% hemorrhage, PbrO2 declined rapidly from 39.8 +/- 4.6 mm Hg to 11.4 +/- 2.2 mm Hg. Hyperventilation resulted in a further 56% mean decrease in PbrO2. Hypoventilation produced a 166% mean increase in PbrO2. These changes were significant (p = 0.001) for absolute and percentage differences from baseline. CONCLUSION: During hemorrhage, alterations in ventilation significantly changed PbrO2: hyperventilation increased brain-tissue hypoxia whereas hypoventilation alleviated it. This finding suggests that hyperventilation has deleterious effects on brain oxygenation in patients with hemorrhagic shock and those with head trauma. Conversely, hypoventilation with resultant hypercapnia may actually help resolve hemorrhagic shock-induced cerebral hypoxia.

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