Bidirectional Changes in Anisotropy Are Associated with Outcomes in Mild Traumatic Brain Injury.

BACKGROUND AND PURPOSE: Mild traumatic brain injury results in a heterogeneous constellation of deficits and symptoms that persist in a subset of patients. This prospective longitudinal study identifies early diffusion tensor imaging biomarkers of mild traumatic brain injury that significantly relate to outcomes at 1 year following injury. MATERIALS AND METHODS: DTI was performed on 39 subjects with mild traumatic brain injury within 16 days of injury and 40 controls; 26 subjects with mild traumatic brain injury returned for follow-up at 1 year. We identified subject-specific regions of abnormally high and low fractional anisotropy and calculated mean fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity across all white matter voxels brain-wide and each of several white matter regions. Assessment of cognitive performance and symptom burden was performed at 1 year. RESULTS: Significant associations of brain-wide DTI measures and outcomes included the following: mean radial diffusivity and mean diffusivity with memory; and mean fractional anisotropy, radial diffusivity, and mean diffusivity with health-related quality of life. Significant differences in outcomes were found between subjects with and without abnormally high fractional anisotropy for the following white matter regions and outcome measures: left frontal lobe and left temporal lobe with attention at 1 year, left and right cerebelli with somatic postconcussion symptoms at 1 year, and right thalamus with emotional postconcussion symptoms at 1 year. CONCLUSIONS: Individualized assessment of DTI abnormalities significantly relates to long-term outcomes in mild traumatic brain injury. Abnormally high fractional anisotropy is significantly associated with better outcomes and might represent an imaging correlate of postinjury compensatory processes.

Relaxation of porcine coronary artery to bradykinin. Role of arachidonic acid.

Bradykinin-induced relaxation of precontracted, porcine coronary artery (PCA) rings is mediated by distinctly different endothelium-derived relaxing factors depending on the contractile agent used. Thus when contracted with KCl, bradykinin-induced relaxation of PCA rings is mediated solely by nitric oxide (NO), whereas when contracted with the thromboxane mimetic U46619, a small component of the relaxation is attributable to NO and a large component is attributable to a non-NO mechanism that is independent of cyclooxygenase activity. We hypothesized that the non-NO component was mediated by arachidonic acid (AA) or by a non-cyclooxygenase product of AA metabolism. Bradykinin-induced relaxations of PCA rings precontracted with U46619 in the presence of indomethacin (10 mumol/L) were moderately attenuated by the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 100 mumol/L), whereas when precontracted with KCl, L-NAME abolished the relaxations. AA produced endothelium-dependent relaxations of rings precontracted with U46619 that were unaffected by L-NAME, whereas AA did not relax rings precontracted with KCl. In rings precontracted with U46619, in the presence of L-NAME and indomethacin the phospholipase inhibitors quinacrine (50 mumol/L) and 4-bromophenacyl bromide (10 mumol/L) attenuated bradykinin- but not AA-induced relaxations. Inhibitors of both lipoxygenase (BW 755c [100 mumol/L] and nafazatrom [20 mumol/L]) and cytochrome P-450 (proadifen [10 mumol/L] and clotrimazole [10 mumol/L]) pathways did not eliminate bradykinin- or AA-induced relaxations, although clotrimazole partially attenuated AA-induced relaxations. These findings suggest that bradykinin-induced relaxation of PCA rings is mediated by AA through a mechanism that is not dependent on cyclooxygenase, lipoxygenase, or cytochrome P-450 pathways.

Dichotomous cardiac and systemic vascular responses to cocaine in conscious rats.

This study examined the effects of cocaine on cardiac output in conscious freely-moving rats. Although pressor responses were similar at all doses, 14 of 32 rats had consistent declines in cardiac output (> 15%) and greater increases in systemic vascular resistance after administration of cocaine (5 mg/Kg, i.v.). Procaine (10 mg/Kg i.v.) did not mimic this effect in either subgroup. We propose that a subpopulation of rats exists with an enhanced susceptibility to cocaine-induced cardiac and systemic vascular alterations at higher doses.

Perfusion imaging by un-inverted flow-sensitive alternating inversion recovery (UNFAIR).

A new pulse sequence for estimating cerebral blood flow called UNFAIR, which uses a combination of sequential hyperbolic secant preparatory pulses, is introduced. This sequence is based on the same generalized conditions as previously introduced inversion recovery techniques except that the spins in the image slice of interest always have +z magnetization and the in-flowing spins are alternately inverted and uninverted. CBF-weighted images of rat brain under conditions of normocpnia and hypercapnia are presented and demonstrate the expected CBF response. A model describing the signal response to this pulse sequence is also presented and compared with in-vivo data acquired from gray and white matter.

Neuropsychological dose effects of a freon, trifluoromethane (FC-23), compared to N2O.

Animal studies show FC-23 to be a promising magnetic resonance imaging indicator of regional cerebral blood flow. In a Phase 1, dose ranging (investigative new drug) study, neuropsychological (NP) tests, subjective ratings, and intensive physiological monitoring were used to determine the maximum tolerated concentration of FC-23 for human application. Five normal healthy male volunteers were exposed to concentrations of FC-23 between 10% and 60% [randomly interleaved with exposures to both room air and 40% nitrous oxide (N2O)] in a within-subjects, double-blind design. Analyses of individual cases and ranked group data showed that individuals tolerated the 30% concentration of FC-23 according to established criteria. Planned comparisons indicated that inhalation of FC-23 produced smaller NP changes and fewer negative symptoms than 40% N2O but poorer NP performance and more negative symptoms than room air. This study indicated that FC-23 is not inert and that humans do not tolerate concentrations suitable for current MRI technology. NP and subjective data assisted in characterizing the sedative effect of FC-23.

Cardiovascular responses to cocaine are initially mediated by the central nervous system in rats.

Cocaine produces a pressor response reportedly resulting from both potentiation of peripheral catecholamine activity and a centrally mediated sympathoexcitation. In the present study we sought to differentiate the central nervous system and peripheral contributions to the hemodynamic effects of cocaine. In conscious rats, cocaine (5 mg/kg i.v.) produced a pressor response with two distinct components consisting of a brief, substantial increase in mean arterial pressure (MAP) associated with hindquarters and mesenteric vasoconstriction followed by a sustained, modest response associated with mesenteric vasoconstriction and bradycardia. Pentolinium (7.5 mg/kg i.v.) or adrenal demedullation attenuated the peak increase in MAP by attenuating increases in mesenteric and hindquarters vascular resistance, but did not affect the sustained increase in MAP. Methyl atropine (0.5 or 1 mg/kg i.v.) pretreatment reduced the cocaine-induced increase in systemic vascular resistance and enhanced the hindquarters vasodilation during the sustained MAP response. In contrast, adrenal demedullation abolished the hindquarters vasodilation. The bradycardic response was prevented by pentolinium and reduced by methyl atropine. Sympathetic nerve activity was reduced dramatically after cocaine or procaine administration for several minutes in conscious and in chloralose-anesthetized rats. In several anesthetized rats, the sympathoinhibition was preceded by a brief (3-8 sec) increase in renal sympathetic nerve activity. Procaine or cocaine produced little change in cortical cerebral blood flow as estimated by using a laser Doppler flowmeter. These data suggest that cocaine produces an initial, brief centrally mediated sympathoexcitation, but the sustained, modest pressor response is dependent upon peripheral actions that are diminished by baroreflex activation.

Calcium channel antagonists reduce the cocaine-induced decrease in cardiac output in a subset of rats.

Intravenous (i.v.) cocaine administration elicits a decrease in cardiac output (CO) in some but not all rats. In the present study, we examined the effects of L-type calcium channel antagonists on cardiovascular responses in conscious freely moving rats with a cocaine-induced decrease in CO. Arterial blood pressure (ABP), heart rate (HR), and CO (pulsed Doppler flowmetry) were measured, and estimates of changes in systemic vascular resistance (SVR), stroke volume (SV), and rate-pressure product (RPP) were calculated from these values. After recovery, rats were treated with cocaine (5 mg/kg, i.v.) to ascertain their myocardial responses. Some rats demonstrated a decrease in CO, usually during the peak pressor response after cocaine administration, whereas others experienced only slight increases in CO. Rats demonstrating a minimum 15% decrement in CO were pretreated with either verapamil or nifedipine before cocaine was readministered. Verapamil (150 micrograms/kg) or nifedipine (100 micrograms/kg) selectively reduced the peak fall in CO and the increase in SVR after cocaine administration, whereas nifedipine (25 micrograms/kg) had little effect on these parameters. Neither drug affected the pressor response to cocaine. These data suggest that calcium channel antagonists can selectively reduce cocaine-induced decreases in CO and increases in SVR without reducing afterload in a subset of rats sensitive to the cardiodepressive effects of cocaine.

Causes of differential cardiovascular sensitivity to cocaine. II: Sympathetic, metabolic and cardiac effects.

Cocaine elicits a decrease in cardiac output only in a subset of rats; this reduction is mitigated by prazosin, nifedipine, verapamil or pentolinium and exacerbated by propranolol. In the present study, we examined other correlates or causes of differential responsiveness, including differences in cocaine metabolism, sympathetic nerve responses, catecholamine sensitivity and direct cardiac actions. Arterial pressure and heart rate responses to cocaine (5 mg/kg i.v.) were similar in all rats, yet cardiac output responses, as determined by pulsed Doppler flowmetry, varied widely. Cocaine elicited a mean maximal decrease of more than 15% in 17 rats designated responders, whereas the remaining rats (n = 19) were classified as nonresponders. Maximal heart rate responses to phenylephrine- and nitroprusside-induced pressor and depressor stimuli were greater in responders than in nonresponders. Phenylephrine also elicited significantly greater decreases in cardiac output and smaller increases in stroke volume in responders. After we determined the responses to cocaine in conscious rats, animals were anesthetized with alpha-chloralose for renal nerve recording. Several rats (14 of 21 tested) demonstrated an initial brief (2-12 sec) increase in sympathetic activity, whereas all rats subsequently had a delayed sympathoinhibition. Responders were more likely to have sympathoexcitation compared with nonresponders and had an enhanced initial pressor response and a smaller decrease in heart rate. There were no differences in plasma or cerebrospinal fluid levels of cocaine or its metabolites, benzoylecgonine and ecgonine methyl ester. Intravenous benzoylecgonine elicited a pressor response and bradycardia in conscious rats. Finally, there were no differences in contractile, electrocardiographic or coronary vascular responses to cocaine in isolated, perfused hearts from responders and nonresponders. These results suggest that the differential cardiovascular responsiveness to cocaine in rats is mediated, at least in part, by central sympathoexcitation and not by differences in cocaine metabolism or in direct cardiac responsiveness to cocaine.

Causes of differential cardiovascular sensitivity to cocaine. I: Studies in conscious rats.

Cocaine produces apparent myocardial ischemia in some individuals without deleterious effects in others. The authors identified a subset of rats in which cocaine produces a decrease in cardiac output and an increase in cardiomyopathies. In the present study, several potential causes of this differential responsiveness were examined in conscious rats instrumented for cardiac output determination by using pulsed Doppler flowmetry. Although arterial pressure and heart rate responses to cocaine (5 mg/kg i.v.) were similar in all rats, cardiac output responses varied widely. Specifically, in 17 of 36 rats, cocaine elicited a maximum decrease of greater than 15% that was relatively consistent with repeated trials. These rats were designated responders, whereas the remaining rats with little change or an increase in cardiac output were classified as nonresponders. Pentolinium (7.5 mg/kg) or adrenal demedullation reduced the peak cardiac output responses in both groups such that there was no longer a difference between responders and nonresponders. Prazosin (0.1 mg/kg) reduced the cocaine-induced pressor responses in all rats and selectively reduced the decrease in cardiac output in responders. Propranolol (1 mg/kg) reduced the peak pressor response but enhanced the decrease in cardiac output in responders. Neither indomethacin (5 mg/kg) or heparin (300 units) pretreatment altered the cocaine-induced cardiac output or peripheral vascular effects in either responders or nonresponders. Amphetamine (1 mg/kg) elicited smaller pressor responses but still evoked a net decrease in cardiac output in responders.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic mechanisms underlying cardiac and vascular responses to cocaine in conscious rats.

The contribution of adrenergic receptors to the cardiovascular responses to cocaine (5 mg/kg i.v.) were examined in conscious, free-moving rats instrumented for continuous measurement of arterial pressure, heart rate and blood flows in the mesentery and hindquarters or ascending aorta. Cocaine elicits an immediate (peak) and sustained pressor response with a concomitant reduction in heart rate. Prazosin (0.1 mg/kg i.v.) pretreatment significantly reduced both the peak and sustained pressor responses by attenuating the increases in systemic, mesenteric and hindquarters vascular resistances. Idazoxan pretreatment (1 mg/kg i.v.) attenuated the peak increase in hindquarters vascular resistance. Whereas propranolol pretreatment (1 mg/kg i.v.) attenuated the peak pressor response, the sustained pressor response was enhanced due to increased hindquarters and systemic vascular resistances. Metoprolol pretreatment (1 mg/kg i.v.) enhanced the sustained pressor response to cocaine, in part due to increased heart rate and mesenteric vascular resistances. Upon examination of the cardiac effects of cocaine, a sustained bradycardic response was observed, whereas stroke volume and cardiac output were relatively unaffected. The bradycardic response to cocaine was attenuated by yohimbine (0.1 mg/kg i.v.), prevented by prazosin and converted to a tachycardia after idazoxan (1 mg/kg) pretreatment. After propranolol pretreatment, cocaine substantially decreased cardiac output and stroke volume. Our results demonstrate that cocaine produces a biphasic pressor response in conscious rats and that the mechanisms underlying the dual responses vary in intensity and mode of action in different vascular beds, but are primarily dependent upon alpha-1 adrenergic receptor-mediated vasoconstriction.

Perfusion imaging using FOCI RF pulses.

Pulsed arterial spin-tagging techniques for perfusion measurements (e.g., echo planar MR imaging and signal targeting with alternating radiofrequency (EPISTAR), flow-sensitive alternating inversion recovery (FAIR), quantitative imaging of perfusion using a single subtraction (QUIPPS), uninverted FAIR (UNFAIR)) generally use hyperbolic secant (HS) pulses for spin inversion. The performance of these techniques depends on the inversion efficiency, as well as the sharpness of the slice profiles. Frequency offset corrected inversion (FOCI) pulses, a recently proposed HS variant, can provide slice profiles with edges that can be up to 10 times sharper than those obtained with conventional HS pulses. In this communication, the implementation and application of the C-shape FOCI pulse for perfusion imaging in rat brain with the FAIR technique is summarized. Despite providing a more rectangular slice profile than a conventional HS pulse, it is demonstrated both theoretically and experimentally that the FAIR perfusion signal is not increased by using a FOCI tagging pulse. However, the use of a FOCI inversion pulse is shown to significantly minimize static signal subtraction errors that are common with conventional HS pulses. Finally, the suitability of the pulse for perfusion studies is demonstrated, in vivo, on rat brain.

Cocaine-induced myocardial ultrastructural alterations and cardiac output responses in rats.

Cocaine use has been associated with profound functional and pathological myocardial responses in otherwise asymptomatic humans, yet a number of individuals appear to tolerate large doses of the drug. This study was designed to determine whether there is a relationship between the differential effects of cocaine administration on cardiovascular responses and on the development of cardiomyopathies in rats. After instrumentation for determination of cardiac output, conscious, freely moving rats were treated with cocaine (5 mg/kg) or saline intravenously twice daily for 14 days before removing the myocardium for analysis. Although most cardiovascular responses were similar, cocaine administration elicited consistent decreases in cardiac output in some rats, whereas others showed little change or an increase. While little change was evident at low magnification, electron microscopy revealed diffusely distributed myocardial lesions including focally dilated sarcoplasmic reticulum and myofibrillar derangement, early signs of mitochondrial alterations, and foci of myocardial fibrosis. The incidence of these alterations was greater in rats with a decrease in cardiac output. We also observed these lesions in a subset of rats treated with cocaine without cardiac output instrumentation. These data represent the first evidence that there is a relationship between cocaine-induced functional and pathological alterations and that rats, like humans, may be differentially sensitive to these effects.

RF excitation profiles with FAIR: impact of truncation of the arterial input function on quantitative perfusion.

This study investigates the impact of imaging coil length and consequent truncation of the arterial input function on the perfusion signal contrast obtained in the flow-sensitive alternating inversion recovery (FAIR) perfusion imaging measurement. We examined the difference in perfusion contrast achieved with head, head and neck, and body imaging coils based on the hypothesis that the standard head coil provides a truncated input function compared with that provided by the body coil and that this effect will be accentuated at long inversion times. The TI-dependent cerebral response of the FAIR sequence was examined at 1.5 T by varying the TI from 200 to 3500 msec with both the head and whole body coils (n = 5) as well as using a head and neck coil (n = 3). Difference signal intensity DeltaM and quantitative cerebral blood flow (CBF) were plotted against TI for each coil configuration. Despite a lower signal-to-noise ratio, relative CBF was significantly greater when measured with the body or head and neck coil compared with the standard head coil for longer inversion times (two-way ANOVA, P < or = 0.002). This effect is attributed to truncation of the arterial input function of labeled water by the standard head coil and the resultant inflow of unlabeled spins to the image slice during control image acquisition, resulting in overestimation of CBF. The results support the conclusion that the arterial input function depends on the anatomic extent of the inversion pulse in FAIR, particularly at longer mixing times (TI > 1200 msec at 1.5 T). Use of a head and neck coil ensures adequate inversion while preserving SNR that is lost in the body coil.

Effect of leukocyte-endothelial adhesion antagonism on neutrophil migration and neurologic outcome after cortical trauma.

BACKGROUND: Administration of anti-CD11B, a monoclonal antibody directed against the leukocyte adhesion molecule CD11B, results in decreased neutrophil infiltration into injured tissue after experimental ischemia. We determined the effect of anti-CD11B administration on neutrophil migration and neurologic functioning after experimental cortical trauma. METHODS: Injuries were produced by a pneumatic impactor. Treatment animals received anti-CD11B after injury. Neurologic functioning was quantitated at 1, 12, and 24 hours after injury. Neutrophil migration was assessed with the myeloperoxidase assay. RESULTS: Neutrophil influx was increased in injured cortex after trauma. Anti-CD11B significantly reduced neutrophil influx. There was no significant improvement in neurologic functioning after MAb administration. CONCLUSIONS: These results show there is marked neutrophil response to injury as produced with the pneumatic contusion model. This migration may be significantly attenuated by administration of a anti-CD11B.

Stress and cocaine elicit similar cardiac output responses in individual rats.

Cocaine use and behavioral stress elicit variable cardiovascular responses in individuals. In the present study, we examined the effects of cocaine or stress on arterial pressure, heart rate, and cardiac output in conscious rats. Rats were instrumented for determination of ascending aortic blood flow as an index of cardiac output using pulsed Doppler flow-metry. Cocaine administration elicited consistent decreases in cardiac output in some rats, whereas others had increases. In contrast, the pressor and heart rate responses were similar in these two groups of animals. Air jet stress also elicited a decrease in cardiac output only in a subset of conscious rats, yet produced equivalent pressor responses in all rats. Cardiac output responses to cocaine and air jet stress were closely correlated in individual rats, indicating that these stimuli evoke similar hemodynamic responses in individual rats. These observations suggest that the rat may provide a model for understanding differential cardiovascular sensitivity to cocaine and/or stress in humans.

The application of diffusion-weighted line-scanning for the rapid assessment of water ADC changes in stroke at high magnetic fields.

Rapid changes in the apparent diffusion coefficient of water following brain ischemia have been extensively studied using echo planar diffusion imaging at low fields (2.0 T). There is a desire to perform these studies at higher fields (> 3.0 T) where the benefits of improved signal-to-noise can be exploited. Unfortunately, EPI diffusion is technically difficult to implement at high fields because of large magnetic susceptibility effects. This article demonstrates the feasibility of employing a line-scan diffusion protocol for ADCw measurements in stroke. The technique was applied on a 4.0 T system to monitor the decline in ADCw following the induction of focal cerebral ischemia in rat. ADCw data were acquired every 15 s with 10 b-values or every 22.5 s with 15 b-values, with a cubic spatial resolution of 1.5 mm. The results demonstrate that estimates of ADCw can be acquired with coefficients of variation under 3.0%, and with a combination of spatial and temporal resolution comparable to that previously reported for EPI.

19F NMR imaging of cerebral blood flow.

Techniques for the quantitative imaging assessment of cerebral blood flow are presented in a cat using 19F NMR imaging of trifluoromethane. The input function of the indicator was acquired noninvasively, while its uptake and clearance were followed in 2-cc volume voxels from images acquired at 67 s intervals. A single compartment model yielded normal cerebral blood flow estimates.

Nonadrenergic mechanisms of cocaine-induced regional vascular responses in rats.

The pressor response to cocaine is a consequence of mesenteric vasoconstriction and hindquarters vasodilation as a result of activation of alpha 1- and beta-adrenergic receptors, respectively. In the present study, evidence for additional, nonadrenergic effects of cocaine-induced changes in regional blood flow was obtained using pulsed Doppler flowmetry in conscious rats. Cocaine produced dose-dependent initial peaks (within 1 min) in mean arterial pressure concomitant with an increase in hindquarters and mesenteric vascular resistance. The sustained, modest pressor response was associated with hindquarters vasodilation and bradycardia. The cocaine-induced vasodilation was enhanced by pretreatment with indomethacin (5 mg/kg), prevented by ibuprofen (12.5 mg/kg) or 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C, 10.5 mg/kg) pretreatment, and unaffected by meclofenamate administration (2.5 mg/kg). Equipotent local anesthetic doses of procaine produced equivalent hindquarters vasodilator responses and more modest pressor responses. Dial-urethane anesthesia did not affect hindquarters vasodilation in response to cocaine or procaine but did reduce the mesenteric vasoconstrictor and pressor responses. These data demonstrate that the cocaine-induced hindquarters vasodilation is not mediated solely by beta-adrenergic receptors but is also dependent upon eicosanoids. Furthermore, the cocaine-induced vasodilation may be due, in part, to a direct local anesthetic effect but is not dependent upon a locomotor or behavioral stress induced increase in blood flow.

Phencyclidine and violent deaths in St. Louis, Missouri: a survey of medical examiners' cases from 1977 through 1986.

A survey of 104 deaths involving phencyclidine (PCP) occurring from 1981 through 1986 in metropolitan St. Louis, Missouri, is presented. Four black males (22-33 yr) died from fatal PCP intoxication. PCP was detected in an additional 100 deaths: 81 homicides, 13 suicides, and 6 accidental deaths. Seventy-five of these deaths were homicides of Black males (mean age 27 years) typically dying from gunshot wounds, 64 cases. In 50% of deaths where PCP was detected, other drugs were co-administered: ethanol (35%) and cocaine (20%) being the most common mixtures. A dramatic continuous increase in PCP abuse from 1984 through 1986 was demonstrated by drug abuse indicator data: treatment admissions, emergency room episodes, police exhibits, and driving under the influence of PCP arrests. Increased abuse of PCP in St. Louis has been associated with increased medical emergencies and violence against persons.

Rapid and continuous monitoring of cerebral perfusion by magnetic resonance line scan assessment with arterial spin tagging.

A new approach is presented for rapid and continuous monitoring of cerebral perfusion which is based upon line-scan MR column imaging with arterial spin tagging (AST) of endogenous water. Spin tagging of arterial water protons is accomplished using adiabatic fast passage inversion, followed by acquisition of the perfusion sensitive MR signal from a column placed at the desired level through the brain using line scan localization techniques. A perfusion sensitive line scan is followed by a non-perfusion sensitive line scan, and perfusion is calculated pixel-by-pixel from the intensity difference of the two lines. Continuous perfusion measurements are reported with temporal resolution of 10 s in pixels of volume 0.027 cm3 or less. Examples of the methodology are given during hypercapnic challenge induced with carbon dioxide, and during an ischemic event induced by reversible middle cerebral artery occlusion. The method is also used to characterize the signal response as a function of arterial inversion time and post inversion acquisition delay. These methods permit rapid and continuous monitoring of cerebral perfusion with high spatial resolution, and can be interleaved with MR measurements of diffusion and T1 to follow the progression of cerebral events during physiological or pharmacological intervention.