Accompanies Brain Injury Research Articles

Rat Brain Global Ischemia-Induced Diffusion Changes Revisited: Biophysical Modeling of the Water and NAA MR "Diffusion Signal".

To assess changes in intracellular diffusion as a mechanism for the reduction in water ADC that accompanies brain injury. Using NAA as a marker of neuronal cytoplasmic diffusion, NAA diffusion was measured before and after global ischemia (immediately postmortem) in the female Sprague-Dawley rat. Diffusion-weighted PRESS spectra, with diffusion encoding in a single direction, were acquired from large voxels of rat brain gray matter in vivo and postischemia employing either pairs of pulsed half-sine-shaped gradients (in vivo and postischemia, bmax = 19 ms/μm2 ) or sinusoidal oscillating gradients (in vivo only) with frequencies of 99.2-250 Hz. A 2D randomly oriented cylinder (neurite) model gave estimates of longitudinal and transverse diffusivities (DL and DT , respectively). In this model, DL represents the "free" diffusivity of NAA, whereas DT reflects highly restricted diffusion. Using oscillating gradients, the frequency dependence of DT [DT (ω)] gave estimates of the cylinder (axon/dendrite) radius. A 10% decrease in DL,NAA followed global ischemia, dropping from 0.391 ± 0.012μm2 /ms to 0.350 ± 0.009μm2 /ms. Modeling DT,NAA (ω) provided an estimate of the neurite radius of 1.0± 0.6μm. Whereas the increase in apparent intraneuronal viscosity suggested by changes in DL,NAA may contribute to the overall reduction in water ADC associated with brain injury, it is not sufficient to be the sole explanation. Estimates of neurite radius based on DT (ω) were consistent with literature values.

Traumatic brain injury, the hidden pandemic: A focused response to family and patient experiences and needs.

Traumatic brain injury (TBI) has many potential cognitive, behavioural and psychological consequences, and contributes significantly to the national burden of disease and to ongoing violent behaviour. Few resources are available for the rehabilitation of patients with TBI in South Africa, and access to rehabilitation facilities in the public sector is limited. Consequently, it is the families impacted on by TBI that ultimately carry the care and rehabilitation burden once survivors are discharged from hospital. Families are generally ill equipped to cope with the complex and potentially long-term disabilities that accompany brain injury. Reviewing interviews with 175 family members and 354 patients recovering from TBI helped identify the key challenges that the survivors of TBI and their families face. Nine problem areas were identified that formed the basis for development of a discharge resource, the S-Plan, which serves to inform patients and carers and provide practical solutions for the problems they face. The experiences of TBI survivors and their family members served to inform the development of simple, integrated coping strategies, namely two S-Plan tools, one for survivors and their families/caregivers and the other for care workers, in conjunction with counselling and support group processes. The S-Plan constitutes a discharge resource to inform patients and carers and provide practical solutions for the problems they face in caring for family members who have suffered TBI.

Effect of blood in the cerebrospinal fluid on the accuracy of cerebral oxygenation measured by near infrared spectroscopy.

Near infrared spectroscopy (NIRS) is an optical technique used to examine the oxygenation state of tissues such as the brain in patients, including those with brain injury. We have examined the effect of a cerebrospinal fluid (CSF) contaminant, specifically haemoglobin, on the sensitivity of cerebral NIRS signals through computer simulation. Previous models of light transport in the head have shown that the clear CSF layer has a profound effect on the sensitivity profile of the NIRS signal due to its low absorbing, low scattering qualities. In subarachnoid haemorrhage, which may accompany brain injury, the principal near infrared chromophore, haemoglobin, is released into the CSF. Sensitivity was measured through forward modeling and the presence of haemoglobin within the CSF was modeled by increasing the absorption coefficient of the layer, with sensitivity quantified in terms of the partial pathlength of light within the brain. The model demonstrated that increases in the CSF absorption led to a marked decrease in the sensitivity to changes in the brain layer. This suggests that blood or other contaminants in the CSF may have a significant effect on the utility of NIRS for measurement of cerebral oxygenation, and merits further investigation.

Hemispatial neglect: clinical features, assessment and treatment

Hemispatial neglect is a disorder of attention that commonly follows from damage to the right side of the brain. Patients with neglect show symptoms of lateralised inattention, failing to acknowledge or report information on the left side. Neglect is a poor prognostic indicator for general functional recovery from stroke, and is associated with a range of co-morbid conditions including denial or indifference to the brain injury, hemiplegia and visual field loss. Mild-to-moderate cases can be overshadowed by the more gross symptoms that accompany brain injury; however, assessment and diagnosis are relatively quick and simple. Current treatment guidelines suggest that patients should be taught compensatory strategies, but these are largely ineffective. Although recent research has identified more promising treatment approaches, investigations are still preliminary. Given the prevalence and debilitating nature of neglect, there is a clear need to raise awareness and understanding of the condition among carers and health professionals.

The use of MR‐detectable reporter molecules and ions to evaluate diffusion in normal and ischemic brain

As a result of the technical challenges associated with distinguishing the MR signals arising from intracellular and extracellular water, a variety of endogenous and exogenous MR-detectable molecules and ions have been employed as compartment-specific reporters of water motion. Although these reporter molecules and ions do not have the same apparent diffusion coefficients (ADCs) as water, their ADCs are assumed to be directly related to the ADC of the water in which they are solvated. This approach has been used to probe motion in the intra- and extracellular space of cultured cells and intact tissue. Despite potential interpretative challenges with the use of reporter molecules or ions and the wide variety used, the following conclusions are consistent considering all studies: (i) the apparent free diffusive motion in the intracellular space is approximately one-half of that in dilute aqueous solution; (ii) ADCs for intracellular and extracellular water are similar; (iii) the intracellular ADC decreases in association with brain injury. These findings provide support for the hypothesis that the overall brain water ADC decrease that accompanies brain injury is driven primarily by a decrease in the ADC of intracellular water. We review the studies supporting these conclusions, and interpret them in the context of explaining the decrease in overall brain water ADC that accompanies brain injury.

Cs + ADC in rat brain decreases markedly at death

Spectroscopic resolution of intracellular and extracellular compartments can be used to probe the kinetic environment of those spaces and the compartment-specific changes that occur following injury. This is important for understanding the biophysical mechanisms that underlie the remarkable diffusion-weighted MRI contrast of injured central nervous system (CNS) tissue. Cesium-133 is a physiologic analog of potassium that is actively taken up by cells and resides primarily in the intracellular space. The (133)Cs(+) signal can, thus, be exploited to probe the kinetic environment of the intracellular space. Two principal (133)Cs(+) resonances were observed at 11.74 T. These resonances arise separately from (133)Cs(+) in brain and temporalis muscle. The apparent diffusion coefficient (ADC) of Cs(+) in brain decreased from 1.0 +/- 0.2 microm(2)/ms in healthy tissue to 0.24 +/- 0.04 microm(2)/ms following global ischemia (average ADC +/- average uncertainty), while there was no significant change in the ADC of Cs(+) in temporalis muscle after injury. This finding underscores the tissue-specific nature of the decrease in ADC that accompanies brain injury. Further, as the Cs(+) ADC should reflect water ADC in the intracellular space, these results strongly support the hypothesis that the decrease in water ADC associated with CNS injury arises largely from kinetic changes taking place in the intracellular space.

Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES)

The release of GA (mitochondrial glutaminase) from neurons following acute ischaemia or during chronic neurodegenerative diseases may contribute to the propagation of glutamate excitotoxicity. Thus an inhibitor that selectively inactivates the released GA may limit the accumulation of excess glutamate and minimize the loss of neurological function that accompanies brain injury. The present study examines the mechanism of inactivation of rat KGA (kidney GA isoform) by the small-molecule inhibitor BPTES [bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide]. BPTES is a potent inhibitor of KGA, but not of the liver GA isoform, glutamate dehydrogenase or gamma-glutamyl transpeptidase. Kinetic studies indicate that, with respect to glutamine, BPTES has a K(i) of approx. 3 microM. Moreover, these studies suggest that BPTES inhibits the allosteric activation caused by phosphate binding and promotes the formation of an inactive complex. Gel-filtration chromatography and sedimentation-velocity analysis were used to examine the effect of BPTES on the phosphate-dependent oligomerization of KGA. This established that BPTES prevents the formation of large phosphate-induced oligomers and instead promotes the formation of a single oligomeric species with distinct physical properties. Sedimentation-equilibrium studies determined that the oligomer produced by BPTES is a stable tetramer. Taken together, the present work indicates that BPTES is a unique and potent inhibitor of rat KGA and elucidates a novel mechanism of inactivation.

Cortical edema in moderate fluid percussion brain injury is attenuated by vagus nerve stimulation

Development of cerebral edema (intracellular and/or extracellular water accumulation) following traumatic brain injury contributes to mortality and morbidity that accompanies brain injury. Chronic intermittent vagus nerve stimulation (VNS) initiated at either 2 h or 24 h (VNS: 30 s train of 0.5 mA, 20 Hz, biphasic pulses every 30 min) following traumatic brain injury enhances recovery of motor and cognitive function in rats in the weeks following brain injury; however, the mechanisms of facilitated recovery are unknown. The present study examines the effects of VNS on development of acute cerebral edema following unilateral fluid percussion brain injury (FPI) in rats, concomitant with assessment of their behavioral recovery. Two hours following FPI, VNS was initiated. Behavioral testing, using both beam walk and locomotor placing tasks, was conducted at 1 and 2 days following FPI. Edema was measured 48 h post-FPI by the customary method of region-specific brain weights before and after complete dehydration. Results of this study replicated that VNS initiated at 2 h after FPI: 1) effectively facilitated the recovery of vestibulomotor function at 2 days after FPI assessed by beam walk performance ( P<0.01); and 2) tended to improve locomotor placing performance at the same time point ( P=0.18). Most interestingly, results of this study showed that development of edema within the cerebral cortex ipsilateral to FPI was significantly attenuated at 48 h in FPI rats receiving VNS compared with non-VNS FPI rats ( P<0.04). Finally, a correlation analysis between beam walk performance and cerebral edema following FPI revealed a significant inverse correlation between behavior performance and cerebral edema. Together, these results suggest that VNS facilitation of motor recovery following experimental brain injury in rats is associated with VNS-mediated attenuation of cerebral edema.

Extensive Turnover of Dendritic Spines and Vascular Remodeling in Cortical Tissues Recovering from Stroke

Recovery of function after stroke is thought to be dependent on the reorganization of adjacent, surviving areas of the brain. Macroscopic imaging studies (functional magnetic resonance imaging, optical imaging) have shown that peri-infarct regions adopt new functional roles to compensate for damage caused by stroke. To better understand the process by which these regions reorganize, we used in vivo two-photon imaging to examine changes in dendritic and vascular structure in cortical regions recovering from stroke. In adult control mice, dendritic arbors were relatively stable with very low levels of spine turnover (<0.5% turnover over 6 h). After stroke, however, the organization of dendritic arbors in peri-infarct cortex was fundamentally altered with both apical dendrites and blood vessels radiating in parallel from the lesion. On a finer scale, peri-infarct dendrites were exceptionally plastic, manifested by a dramatic increase in the rate of spine formation that was maximal at 1-2 weeks (5-8-fold increase), and still evident 6 weeks after stroke. These changes were selective given that turnover rates were not significantly altered in ipsilateral cortical regions more distant to the lesion (>1.5 mm). These data provide a structural framework for understanding functional and behavioral changes that accompany brain injury and suggest new targets that could be exploited by future therapies to rebuild and rewire neuronal circuits lost to stroke.

Trophic actions of extracellular ATP: gene expression profiling by DNA array analysis

In addition to Professor Burnstock’s work on the short-term signaling actions of extracellular nucleotides and nucleosides, Geoff has had a long-standing interest in trophic actions of purines in development and in pathophysiological conditions which has been instrumental in encouraging my work in this area. The trophic actions of extracellular ATP, alone or in combination with polypeptide growth factors, may play an important role in brain development and may contribute to the reactive gliosis that accompanies brain injury and neurodegeneration. P2Y receptors in astrocytes are coupled to the ERK/MAPK cascade, a signal transduction mechanism crucial for cellular proliferation and differentiation. The mitogenic signaling pathway from P2Y receptors to ERK involves phospholipase D and a calcium-independent PKC isoform, PKCδ. DNA array analysis reveals a number of changes in gene expression after P2Y receptor occupancy, indicating that this methodology will be a powerful tool in understanding the mechanisms underlying the trophic actions of extracellular nucleotides and nucleosides.

Modifying the environment to optimize outcome for people with behavior disorders associated with anosognosia

Denial of deficits often accompanies brain injury. Unfortunately, confronting unrealistic beliefs directly is sometimes ineffective. Alternative approaches include embedding, substitution, distraction, time out on the spot, teaching natural facilitative techniques and exploiting implicit recognition of deficits. The authors describe how these techniques improved the rehabilitation outcomes for two clients.

Fibroblast growth factor and cerebral ischaemia

Although the cellular events that accompany brain injury have been well characterized, the factors that mediate growth and repair in the central nervous system (CNS) are only beginning to be identified. One such is fibroblast growth factor. The fibroblast growth factor (FGF) family of proteins includes, at this moment, seven structurally related polypeptides. Acidic and basic FGF (aFGF and bFGF) were the first described members of the family, and are the best characterized. Both proteins bind with high affinity to the same kind of receptor at the plasma membrane through which they induce a whole series of intracellular events that mediate their physiological functions. FGF, which displays pleiotrophic biological activities including mitogenesis, chemotaxis, and induction of differentiation is a potent angiogenic factor in vivo, tested in assays as different as the rabbit cornea, the chick chorioalantoic membrane (CAM), the rat common carotid artery, and the rat brain.

Practical Issues in Behavior Management for Family Members of Individuals with Traumatic Brain Injury

Changes in behavior, both cognitive and emotional, are common following traumatic brain injury (TBI). Typically, these changes have a greater impact on family members than the physical limitations that often accompany brain injury. In this article, we present an overview of the behavioral techniques that have been used by family members of individuals with brain injury to deal with these problematic behavior changes. Clinical vignettes are presented that describe the actual solutions that family members have used in the home to help deal with behavior changes. The importance of determining the source of the behavior changes is highlighted, and the need to apply behavior intervention programs with consistency is discussed. In addition, this article stresses the need for continued interaction between rehabilitation staff and family members beyond the period of inpatient rehabilitation.

An increase in glial fibrillary acidic protein follows brain hyperthermia in rats

Previously, we have demonstrated that an increase in the astrocyte-associated protein, glial fibrillary acidic protein (GFAP), accompanies brain injury induced by a variety of chemical insults. In the present study we examined the effects of microwave-induced hyperthermia of the CNS on the concentration of GFAP in several brain regions of the Long-Evans rat. Irradiation resulted in a time-related increase in GFAP in olfactory bulbs and cortex, areas of maximum heating. The increase in GFAP following a brain temperature increase suggests that heating of brain tissue may be sufficient to provoke an injury response comparable to that induced by chemical and physical insult.