Traumatic brain injury (TBI) has been associated with intravascular coagulation, which may be a r... more Traumatic brain injury (TBI) has been associated with intravascular coagulation, which may be a result of thromboplastin released following brain injury. Clots thus formed are lysed by plasmin, which is activated by tissue-type and urokinase-type plasminogen activators (uPA). To evaluate the association between traumatic intravascular coagulation and post-traumatic outcome, uPA knockout (uPA-/-) transgenic mice (n=12) or wild-type littermates (WT; n=12) were anesthetized and subjected to controlled cortical impact (CCI) brain injury. A second group of uPA-/- (n=12) and WT mice (n=12) were subjected to sham injury. Motor function was assessed over 2 weeks using the composite neuroscore test and cognition (learning) was assessed with the Morris Water Maze (MWM) at 2 weeks post-injury, whereupon the animals were sacrificed for cortical lesion volume analysis. Motor function was significantly worse in the brain-injured uPA-/- mice when compared to brain-injured WT mice at 48 h (p<0.05) and one week post-injury (p<0.05). These differences resolved by 2 weeks post-injury. There was no significant difference in post-injury cognitive function between uPA-/- mice and WT mice. However, at 2 weeks post-injury, the brain-injured uPA-/- had a significantly larger volume of cortical tissue loss than their WT counterparts (p<0.05). These results demonstrate that the absence of uPA in mice aggravates acute motor deficit and exacerbates cortical tissue loss following CCI brain injury, and suggests a neuroprotective role of the fibrinolytic process following TBI.
We sought to evaluate the potential of C17.2 neural progenitor cells (NPCs) engineered to secrete... more We sought to evaluate the potential of C17.2 neural progenitor cells (NPCs) engineered to secrete glial cell line-derived neurotrophic factor (GDNF) to survive, differentiate and promote functional recovery following engraftment into the brains of adult male Sprague–Dawley rats subjected to lateral fluid percussion brain injury. First, we demonstrated continued cortical expression of GDNF receptor components (GFRα-1, c-Ret), suggesting that GDNF could have a physiological effect in the immediate post-traumatic period. Second, we demonstrated that GDNF over-expression reduced apoptotic NPC death in vitro. Finally, we demonstrated that GDNF over-expression improved survival, promoted neuronal differentiation of GDNF-NPCs at 6 weeks, as compared with untransduced (MT) C17.2 cells, following transplantation into the perilesional cortex of rats at 24 h post-injury, and that brain-injured animals receiving GDNF-C17.2 transplants showed improved learning compared with those receiving vehicle or MT-C17.2 cells. Our results suggest that transplantation of GDNF-expressing NPCs in the acute post-traumatic period promotes graft survival, migration, neuronal differentiation and improves cognitive outcome following traumatic brain injury.
Studies involving animal models of acute central nervous system (CNS) stroke and trauma strongly ... more Studies involving animal models of acute central nervous system (CNS) stroke and trauma strongly indicate that sex and/or hormonal status are important determinants of outcome after brain injury. The present study was undertaken to examine the ability of estradiol to protect hippocampal neurons from lateral fluid percussion brain injury. Sprague-Dawley female rats (211-285 g; n = 119) were ovariectomized, and a subset (n = 66) were implanted with 17beta-estradiol pellets to provide near physiological levels of estradiol. Animals were subjected to lateral fluid percussion brain injury or sham injury 1 week later. Activation of caspase-3 (n = 26) and TUNEL staining (n = 21) were assessed at 3 and 12 h after injury, respectively, in surviving control and estradiol-treated animals. Memory retention was examined using a Morris water maze test in a separate subset of animals (n = 43) at 8 days after injury. Activated caspase-3 and TUNEL staining were observed in the dentate hilus, granule cell layer, and CA3 regions in all injured rats, indicative of selective hippocampal cell apoptosis in the acute posttraumatic period. Estradiol did not significantly alter the number of hippocampal neurons exhibiting caspase-3 activity or TUNEL staining. Brain injury impaired cognitive ability, assessed at 1 week post-injury (p < 0.001). However, estradiol at physiological levels did not significantly alter injury-induced loss of memory. These data indicate that estradiol at physiological levels does not ameliorate trauma-induced hippocampal injury or cognitive deficits in ovariectomized female rats.
Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinica... more Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinical outcome. Following central nervous system injury, axons regenerate poorly, in part due to the presence of molecules associated with myelin that inhibit axonal outgrowth, including myelin-associated glycoprotein (MAG). The involvement of MAG in neurobehavioral deficits and tissue loss following experimental TBI remains unexplored and was evaluated in the current study using an MAG-specific monoclonal antibody (mAb). Anesthetized rats (n = 102) were subjected to either lateral fluid percussion brain injury (n = 59) or sham injury (n = 43). In surviving animals, beginning at 1 h post-injury, 8.64 µg anti-MAG mAb (n = 33 injured, n = 21 sham) or control IgG (n = 26 injured, n = 22 sham) was infused intracerebroventricularly for 72 h. One group of these rats (n = 14 sham, n = 11 injured) was killed at 72 h post-injury for verification of drug diffusion and MAG immunohistochemistry. All other animals were evaluated up to 8 weeks post-injury using tests for neurologic motor, sensory and cognitive function. Hemispheric tissue loss was also evaluated at 8 weeks post-injury. At 72 h post-injury, increased immunoreactivity for MAG was seen in the ipsilateral cortex, thalamus and hippocampus of brain-injured animals, and anti-MAG mAb was detectable in the hippocampus, fimbria and ventricles. Brain-injured animals receiving anti-MAG mAb showed significantly improved recovery of sensorimotor function at 6 and 8 weeks (P < 0.01) post-injury when compared with brain-injured IgG-treated animals. Additionally, at 8 weeks post-injury, the anti-MAG mAb-treated brain-injured animals demonstrated significantly improved cognitive function and reduced hemispheric tissue loss (P < 0.05) when compared with their brain-injured controls. These results indicate that MAG may contribute to the pathophysiology of experimental TBI and treatment strategies that target MAG may be suitable for further evaluation.
Approximately 4000 human beings experience a traumatic brain injury each day in the United States... more Approximately 4000 human beings experience a traumatic brain injury each day in the United States ranging in severity from mild to fatal. Improvements in initial management, surgical treatment, and neurointensive care have resulted in a better prognosis for traumatic brain injury patients but, to date, there is no available pharmaceutical treatment with proven efficacy, and prevention is the major protective strategy. Many patients are left with disabling changes in cognition, motor function, and personality. Over the past two decades, a number of experimental laboratories have attempted to develop novel and innovative ways to replicate, in animal models, the different aspects of this heterogenous clinical paradigm to better understand and treat patients after traumatic brain injury. Although several clinically-relevant but different experimental models have been developed to reproduce specific characteristics of human traumatic brain injury, its heterogeneity does not allow one single model to reproduce the entire spectrum of events that may occur. The use of these models has resulted in an increased understanding of the pathophysiology of traumatic brain injury, including changes in molecular and cellular pathways and neurobehavioral outcomes. This review provides an up-to-date and critical analysis of the existing models of traumatic brain injury with a view toward guiding and improving future research endeavors.
Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS ax... more Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS axons may recover poorly following TBI due to expression of myelin-derived inhibitors to axonal outgrowth such as Nogo-A. To study the role of Nogo-A/B in the pathophysiological response of the elderly to TBI, 1-year-old mice deficient in Nogo-A/B (Nogo-A/B homozygous−/− mice), Nogo-A/B heterozygous−/+ mice, and age-matched wild-type (WT) littermate controls were subjected to a controlled cortical impact (CCI) TBI. Sham-injured WT mice (7 months old) and 12 month old naïve Nogo-A/B−/− and Nogo-A/B−/+ served as controls. Neurological motor function was evaluated up to 3 weeks, and cognitive function, hemispheric tissue loss, myelin staining and hippocampal β-amyloid (Aβ) immunohistochemistry were evaluated at 4 weeks post-injury. In WT littermates, TBI significantly impaired learning ability at 4 weeks and neurological motor function up to 2 weeks post-injury and caused a significant loss of hemispheric tissue. Following TBI, Nogo-A/B−/− mice showed significantly less recovery from neurological motor and cognitive deficits compared to brain-injured WT mice. Naïve Nogo-A/B−/− and Nogo-A/B−/+ mice quickly learned the MWM task in contrast to brain-injured Nogo-A/B−/− mice who failed to learn the MWM task at 4 weeks post-injury. Hemispheric tissue loss and cortical lesion volume were similar among the brain-injured genotypes. Neither TBI nor the absence of NogoA/B caused an increased Aβ expression. Myelin staining showed a reduced area and density in the corpus callosum in brain-injured Nogo-A/B−/− animals compared to their littermate controls. These novel and unexpected behavioral results demonstrate that the absence of Nogo-A/B may negatively influence outcome, possibly related to hypomyelination, following TBI in mice and suggest a complex role for this myelin-associated axonal growth inhibitor following TBI.
The reorganization of neuronal circuits after traumatic brain injury (TBI) consists of several ne... more The reorganization of neuronal circuits after traumatic brain injury (TBI) consists of several neurobiological alterations that are orchestrated in parallel and serial fashion. These include cellular death, axonal and dendritic plasticity, neurogenesis and gliogenesis, vascular alterations, axonal damage and remodelling of extracellular matrix and cellular membranes. Based on current knowledge, prevention or alleviation of neurodegeneration remains an attractive target for therapeutic attempts to improve the outcome following TBI. Here, we focus on the most recent studies that have advanced our understanding of the molecular mechanisms of TBI-induced neuronal death. These data provide candidate targets for design of novel therapies and for identification of biomarkers or surrogate markers for predicting the outcome or therapy response.Andrey Mazarati – Department of Pediatrics, UCLA, USAClaude Wasterlain – Department of Cardiology, UCLA, USA
This paper presents an Electrical Capacitance Tomography (ECT) sensor scheme consisting of N segm... more This paper presents an Electrical Capacitance Tomography (ECT) sensor scheme consisting of N segments linked in four groups, treated as single, extremely broad electrodes forming a 4-electrode sensor. This configuration is repeated along the pipe circumference, selecting different segments in order to form N/4 independent 4-electrode schemes. The response of this sensor is studied by means of Finite Element Method (FEM)-based simulations, and the results are compared to the response of a 12-electrode conventional sensor. The image reconstruction proved to have lower error when using the segmented sensor, and it is less sensitive to white noise affecting the measurements. A tomograph with 20 segments based on a FPGA core has been developed and tested using a test phantom. Results show that high values of inter-electrode capacitances and better image reconstruction can be achieved.
This paper presents an electrocardiogram (ECG) acquisition system based on reconfigurable devices... more This paper presents an electrocardiogram (ECG) acquisition system based on reconfigurable devices. This system allows redesigning the analog conditioning stage thanks to the use of a Field Programmable Analog Array (FPAA) device, which may be adapted to the requirements of the signal shape and/or medical specifications. Simulated and real ECG signals have been acquired using this system in a three-lead configuration. A detailed study of its technical features has been carried out, showing good suitability for ECG acquisition. Further digital ECG signal processing is performed on a Field Programmable Gate Array (FPGA) device, which has allowed different digital configurations to be tested, including FIR and wavelet filtering and identification of wave features such as the QRS complex. In addition, the FPGA device is in charge of FPAA reconfiguration. Thus, the pairing of FPAA and FPGA devices conforms a compact and versatile bio-signal acquisition platform. This platform has shown very good performance with different types of electrodes, and has also demonstrated the dynamic reconfiguration capabilities of these devices, which enable, for example, the tuning of gain and bandwidth as required by different input conditions and ECG application requirements. The analyzed performance parameters provide values such as 102 dB CMRR (Common-Mode Rejection Ratio), 14-bit ADC resolution, and 75 dB SNR (signal-to-noise ratio), among others, thus satisfying the minimum requirements for clinical use.
This work describes an analog reconfiguration technique for acquisition and processing of analog ... more This work describes an analog reconfiguration technique for acquisition and processing of analog sensor signals that involves field programmable analog arrays (FPAAs) and field programmable gate arrays (FPGAs). The main objective is to exploit their natural reconfiguration capabilities that allow the increase of the analog-to-digital conversion (ADC) resolution and an adaptive post processing of the digital signal. This work is completed by the demonstration of this technique with an NTC temperature sensor signal, increasing the ADC resolution. The proposed system acquires the analog signal with filtering, amplifications and ADC being performed on the FPAA, while dynamically tuning the analog conditioning on the FPAA; after that, the FPGA processes the digital signal and delivers the final result to the end user, also involving the use of an embedded PicoBlaze.
This work describes the application of both field programmable analog arrays (FPAAs) and field pr... more This work describes the application of both field programmable analog arrays (FPAAs) and field programmable gate arrays (FPGAs) for signal conditioning and processing in smart sensor applications. The main objective is to exploit their natural reconfiguration capabilities, which will expand the application field to more complex measurement and control systems. On the other hand, the introduction of IEEE 1451-compliant sensors allows for the development of multi-sensor and multi-purpose platforms, that may benefit from programmable technologies. Thus, this paper includes initial developments for IEEE 1451 smart sensor interfacing and its application to instrumentation.
Traumatic brain injury (TBI) has been associated with intravascular coagulation, which may be a r... more Traumatic brain injury (TBI) has been associated with intravascular coagulation, which may be a result of thromboplastin released following brain injury. Clots thus formed are lysed by plasmin, which is activated by tissue-type and urokinase-type plasminogen activators (uPA). To evaluate the association between traumatic intravascular coagulation and post-traumatic outcome, uPA knockout (uPA-/-) transgenic mice (n=12) or wild-type littermates (WT; n=12) were anesthetized and subjected to controlled cortical impact (CCI) brain injury. A second group of uPA-/- (n=12) and WT mice (n=12) were subjected to sham injury. Motor function was assessed over 2 weeks using the composite neuroscore test and cognition (learning) was assessed with the Morris Water Maze (MWM) at 2 weeks post-injury, whereupon the animals were sacrificed for cortical lesion volume analysis. Motor function was significantly worse in the brain-injured uPA-/- mice when compared to brain-injured WT mice at 48 h (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) and one week post-injury (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). These differences resolved by 2 weeks post-injury. There was no significant difference in post-injury cognitive function between uPA-/- mice and WT mice. However, at 2 weeks post-injury, the brain-injured uPA-/- had a significantly larger volume of cortical tissue loss than their WT counterparts (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). These results demonstrate that the absence of uPA in mice aggravates acute motor deficit and exacerbates cortical tissue loss following CCI brain injury, and suggests a neuroprotective role of the fibrinolytic process following TBI.
We sought to evaluate the potential of C17.2 neural progenitor cells (NPCs) engineered to secrete... more We sought to evaluate the potential of C17.2 neural progenitor cells (NPCs) engineered to secrete glial cell line-derived neurotrophic factor (GDNF) to survive, differentiate and promote functional recovery following engraftment into the brains of adult male Sprague–Dawley rats subjected to lateral fluid percussion brain injury. First, we demonstrated continued cortical expression of GDNF receptor components (GFRα-1, c-Ret), suggesting that GDNF could have a physiological effect in the immediate post-traumatic period. Second, we demonstrated that GDNF over-expression reduced apoptotic NPC death in vitro. Finally, we demonstrated that GDNF over-expression improved survival, promoted neuronal differentiation of GDNF-NPCs at 6 weeks, as compared with untransduced (MT) C17.2 cells, following transplantation into the perilesional cortex of rats at 24 h post-injury, and that brain-injured animals receiving GDNF-C17.2 transplants showed improved learning compared with those receiving vehicle or MT-C17.2 cells. Our results suggest that transplantation of GDNF-expressing NPCs in the acute post-traumatic period promotes graft survival, migration, neuronal differentiation and improves cognitive outcome following traumatic brain injury.
Studies involving animal models of acute central nervous system (CNS) stroke and trauma strongly ... more Studies involving animal models of acute central nervous system (CNS) stroke and trauma strongly indicate that sex and/or hormonal status are important determinants of outcome after brain injury. The present study was undertaken to examine the ability of estradiol to protect hippocampal neurons from lateral fluid percussion brain injury. Sprague-Dawley female rats (211-285 g; n = 119) were ovariectomized, and a subset (n = 66) were implanted with 17beta-estradiol pellets to provide near physiological levels of estradiol. Animals were subjected to lateral fluid percussion brain injury or sham injury 1 week later. Activation of caspase-3 (n = 26) and TUNEL staining (n = 21) were assessed at 3 and 12 h after injury, respectively, in surviving control and estradiol-treated animals. Memory retention was examined using a Morris water maze test in a separate subset of animals (n = 43) at 8 days after injury. Activated caspase-3 and TUNEL staining were observed in the dentate hilus, granule cell layer, and CA3 regions in all injured rats, indicative of selective hippocampal cell apoptosis in the acute posttraumatic period. Estradiol did not significantly alter the number of hippocampal neurons exhibiting caspase-3 activity or TUNEL staining. Brain injury impaired cognitive ability, assessed at 1 week post-injury (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). However, estradiol at physiological levels did not significantly alter injury-induced loss of memory. These data indicate that estradiol at physiological levels does not ameliorate trauma-induced hippocampal injury or cognitive deficits in ovariectomized female rats.
Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinica... more Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinical outcome. Following central nervous system injury, axons regenerate poorly, in part due to the presence of molecules associated with myelin that inhibit axonal outgrowth, including myelin-associated glycoprotein (MAG). The involvement of MAG in neurobehavioral deficits and tissue loss following experimental TBI remains unexplored and was evaluated in the current study using an MAG-specific monoclonal antibody (mAb). Anesthetized rats (n = 102) were subjected to either lateral fluid percussion brain injury (n = 59) or sham injury (n = 43). In surviving animals, beginning at 1 h post-injury, 8.64 µg anti-MAG mAb (n = 33 injured, n = 21 sham) or control IgG (n = 26 injured, n = 22 sham) was infused intracerebroventricularly for 72 h. One group of these rats (n = 14 sham, n = 11 injured) was killed at 72 h post-injury for verification of drug diffusion and MAG immunohistochemistry. All other animals were evaluated up to 8 weeks post-injury using tests for neurologic motor, sensory and cognitive function. Hemispheric tissue loss was also evaluated at 8 weeks post-injury. At 72 h post-injury, increased immunoreactivity for MAG was seen in the ipsilateral cortex, thalamus and hippocampus of brain-injured animals, and anti-MAG mAb was detectable in the hippocampus, fimbria and ventricles. Brain-injured animals receiving anti-MAG mAb showed significantly improved recovery of sensorimotor function at 6 and 8 weeks (P < 0.01) post-injury when compared with brain-injured IgG-treated animals. Additionally, at 8 weeks post-injury, the anti-MAG mAb-treated brain-injured animals demonstrated significantly improved cognitive function and reduced hemispheric tissue loss (P < 0.05) when compared with their brain-injured controls. These results indicate that MAG may contribute to the pathophysiology of experimental TBI and treatment strategies that target MAG may be suitable for further evaluation.
Approximately 4000 human beings experience a traumatic brain injury each day in the United States... more Approximately 4000 human beings experience a traumatic brain injury each day in the United States ranging in severity from mild to fatal. Improvements in initial management, surgical treatment, and neurointensive care have resulted in a better prognosis for traumatic brain injury patients but, to date, there is no available pharmaceutical treatment with proven efficacy, and prevention is the major protective strategy. Many patients are left with disabling changes in cognition, motor function, and personality. Over the past two decades, a number of experimental laboratories have attempted to develop novel and innovative ways to replicate, in animal models, the different aspects of this heterogenous clinical paradigm to better understand and treat patients after traumatic brain injury. Although several clinically-relevant but different experimental models have been developed to reproduce specific characteristics of human traumatic brain injury, its heterogeneity does not allow one single model to reproduce the entire spectrum of events that may occur. The use of these models has resulted in an increased understanding of the pathophysiology of traumatic brain injury, including changes in molecular and cellular pathways and neurobehavioral outcomes. This review provides an up-to-date and critical analysis of the existing models of traumatic brain injury with a view toward guiding and improving future research endeavors.
Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS ax... more Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS axons may recover poorly following TBI due to expression of myelin-derived inhibitors to axonal outgrowth such as Nogo-A. To study the role of Nogo-A/B in the pathophysiological response of the elderly to TBI, 1-year-old mice deficient in Nogo-A/B (Nogo-A/B homozygous−/− mice), Nogo-A/B heterozygous−/+ mice, and age-matched wild-type (WT) littermate controls were subjected to a controlled cortical impact (CCI) TBI. Sham-injured WT mice (7 months old) and 12 month old naïve Nogo-A/B−/− and Nogo-A/B−/+ served as controls. Neurological motor function was evaluated up to 3 weeks, and cognitive function, hemispheric tissue loss, myelin staining and hippocampal β-amyloid (Aβ) immunohistochemistry were evaluated at 4 weeks post-injury. In WT littermates, TBI significantly impaired learning ability at 4 weeks and neurological motor function up to 2 weeks post-injury and caused a significant loss of hemispheric tissue. Following TBI, Nogo-A/B−/− mice showed significantly less recovery from neurological motor and cognitive deficits compared to brain-injured WT mice. Naïve Nogo-A/B−/− and Nogo-A/B−/+ mice quickly learned the MWM task in contrast to brain-injured Nogo-A/B−/− mice who failed to learn the MWM task at 4 weeks post-injury. Hemispheric tissue loss and cortical lesion volume were similar among the brain-injured genotypes. Neither TBI nor the absence of NogoA/B caused an increased Aβ expression. Myelin staining showed a reduced area and density in the corpus callosum in brain-injured Nogo-A/B−/− animals compared to their littermate controls. These novel and unexpected behavioral results demonstrate that the absence of Nogo-A/B may negatively influence outcome, possibly related to hypomyelination, following TBI in mice and suggest a complex role for this myelin-associated axonal growth inhibitor following TBI.
The reorganization of neuronal circuits after traumatic brain injury (TBI) consists of several ne... more The reorganization of neuronal circuits after traumatic brain injury (TBI) consists of several neurobiological alterations that are orchestrated in parallel and serial fashion. These include cellular death, axonal and dendritic plasticity, neurogenesis and gliogenesis, vascular alterations, axonal damage and remodelling of extracellular matrix and cellular membranes. Based on current knowledge, prevention or alleviation of neurodegeneration remains an attractive target for therapeutic attempts to improve the outcome following TBI. Here, we focus on the most recent studies that have advanced our understanding of the molecular mechanisms of TBI-induced neuronal death. These data provide candidate targets for design of novel therapies and for identification of biomarkers or surrogate markers for predicting the outcome or therapy response.Andrey Mazarati – Department of Pediatrics, UCLA, USAClaude Wasterlain – Department of Cardiology, UCLA, USA
This paper presents an Electrical Capacitance Tomography (ECT) sensor scheme consisting of N segm... more This paper presents an Electrical Capacitance Tomography (ECT) sensor scheme consisting of N segments linked in four groups, treated as single, extremely broad electrodes forming a 4-electrode sensor. This configuration is repeated along the pipe circumference, selecting different segments in order to form N/4 independent 4-electrode schemes. The response of this sensor is studied by means of Finite Element Method (FEM)-based simulations, and the results are compared to the response of a 12-electrode conventional sensor. The image reconstruction proved to have lower error when using the segmented sensor, and it is less sensitive to white noise affecting the measurements. A tomograph with 20 segments based on a FPGA core has been developed and tested using a test phantom. Results show that high values of inter-electrode capacitances and better image reconstruction can be achieved.
This paper presents an electrocardiogram (ECG) acquisition system based on reconfigurable devices... more This paper presents an electrocardiogram (ECG) acquisition system based on reconfigurable devices. This system allows redesigning the analog conditioning stage thanks to the use of a Field Programmable Analog Array (FPAA) device, which may be adapted to the requirements of the signal shape and/or medical specifications. Simulated and real ECG signals have been acquired using this system in a three-lead configuration. A detailed study of its technical features has been carried out, showing good suitability for ECG acquisition. Further digital ECG signal processing is performed on a Field Programmable Gate Array (FPGA) device, which has allowed different digital configurations to be tested, including FIR and wavelet filtering and identification of wave features such as the QRS complex. In addition, the FPGA device is in charge of FPAA reconfiguration. Thus, the pairing of FPAA and FPGA devices conforms a compact and versatile bio-signal acquisition platform. This platform has shown very good performance with different types of electrodes, and has also demonstrated the dynamic reconfiguration capabilities of these devices, which enable, for example, the tuning of gain and bandwidth as required by different input conditions and ECG application requirements. The analyzed performance parameters provide values such as 102 dB CMRR (Common-Mode Rejection Ratio), 14-bit ADC resolution, and 75 dB SNR (signal-to-noise ratio), among others, thus satisfying the minimum requirements for clinical use.
This work describes an analog reconfiguration technique for acquisition and processing of analog ... more This work describes an analog reconfiguration technique for acquisition and processing of analog sensor signals that involves field programmable analog arrays (FPAAs) and field programmable gate arrays (FPGAs). The main objective is to exploit their natural reconfiguration capabilities that allow the increase of the analog-to-digital conversion (ADC) resolution and an adaptive post processing of the digital signal. This work is completed by the demonstration of this technique with an NTC temperature sensor signal, increasing the ADC resolution. The proposed system acquires the analog signal with filtering, amplifications and ADC being performed on the FPAA, while dynamically tuning the analog conditioning on the FPAA; after that, the FPGA processes the digital signal and delivers the final result to the end user, also involving the use of an embedded PicoBlaze.
This work describes the application of both field programmable analog arrays (FPAAs) and field pr... more This work describes the application of both field programmable analog arrays (FPAAs) and field programmable gate arrays (FPGAs) for signal conditioning and processing in smart sensor applications. The main objective is to exploit their natural reconfiguration capabilities, which will expand the application field to more complex measurement and control systems. On the other hand, the introduction of IEEE 1451-compliant sensors allows for the development of multi-sensor and multi-purpose platforms, that may benefit from programmable technologies. Thus, this paper includes initial developments for IEEE 1451 smart sensor interfacing and its application to instrumentation.
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Papers by Diego Morales