This Research Topic surrounds the information presented at the upcoming conference Neurotrama Symposium held at the Centre for Trauma Research, September 15-16 2010. Traumatic injury to the central nervous system (CNS) is the leading cause of death and disability for people up to about 40 years of age. Examples and experiences of CNS trauma and medical care during historic and ongoing wars will be given, referring to the early history of Karolinska Institutet (KI).

Karolinska Institutet (KI)

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Frontiers in Neurology

Neurotrauma

Traumatic injuries in the nervous system

A new in vivo animal model that produces diffuse brain injuries in sagittal plane rearward rotational acceleration has been developed. In this model, the skull of an anesthetized adult rat is tightly secured to a rotating bar. During trauma, the bar is impacted by a striker that causes the bar and the animal head to rotate rearward; the acceleration phase last 0.4 ms and is followed by a rotation at constant speed and a gentle deceleration when the bar makes contact with a padded stop. The total head angle change is less than 30°. By adjusting the air pressure in the rifle used to accelerate the striker, resulting rotational acceleration between 0.3 and 2.1 Mrad/s2 can be produced. Numerous combinations of trauma levels, post-trauma survival times, brain and serum retrieval, and tissue preparation techniques were adopted to characterize this new model. The trauma caused subdural bleedings in animals exposed to severe trauma. Staining brain tissue with β-Amyloid Precursor Protein antibodies and FD Neurosilver that detect degenerating axons revealed wide spread axonal injuries (AI) in the corpus callosum, the border between the corpus callosum and cortex and in tracts in the brain stem. The observed AIs were apparent only when the rotational acceleration level was moderate and above. On the contrary, only limited signs of contusion injuries were observed following trauma. Macrophage invasions, glial fibrillary acidic protein redistribution or hypertrophy, and blood brain barrier (BBB) changes were unusual. S100 serum analyses indicate that blood vessel and glia cell injuries occur following moderate levels of trauma despite the absence of obvious BBB injuries. We conclude that this rotational trauma model is capable of producing graded axonal injury, is repeatable and produces limited other types of traumatic brain injuries and as such is useful in the study of injury biomechanics, diagnostics, and treatment strategies following diffuse axonal injury.

A new in vivo animal model that produces diffuse brain injuries in sagittal plane rearward rotational acceleration has been developed. In this model, the skull of an anesthetized adult rat is tightly secured to a rotating bar. During trauma, the bar is impacted by a striker that causes the bar and the animal head to rotate rearward; the acceleration phase last 0.4 ms and is followed by a rotation at constant speed and a gentle deceleration when the bar makes contact with a padded stop. The total head angle change is less than 30°. By adjusting the air pressure in the rifle used to accelerate the striker, resulting rotational acceleration between 0.3 and 2.1 Mrad/s2 can be produced. Numerous combinations of trauma levels, post-trauma survival times, brain and serum retrieval, and tissue preparation techniques were adopted to characterize this new model. The trauma caused subdural bleedings in animals exposed to severe trauma. Staining brain tissue with β-Amyloid Precursor Protein antibodies and FD Neurosilver that detect degenerating axons revealed wide spread axonal injuries (AI) in the corpus callosum, the border between the corpus callosum and cortex and in tracts in the brain stem. The observed AIs were apparent only when the rotational acceleration level was moderate and above. On the contrary, only limited signs of contusion injuries were observed following trauma. Macrophage invasions, glial fibrillary acidic protein redistribution or hypertrophy, and blood brain barrier (BBB) changes were unusual. S100 serum analyses indicate that blood vessel and glia cell injuries occur following moderate levels of trauma despite the absence of obvious BBB injuries. We conclude that this rotational trauma model is capable of producing graded axonal injury, is repeatable and produces limited other types of traumatic brain injuries and as such is useful in the study of injury biomechanics, diagnostics, and treatment strategies following diffuse axonal injury.

A New Model to Produce Sagittal Plane Rotational Induced Diffuse Axonal Injuries

The Karolinska Institutet 200-year anniversary symposium on injuries to the spinal cord and peripheral nervous system gathered expertise in the spinal cord, spinal nerve, and peripheral nerve injury field spanning from molecular prerequisites for nerve regeneration to clinical methods in nerve repair and rehabilitation. The topics presented at the meeting covered findings on adult neural stem cells that when transplanted to the hypoglossal nucleus in the rat could integrate with its host and promote neuron survival. Studies on vascularization after intraspinal replantation of ventral nerve roots and microarray studies in ventral root replantation as a tool for mapping of biological patterns typical for neuronal regeneration were discussed. Different immune molecules in neurons and glia and their very specific roles in synapse plasticity after injury were presented. Novel strategies in repair of injured peripheral nerves with ethyl-cyanoacrylate adhesive showed functional recovery comparable to that of conventional epineural sutures. Various aspects on surgical techniques which are available to improve function of the limb, once the nerve regeneration after brachial plexus lesions and repair has reached its limit were presented. Moreover, neurogenic pain after amputation and its treatment with mirror therapy were shown to be followed by dramatic decrease in phantom limb pain. Finally clinical experiences on surgical techniques to repair avulsed spinal nerve root and the motoric as well as sensoric regain of function were presented.

The Karolinska Institutet 200-year anniversary symposium on injuries to the spinal cord and peripheral nervous system gathered expertise in the spinal cord, spinal nerve, and peripheral nerve injury field spanning from molecular prerequisites for nerve regeneration to clinical methods in nerve repair and rehabilitation. The topics presented at the meeting covered findings on adult neural stem cells that when transplanted to the hypoglossal nucleus in the rat could integrate with its host and promote neuron survival. Studies on vascularization after intraspinal replantation of ventral nerve roots and microarray studies in ventral root replantation as a tool for mapping of biological patterns typical for neuronal regeneration were discussed. Different immune molecules in neurons and glia and their very specific roles in synapse plasticity after injury were presented. Novel strategies in repair of injured peripheral nerves with ethyl-cyanoacrylate adhesive showed functional recovery comparable to that of conventional epineural sutures. Various aspects on surgical techniques which are available to improve function of the limb, once the nerve regeneration after brachial plexus lesions and repair has reached its limit were presented. Moreover, neurogenic pain after amputation and its treatment with mirror therapy were shown to be followed by dramatic decrease in phantom limb pain. Finally clinical experiences on surgical techniques to repair avulsed spinal nerve root and the motoric as well as sensoric regain of function were presented.

Karolinska Institutet 200-Year Anniversary. Symposium on Traumatic Injuries in the Nervous System: Injuries to the Spinal Cord and Peripheral Nervous System – Injuries and Repair, Pain Problems, Lesions to Brachial Plexus

There is a need for complementary surgical techniques that enable rapid and reliable primary repair of transected nerves. Previous studies after peripheral nerve transection and repair with synthetic adhesives have demonstrated regeneration to an extent comparable to that of conventional techniques. The aim of this study was to compare two different repair techniques on the selectivity of muscle reinnervation after repair and completed regeneration. We used the cholera toxin B technique of retrograde axonal tracing to evaluate the morphology, the number, and the three-dimensional location of α-motoneurons innervating the lateral gastrocnemius muscle and compared the results after repair with either ethyl cyanoacrylate (ECA) or epineural sutures of the transected parent sciatic nerve. In addition, we recorded the wet weight of the muscle. Six months after transection and repair of the sciatic nerve, the redistribution of the motoneuron pool was markedly disorganized, the motoneurons had apparently increased in number, and they were scattered throughout a larger volume of the spinal cord gray matter with a decrease in the synaptic coverage compared to controls. A reduction in muscle weight was observed as well. No difference in morphometric variables or muscle weight between the two repair methods could be detected. We conclude that the selectivity of motor reinnervation following sciatic nerve transection and subsequent repair with ECA is comparable to that following conventional micro suturing.

There is a need for complementary surgical techniques that enable rapid and reliable primary repair of transected nerves. Previous studies after peripheral nerve transection and repair with synthetic adhesives have demonstrated regeneration to an extent comparable to that of conventional techniques. The aim of this study was to compare two different repair techniques on the selectivity of muscle reinnervation after repair and completed regeneration. We used the cholera toxin B technique of retrograde axonal tracing to evaluate the morphology, the number, and the three-dimensional location of &#x3b1;-motoneurons innervating the lateral gastrocnemius muscle and compared the results after repair with either ethyl cyanoacrylate (ECA) or epineural sutures of the transected parent sciatic nerve. In addition, we recorded the wet weight of the muscle. Six months after transection and repair of the sciatic nerve, the redistribution of the motoneuron pool was markedly disorganized, the motoneurons had apparently increased in number, and they were scattered throughout a larger volume of the spinal cord gray matter with a decrease in the synaptic coverage compared to controls. A reduction in muscle weight was observed as well. No difference in morphometric variables or muscle weight between the two repair methods could be detected. We conclude that the selectivity of motor reinnervation following sciatic nerve transection and subsequent repair with ECA is comparable to that following conventional micro suturing.

Selectivity in the Reinnervation of the Lateral Gastrocnemius Muscle after Nerve Repair with Ethyl Cyanoacrylate in the Rat

The study of those who have sustained traumatic brain injuries (TBI) during military conflicts has greatly facilitated research in the fields of neuropsychology, neurosurgery, psychiatry, neurology, and neuroimaging. The Vietnam Head Injury Study (VHIS) is a prospective, long-term follow-up study of a cohort of 1,221 Vietnam veterans with mostly penetrating brain injuries, which has stretched over more than 40 years. The scope of this study, both in terms of the types of injury and fields of examination, has been extremely broad. It has been instrumental in extending the field of TBI research and in exposing pressing medical and social issues that affect those who suffer such injuries. This review summarizes the history of conflict-related TBI research and the VHIS to date, as well as the vast range of important findings the VHIS has established.

The study of those who have sustained traumatic brain injuries (TBI) during military conflicts has greatly facilitated research in the fields of neuropsychology, neurosurgery, psychiatry, neurology, and neuroimaging. The Vietnam Head Injury Study (VHIS) is a prospective, long-term follow-up study of a cohort of 1,221 Vietnam veterans with mostly penetrating brain injuries, which has stretched over more than 40 years. The scope of this study, both in terms of the types of injury and fields of examination, has been extremely broad. It has been instrumental in extending the field of TBI research and in exposing pressing medical and social issues that affect those who suffer such injuries. This review summarizes the history of conflict-related TBI research and the VHIS to date, as well as the vast range of important findings the VHIS has established.

“Studying Injured Minds” – The Vietnam Head Injury Study and 40 Years of Brain Injury Research

Psychological stress and traumatic brain injury (TBI) can both result in lasting neurobehavioral abnormalities. Post-traumatic stress disorder and blast induced TBI (bTBI) have become the most significant health issues in current military conflicts. Importantly, military bTBI virtually never occurs without stress. In this experiment, we assessed anxiety and spatial memory of rats at different time points after repeated exposure to stress alone or in combination with a single mild blast. At 2 months after injury or sham we analyzed the serum, prefrontal cortex (PFC), and hippocampus (HC) of all animals by proteomics and immunohistochemistry. Stressed sham animals showed an early increase in anxiety but no memory impairment at any measured time point. They had elevated levels of serum corticosterone (CORT) and hippocampal IL-6 but no other cellular or protein changes. Stressed injured animals had increased anxiety that returned to normal at 2 months and significant spatial memory impairment that lasted up to 2 months. They had elevated serum levels of CORT, CK-BB, NF-H, NSE, GFAP, and VEGF. Moreover, all of the measured protein markers were elevated in the HC and the PFC; rats had an increased number of TUNEL-positive cells in the HC and elevated GFAP and Iba1 immunoreactivity in the HC and the PFC. Our findings suggest that exposure to repeated stress alone causes a transient increase in anxiety and no significant memory impairment or cellular and molecular changes. In contrast, repeated stress and blast results in lasting behavioral, molecular, and cellular abnormalities characterized by memory impairment, neuronal and glial cell loss, inflammation, and gliosis. These findings may have implications in the development of diagnostic and therapeutic measures for conditions caused by stress or a combination of stress and bTBI.

Psychological stress and traumatic brain injury (TBI) can both result in lasting neurobehavioral abnormalities. Post-traumatic stress disorder and blast induced TBI (bTBI) have become the most significant health issues in current military conflicts. Importantly, military bTBI virtually never occurs without stress. In this experiment, we assessed anxiety and spatial memory of rats at different time points after repeated exposure to stress alone or in combination with a single mild blast. At 2 months after injury or sham we analyzed the serum, prefrontal cortex (PFC), and hippocampus (HC) of all animals by proteomics and immunohistochemistry. Stressed sham animals showed an early increase in anxiety but no memory impairment at any measured time point. They had elevated levels of serum corticosterone (CORT) and hippocampal IL-6 but no other cellular or protein changes. Stressed injured animals had increased anxiety that returned to normal at 2 months and significant spatial memory impairment that lasted up to 2 months. They had elevated serum levels of CORT, CK-BB, NF-H, NSE, GFAP, and VEGF. Moreover, all of the measured protein markers were elevated in the HC and the PFC; rats had an increased number of TUNEL-positive cells in the HC and elevated GFAP and Iba1 immunoreactivity in the HC and the PFC. Our findings suggest that exposure to repeated stress alone causes a transient increase in anxiety and no significant memory impairment or cellular and molecular changes. In contrast, repeated stress and blast results in lasting behavioral, molecular, and cellular abnormalities characterized by memory impairment, neuronal and glial cell loss, inflammation, and gliosis. These findings may have implications in the development of diagnostic and therapeutic measures for conditions caused by stress or a combination of stress and bTBI.

Stress and Traumatic Brain Injury: A Behavioral, Proteomics, and Histological Study

In this fMRI study, the functions of the anterior cingulate cortex (ACC) were studied in a group of adolescents who had sustained a moderate to severe traumatic brain injury (TBI). A spatial working memory task with varying working memory loads, representing experimental conditions of increasing difficulty, was administered. In a cross-sectional comparison between the patients and a matched control group, patients performed worse than Controls, showing longer reaction times and lower response accuracy on the spatial working memory task. Brain imaging findings suggest a possible double-dissociation: activity of the ACC in the TBI group, but not in the Control group, was associated with task difficulty; conversely, activity of the left sensorimotor cortex (lSMC) in the Control group, but not in the TBI group, was correlated with task difficulty. In addition to the main cross-sectional study, a longitudinal study of a group of adolescent patients with moderate to severe TBI was done using fMRI and the same spatial working memory task. The patient group was studied at two time-points: one time-point during the post-acute phase and one time-point 12 months later, during the chronic phase. Results indicated that patients’ behavioral performance improved over time, suggesting cognitive recovery. Brain imaging findings suggest that, over this 12-month period, patients recruited less of the ACC and more of the lSMC in response to increasing task difficulty. The role of ACC in executive functions following a moderate to severe brain injury in adolescence is discussed within the context of conflicting models of the ACC functions in the existing literature.

In this fMRI study, the functions of the anterior cingulate cortex (ACC) were studied in a group of adolescents who had sustained a moderate to severe traumatic brain injury (TBI). A spatial working memory task with varying working memory loads, representing experimental conditions of increasing difficulty, was administered. In a cross-sectional comparison between the patients and a matched control group, patients performed worse than Controls, showing longer reaction times and lower response accuracy on the spatial working memory task. Brain imaging findings suggest a possible double-dissociation: activity of the ACC in the TBI group, but not in the Control group, was associated with task difficulty; conversely, activity of the left sensorimotor cortex (lSMC) in the Control group, but not in the TBI group, was correlated with task difficulty. In addition to the main cross-sectional study, a longitudinal study of a group of adolescent patients with moderate to severe TBI was done using fMRI and the same spatial working memory task. The patient group was studied at two time-points: one time-point during the post-acute phase and one time-point 12 months later, during the chronic phase. Results indicated that patients&#x2019; behavioral performance improved over time, suggesting cognitive recovery. Brain imaging findings suggest that, over this 12-month period, patients recruited less of the ACC and more of the lSMC in response to increasing task difficulty. The role of ACC in executive functions following a moderate to severe brain injury in adolescence is discussed within the context of conflicting models of the ACC functions in the existing literature.

Pivotal Role of Anterior Cingulate Cortex in Working Memory after Traumatic Brain Injury in Youth

Due to complex injurious environment where multiple blast effects interact with the body parallel, blast-induced neurotrauma is a unique clinical entity induced by systemic, local, and cerebral responses. Activation of autonomous nervous system; sudden pressure increase in vital organs such as lungs and liver; and activation of neuroendocrine–immune system are among the most important mechanisms that contribute significantly to molecular changes and cascading injury mechanisms in the brain. It has been hypothesized that vagally mediated cerebral effects play a vital role in the early response to blast: this assumption has been supported by experiments where bilateral vagotomy mitigated bradycardia, hypotension, and apnea, and also prevented excessive metabolic alterations in the brain of animals exposed to blast. Clinical experience suggests specific blast–body–nervous system interactions such as (1) direct interaction with the head either through direct passage of the blast wave through the skull or by causing acceleration and/or rotation of the head; and (2) via hydraulic interaction, when the blast overpressure compresses the abdomen and chest, and transfers its kinetic energy to the body's fluid phase, initiating oscillating waves that traverse the body and reach the brain. Accumulating evidence suggests that inflammation plays important role in the pathogenesis of long-term neurological deficits due to blast. These include memory decline, motor function and balance impairments, and behavioral alterations, among others. Experiments using rigid body- or head protection in animals subjected to blast showed that head protection failed to prevent inflammation in the brain or reduce neurological deficits, whereas body protection was successful in alleviating the blast-induced functional and morphological impairments in the brain.

Due to complex injurious environment where multiple blast effects interact with the body parallel, blast-induced neurotrauma is a unique clinical entity induced by systemic, local, and cerebral responses. Activation of autonomous nervous system; sudden pressure increase in vital organs such as lungs and liver; and activation of neuroendocrine&#x2013;immune system are among the most important mechanisms that contribute significantly to molecular changes and cascading injury mechanisms in the brain. It has been hypothesized that vagally mediated cerebral effects play a vital role in the early response to blast: this assumption has been supported by experiments where bilateral vagotomy mitigated bradycardia, hypotension, and apnea, and also prevented excessive metabolic alterations in the brain of animals exposed to blast. Clinical experience suggests specific blast&#x2013;body&#x2013;nervous system interactions such as (1) direct interaction with the head either through direct passage of the blast wave through the skull or by causing acceleration and/or rotation of the head; and (2) via hydraulic interaction, when the blast overpressure compresses the abdomen and chest, and transfers its kinetic energy to the body&#x2019;s fluid phase, initiating oscillating waves that traverse the body and reach the brain. Accumulating evidence suggests that inflammation plays important role in the pathogenesis of long-term neurological deficits due to blast. These include memory decline, motor function and balance impairments, and behavioral alterations, among others. Experiments using rigid body- or head protection in animals subjected to blast showed that head protection failed to prevent inflammation in the brain or reduce neurological deficits, whereas body protection was successful in alleviating the blast-induced functional and morphological impairments in the brain.

The Importance of Systemic Response in the Pathobiology of Blast-Induced Neurotrauma

Temperature disturbances are common in patients with severe traumatic brain injury. The possibility of an adaptive, potentially beneficial role for fever in patients with severe brain trauma has been dismissed, but without good justification. Fever might, in some patients, confer benefit. A cadre of clinicians and scientists met to debate the clinically relevant, but often controversial issue about whether raised brain temperature after human traumatic brain injury (TBI) should be regarded as “good or bad” for outcome. The objective was to produce a consensus document of views about current temperature measurement and pyrexia treatment. Lectures were delivered by invited speakers with National and International publication track records in thermoregulation, neuroscience, epidemiology, measurement standards and neurocritical care. Summaries of the lectures and workshop discussions were produced from transcriptions of the lectures and workshop discussions. At the close of meeting, there was agreement on four key issues relevant to modern temperature measurement and management and for undergirding of an evidence-based practice, culminating in a consensus statement. There is no robust scientific data to support the use of hypothermia in patients whose intracranial pressure is controllable using standard therapy. A randomized clinical trial is justified to establish if body cooling for control of pyrexia (to normothermia) vs moderate pyrexia leads to a better patient outcome for TBI patients.

Temperature disturbances are common in patients with severe traumatic brain injury. The possibility of an adaptive, potentially beneficial role for fever in patients with severe brain trauma has been dismissed, but without good justification. Fever might, in some patients, confer benefit. A cadre of clinicians and scientists met to debate the clinically relevant, but often controversial issue about whether raised brain temperature after human traumatic brain injury (TBI) should be regarded as &#x201c;good or bad&#x201d; for outcome. The objective was to produce a consensus document of views about current temperature measurement and pyrexia treatment. Lectures were delivered by invited speakers with National and International publication track records in thermoregulation, neuroscience, epidemiology, measurement standards and neurocritical care. Summaries of the lectures and workshop discussions were produced from transcriptions of the lectures and workshop discussions. At the close of meeting, there was agreement on four key issues relevant to modern temperature measurement and management and for undergirding of an evidence-based practice, culminating in a consensus statement. There is no robust scientific data to support the use of hypothermia in patients whose intracranial pressure is controllable using standard therapy. A randomized clinical trial is justified to establish if body cooling for control of pyrexia (to normothermia) vs moderate pyrexia leads to a better patient outcome for TBI patients.