Is being plastic fantastic? Mechanisms of altered plasticity after developmental traumatic brain injury

Traumatic brain injury (TBI) is predominantly a clinical problem of young persons, resulting in chronic cognitive and behavioral deficits. Specifically, the physiological response to a diffuse biomechanical injury in a maturing brain can clearly alter normal neuroplasticity. To properly evaluate and investigate developmental TBI requires an understanding of normal principles of cerebral maturation, as well as a consideration of experience-dependent changes. Changes in neuroplasticity may occur through many age-specific processes, and our understanding of these responses at a basic neuroscience level is only beginning. In this article, we will particularly discuss mechanisms of TBI-induced altered developmental plasticity such as altered neurotransmission, distinct molecular responses, cell death, perturbations in neuronal connectivity, experience-dependent 'good plasticity' enhancements and chronic 'bad plasticity' sequelae. From this summary, we can conclude that 'young is not always better' and that the developing brain manifests several crucial vulnerabilities to TBI.     

Stem cells for brain repair in neonatal hypoxia–ischemia

Neonatal hypoxic–ischemic insults are a significant cause of pediatric encephalopathy, developmental delays, and spastic cerebral palsy. Although the developing brain’s plasticity allows for remarkable self-repair, severe disruption of normal myelination and cortical development upon neonatal brain injury are likely to generate life-persisting sensory-motor and cognitive deficits in the growing child. Currently, no treatments are available that can address the long-term consequences. Thus, regenerative medicine appears as a promising avenue to help restore normal developmental processes in affected infants. Stem cell therapy has proven effective in promoting functional recovery in animal models of neonatal hypoxic–ischemic injury and therefore represents a hopeful therapy for this unmet medical condition. Neural stem cells derived from pluripotent stem cells or fetal tissues as well as umbilical cord blood and mesenchymal stem cells have all shown initial success in improving functional outcomes. However, much still remains to be understood about how those stem cells can safely be administered to infants and what their repair mechanisms in the brain are. In this review, we discuss updated research into pathophysiological mechanisms of neonatal brain injury, the types of stem cell therapies currently being tested in this context, and the potential mechanisms through which exogenous stem cells might interact with and influence the developing brain.     

Enfermedad cerebral,conectividad, plasticidad y terapia cognitiva. Una visión neurológica del trastorno mental

Introduction

Our conception of the mind-brain relationship has evolved from the traditional idea of dualism to current evidence that mental functions result from brain activity. This paradigm shift, combined with recent advances in neuroimaging, has led to a novel definition of brain functioning in terms of structural and functional connectivity. The purpose of this literature review is to describe the relationship between connectivity, brain lesions, cerebral plasticity, and functional recovery.

The cerebellum and neural networks for rhythmic sensorimotor synchronization in the human brain

Sensorimotor synchronization (SMS) is the rhythmic synchronization between a timed sensory stimulus and a motor response. This rather simple function requires complex cerebral processing whose basic mechanisms are far from clear. The importance of SMS is related to its hypothesized relevance in motor recovery following brain lesions. This is witnessed by the large number of studies in different disciplines addressing this issue. In the present review we will focus on the role of the cerebellum by referring to the general modeling of SMS functioning. Although at present no consensus exists on cerebellar timekeeping function it is generally accepted that cerebellar input and output flow process time information. Reviewed data are considered within the framework of the ‘sensory coordination’ hypothesis of cerebellar functioning. The idea that timing might be within the parameters that are under cerebellar control to optimize cerebral cortical functioning is advanced.     

Outcome from mild traumatic brain injury

PURPOSE OF REVIEW: The focus of this review is outcome from mild traumatic brain injury. Recent literature relating to pathophysiology, neuropsychological outcome, and the persistent postconcussion syndrome will be integrated into the existing literature. RECENT FINDINGS: The MTBI literature is enormous, complex, methodologically flawed, and controversial. There have been dozens of studies relating to pathophysiology, neuropsychological outcome, and the postconcussion syndrome during the past year. Two major reviews have been published. Some of the most interesting prospective research has been done with athletes. SUMMARY: The cognitive and neurobehavioral sequelae are self-limiting and reasonably predictable. Mild traumatic brain injuries are characterized by immediate physiological changes conceptualized as a multilayered neurometabolic cascade in which affected cells typically recover, although under certain circumstances a small number might degenerate and die. The primary pathophysiologies include ionic shifts, abnormal energy metabolism, diminished cerebral blood flow, and impaired neurotransmission. During the first week after injury the brain undergoes a dynamic restorative process. Athletes typically return to pre-injury functioning (assessed using symptom ratings or brief neuropsychological measures) within 2-14 days. Trauma patients usually take longer to return to their pre-injury functioning. In these patients recovery can be incomplete and can be complicated by preexisting psychiatric or substance abuse problems, poor general health, concurrent orthopedic injuries, or comorbid problems (e.g. chronic pain, depression, substance abuse, life stress, unemployment, and protracted litigation).     

Crush head injuries in infants and young children neurologic and neuropsychologic sequelae.

Neurologic and neuropsychologic sequelae of crush head injury, which is produced by static forces occurring when the head is stationary and pinned against a rigid structure, were studied prospectively in a series of eight children ranging in age from 13 to 32 months. Hospital course, computed tomographic findings, and neurologic and developmental outcomes were examined. All children sustained pronounced cerebral trauma characterized by multiple fractures throughout the calvaria, extra-axial hemorrhages, and parenchymal contusions. Cranial nerve injuries were noted in three and hemiparesis in two of the cases. Two months after the injury, 63% of the children displayed deficits in either IQ or motor functioning. One year after the injury, five of the six children reevaluated had a good recovery. Motor scores were significantly lower than cognitive scores at baseline and showed the greatest degree of improvement over time. Neuropsychologic outcome after brain injury produced by static loading of the head is more favorable than from traumatic brain injury associated with dynamic loading.     

Discourse plasticity in children after stroke: age at injury and lesion effects

Studies of children with stroke indicate remarkable recovery of language after some initial delay. However, complex language abilities as measured by discourse (connected language) may be required to detect the full impact of stroke on subsequent cognitive-linguistic development. This study examined discourse ability in children with stroke as compared with orthopedic controls, age-at-injury, and lesion effects. Discourse between two groups of children was compared [stroke (n = 17) vs orthopedic control (n = 17)]. The stroke group was subdivided into early age at stroke (<1 year) and late age at stroke (>1 year). The discourse samples were analyzed along two dimensions: language and information structure. Results revealed that the stroke group performed at significantly lower levels than the orthopedic control group across discourse measures. The most important finding was a poorer outcome for early age at stroke as compared with later age at stroke. These findings alter the widespread belief of optimistic language outcomes after childhood stroke. Interestingly, no site or size-of-lesion effects, common to adult stroke, were identified. These findings identify poor long-term outcome with early brain insults at stages far removed from the onset of injury. The implication is that childhood stroke management should be revised to provide protracted follow-up and treatment.     

New magnetic resonance imaging methods for cerebrovascular disease: emerging clinical applications

During the 1990s, novel magnetic resonance imaging (MRI) techniques have emerged that allow the noninvasive and rapid assessment of normal brain functioning and cerebral pathophysiology. Some of these techniques, including diffusion-weighted imaging and perfusion-weighted imaging, have already been used extensively in specialized centers for the evaluation of patients with cerebrovascular disease. Evidence is now rapidly accumulating that both diffusion- and perfusion-weighted imaging, particularly when used in combination with high-speed MR angiography, will lead to improvements in the clinical management of acute stroke patients. Other novel MR techniques, such as spectroscopic imaging, diffusion tensor imaging, and blood oxygenation level-dependent functional MRI, have not yet assumed a definitive role in the diagnostic evaluation of cerebrovascular disease. However, they are promising research tools that provide noninvasive data about infarct evolution as well as mechanisms of stroke recovery. In this article, we review the basic principles underlying these novel MRI techniques and outline their current and anticipated future impact on the diagnosis and management of patients with cerebrovascular disease.     

The influence of astrocytes on the development,regeneration and reconstruction of the nigrostriatal dopamine system

Over the past few decades astrocytes have emerged from being considered simple packing tissue in the brain to become major players in the development, survival and functioning of central nervous system (CNS) neurons. As the influence that astrocytes (and the various molecules they produce) have on the development of CNS neurons becomes more evident, it will be important to consider how this information can be exploited to bring about better protection, recovery and/or regeneration of circuits which are destroyed in the adult CNS due to trauma or com-mon neurodegenerative episodes. Although the characterisation of astrocytic responses to brain injuries, neurodegenerative disease, and cell transplantation are becoming more common, we still known little about how astrocytes influence the (re)growth or reconstruction of neural circuitry after the development period is ended, or indeed what is the overall impact of an astrocytic presence on the growth of neurons in the adult CNS. With the major hurdle of recognition of the importance astrocytes in the function and recovery of the adult CNS now cleared, a new chapter in the development of powerful new treatments for CNS disorders and injuries is now open. The following is a brief review of what we know about how astrocytes influence the growth and connectivity of the nigrostriatal circuit during development, and how these cells may affect efforts to reform this circuit after it s destruction/degeneration in the adult CNS (as commonly happens in Parkinson s disease). As we obtain more information on the specific influence of these cells in various developmental, traumatic and disease events we can expect to find better ways toward combating major disorders of the human CNS.     

The neurobiology of opiate tolerance,dependence and sensitization: Mechanisms of NMDA receptor-dependent synaptic plasticity

Long-term administration of opiates leads to changes in the effects of these drugs, including tolerance, sensitization and physical dependence. There is, as yet, incomplete understanding of the neural mechanisms that underlie these phenomena. Tolerance, sensitization and physical dependence can be considered adaptive processes similar to other experience-dependent changes in the brain, such as learning and neural development. There is considerable evidence demonstrating that N-methyl-D-aspartate (NMDA) receptors and downstream signaling cascades may have an important role in different forms of experience-dependent changes in the brain and behavior. This review will explore evidence indicating that NMDA receptors and downstream messengers may be involved in opiate tolerance, sensitization and physical dependence. This evidence has been used to develop a cellular model of NMDA receptor/opiate interactions. According to this model, mu opioid receptor stimulation leads to a protein kinase C-mediated activation of NMDA receptors. Activation of NMDA receptors leads to influx of calcium and activation of calcium-dependent processes. These calcium-dependent processes have the ability to produce critical changes in opioid-responsive neurons, including inhibition of opioid receptor/second messenger coupling. This model is similar to cellular models of learning and neural development in which NMDA receptors have a central role. Together, the evidence suggests that the mechanisms that underlie changes in the brain and behavior produced by long-term opiate use may be similar to other central nervous system adaptations. The experimental findings and the resulting model may have implications for the treatment of pain and addiction.     

Cerebral reorganization as a function of linguistic recovery in children: An fMRI study

Characterizing and mapping the relationship between neuronal reorganization and functional recovery are essential to the understanding of cerebral plasticity and the dynamic processes which occur following brain damage. The neuronal mechanisms underlying linguistic recovery following left hemisphere (LH) lesions are still unknown. Using functional magnetic resonance imaging (fMRI), we investigated whether the extent of brain lateralization of linguistic functioning in specific regions of interest (ROIs) is correlated with the level of linguistic performance following recovery from acquired childhood aphasia. The study focused on a rare group of children in whom lesions occurred after normal language acquisition, but prior to complete maturation of the brain. During fMRI scanning, rhyming, comprehension and verb generation activation tasks were monitored. The imaging data were evaluated with reference to linguistic performance measured behaviorally during imaging, as well as outside the scanner. Compared with normal controls, we found greater right hemisphere (RH) lateralization in patients. However, correlations with linguistic performance showed that increased proficiency in linguistic tasks was associated with greater lateralization to the LH. These results were replicated in a longitudinal case study of a patient scanned twice, 3 years apart. Additional improvement in linguistic performance of the patient was accompanied by increasing lateralization to the LH in the anterior language region. This, however, was the result of a decreased involvement of the RH. These findings suggest that recovery is a dynamic, ongoing process, which may last for years after onset. The role of each hemisphere in the recovery process may continuously change within the chronic stage.     

Structure, Function and Cerebral Asymmetry: In Vivo Morphometry of the Planum Temporale

STEINMETZ, H. Structure, function, and cerebral asymmetry: in vivo morphometry of the planum temporale. NEUROSCI BIOBEHAV REV 20(4)587–591, 1996.—Using high-resolution magnetic resonance (MR) imaging, the normal left-right asymmetry of the planum temporale (PT) can be quantified accurately and reliably in the intact human brain. The following main results have emerged from MR measurements of individual direction and degree of PT asymmetry. (1) Normal left-handers are less left-lateralized than normal right-handers, without significant gender effects. This confirms a structural-functional correlation in cerebral asymmetry. (2) The aforementioned handedness difference in PT asymmetry is also found in pairs of normal monozygotic twins discordant for handedness. Thus, structural brain asymmetry may not be genetically determined. (3) Whereas right-handed patients with developmental deficits of phonological processing have been reported to show decreased PT asymmetry, musicians with perfect pitch display exaggerated leftward asymmetry. Thus, increasing leftward asymmetry of auditory-related cortices covering the PT may be correlated with the processing capacity for certain auditory features. Studies of the PT as a structural marker of cerebral asymmetry will continue to contribute to a better understanding of the phylogeny and ontogeny of laterality. Copyright © 1996 Elsevier Science Ltd.     

Recovery recapitulates ontogeny

Several studies support the hypothesis that after stroke, specific features of brain function revert to those seen at an early stage of development, with the subsequent process of recovery recapitulating ontogeny in many ways. Many clinical characteristics of stroke recovery resemble normal development, particularly in the motor system. Consistent with this, brain-mapping studies after an ischemic insult suggest re-emergence of childhood organizational patterns: recovery being associated with a return to adult patterns. Experimental animal studies demonstrate increased levels of developmental proteins, particularly in the area surrounding an infarct, suggesting an active process of reconditioning in response to cerebral ischemia. Understanding the patterns of similarity between normal development and stroke recovery might be of value in its treatment.     

Clinical disorders of brain plasticity

Clinical disorders of brain plasticity are common in the practice of child neurology. Children have an enhanced capacity for brain plasticity compared to adults as demonstrated by their superior ability to learn a second language or their capacity to recover from brain injuries or radical surgery such as hemispherectomy for epilepsy. Basic mechanisms that support plasticity during development include persistence of neurogenesis in some parts of the brain, elimination of neurons through apoptosis or programmed cell death, postnatal proliferation and pruning of synapses, and activity-dependent refinement of neuronal connections. Brain plasticity in children can be divided into four types: adaptive plasticity that enhances skill development or recovery from brain injury; impaired plasticity associated with cognitive impairment; excessive plasticity leading to maladaptive brain circuits; and plasticity that becomes the brain's 'Achilles' Heel' because makes it vulnerable to injury. A broad group of pediatric neurologic disorders can be understood in terms of their impact on fundamental mechanisms for brain plasticity. These include neurofibromatosis, tuberous sclerosis, Fragile X syndrome, other inherited forms of mental retardation, cretinism, Coffin-Lowry syndrome, lead poisoning, Rett syndrome, epilepsy, hypoxic-ischemic encephalopathy and cerebral palsy.     

Clinical applications of neuropsychological assessment

Neuropsychological assessment is a performance-based method to assess cognitive functioning. This method is used to examine the cognitive consequences of brain damage, brain disease, and severe mental illness. There are several specific uses of neuropsychological assessment, including collection of diagnostic information, differential diagnostic information, assessment of treatment response, and prediction of functional potential and functional recovery. We anticipate that clinical neuropsychological assessment will continue to be used, even in the face of advances in imaging technology, because it is already well known that the presence of significant brain changes can be associated with nearly normal cognitive functioning, while individuals with no lesions detectable on imaging can have substantial cognitive and functional limitations.     

Adult neurogenesis and neuroplasticity

After cerebral strokes and traumatic brain injuries (TBIs), there is a striking amount of neurological recovery in the following months and years, despite often-permanent structural damage. Though the mechanisms underlying such recovery are not fully understood, properties of plasticity of the central nervous system (CNS), such as the reorganization of the pre-existing network and axonal sprouting have been implicated in the recovery. With the recent evidences that neurogenesis occurs in the adult brain, and neural stem cells (NSCs) reside in the adult CNS, the involvement of newly generated neuronal cells in the recovery following injury to the CNS remains to be established. Neurogenesis is increased bilaterally in the dentate gyrus (DG) and the subventicular zone (SVZ) after cerebral strokes and TBIs, and new neuronal cells are generated at the sites of injury, where they replace some of the degenerated nerve cells. Newly generated neuronal cells at the sites of injury may represent an attempt by the CNS to regenerate itself after injury, whereas the increased neurogenesis in the DG and SVZ would also contribute to the CNS plasticity. Thus, injury-induced neurogenesis may contribute to the recovery and plasticity of the CNS.     

Assessing executive functions in children: biological,psychological, and developmental considerations

Executive functions may be defined as those skills necessary for purposeful, goal-directed activity, and are generally considered to be largely mediated by the frontal and prefrontal cortices of the brain. These cerebral regions are relatively immature during childhood, with development thought to be a protracted process which continues into early adolescence. While early theorists suggested that executive skills were not functional until cerebral maturity, recent research provides evidence that such skills can be elicited in early childhood. The aim of this paper is to review current theories of development of executive functions throughout childhood. In keeping with contemporary approaches to child neuropsychology, three critical dimensions will be evaluated; biological factors, psychological dimensions, and developmental trajectories. In addition, the literature which addresses assessment of these functions will be examined, with reference to developmental trajectories observed in normal populations, and in brain-damaged samples, where there may be disruption to the underlying neural substrates thought to be subsuming these functions.