PEDIATRICS Vol. 117 No. 4 April 2006, pp. 1372-1381 (doi:10.1542/peds.2005-0826)
REVIEW ARTICLE |
The Role of Functional Neuroimaging in Pediatric Brain Injury
Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
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ABSTRACT |
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 TOP ABSTRACT ASSESSMENT OF PEDIATRIC BRAIN...FUNCTIONAL NEUROIMAGING...DIAGNOSIS AND CLINICAL OUTCOME...MECHANISMS OF RECOVERY FROM...MECHANISMS OF RECOVERY AFTER...CONCLUSIONSREFERENCES |
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The aim of this article is to review empirical studies published in the last 10 years that used various functional neuroimaging techniques to assess pediatric patients with brain injury. Overall, these studies have demonstrated the ability of functional neuroimaging to offer unique information concerning the diagnosis, clinical outcome, and recovery mechanisms after pediatric brain injury. Future research using functional neuroimaging is recommended to better understand the functional reorganization and neurodevelopmental consequences resulting from brain injury. Such research might allow clinicians to design tailored early-intervention and rehabilitation programs to maximize the recovery process for pediatric patients. Limitations and advantages associated with the use of functional neuroimaging in pediatric populations are discussed.
Key Words: brain development • functional neuroimaging • brain injury • plasticity • vulnerability
Abbreviations: GCS—Glasgow Coma Scale • PCPCS—Pediatric Cerebral Performance Category Scale • CT—computed tomography • DTI—diffusion tensor imaging • EEG—electroencephalography • fMRI—functional MRI • 1H-MRS—proton magnetic resonance spectroscopy • PET—positron emission tomography • SPECT—single-photon emission computed tomography • BOLD—blood oxygen level–dependent • NAA—N-acetyl-aspartate • Cre—creatine/phosphocreatine • Cho—cytosolic choline compound • 99Tcm-HMPAO—technetium-99m-exametazime • TE—time to echo
Brain injury is among the leading causes of death or permanent disability in children and adolescents living in the United States.1 Approximately 200000 patients with pediatric brain injury are hospitalized each year, and of these children, 
30000 suffer permanent disability.2–4 The cause of injury can be either accidental (eg, near drowning, motor vehicle accident) or nonaccidental (eg, seizures, stroke, hypoglycemia), and the resulting brain lesion can be classified as either primary (occurring immediately after the injury) or secondary (initiated at the moment of injury but evolving over a period of time). Primary brain injury is typically characterized by focal lesions including intracerebral hemorrhages, ischemic infarcts, and contusions, whereas secondary brain injury is distinguished by cerebral edema or hematoma.5
Overall, brain injury can result in a wide array of neuropathological changes that affect tissue density, cerebral blood flow, white matter integrity, and pathway connectivity.6 In children and adolescents, these neuropathological changes have been found to be associated with a variety of neurobehavioral sequelae including memory loss, impaired decision-making and information processing, deficits in executive function, emotional dysfunction, and modifications in behavior and personality.7–9
Our review is unique because it focuses on the last 10 years of published work from researchers using advanced functional neuroimaging techniques in brain injury in the pediatric population including infancy, childhood, and adolescence. These studies are summarized in Table 1. Advantages and drawbacks of these techniques are addressed, and inferences on brain plasticity and related consequences for brain injury outcome are discussed.
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ASSESSMENT OF PEDIATRIC BRAIN INJURY |
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TOPABSTRACTASSESSMENT OF PEDIATRIC BRAIN...FUNCTIONAL NEUROIMAGING...DIAGNOSIS AND CLINICAL OUTCOME...MECHANISMS OF RECOVERY FROM...MECHANISMS OF RECOVERY AFTER...CONCLUSIONSREFERENCES |
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Immediately after injury, patients are typically assessed with both clinical measures and structural neuroimaging techniques. The most prevalent clinical measure is the Glasgow Coma Scale (GCS),10 which evaluates impairment of function based on 3 behavioral responses: verbal, motor, and eye-opening. In accordance to the results of the GCS, the patient's injury is categorized as mild (score of 13–15), moderate (score of 9–12), or severe (score of 3–8 [coma state]). At discharge, the Glasgow Outcome Scale11 is used to classify the overall status of the patient as good recovery, moderate disability, severe disability, persistent vegetative state, or death. Other clinical indices commonly used to evaluate the outcome of brain injury in the pediatric population include the Pediatric Cerebral Performance Category Scale (PCPCS) (a modified version of the Glasgow Outcome Scale),12 the Kriel Outcome Scale (a functional measure designed for older adolescents),13 and the Rancho Los Amigos Cognitive Level (a 10-level measure of cognitive function).14 Although these indices tend to be correlated with outcome of brain injury in adults, acute clinical condition is a less reliable predictor of outcome in children.15
Structural neuroimaging techniques such as computed tomography (CT) and diffusion-weighted magnetic resonance imaging (MRI)16 play a critical role in the acute diagnosis of pediatric brain injury because they provide an immediate estimate of diffuse axonal injury that may require emergency intervention. Newly emerging high-resolution MRI technology (eg, diffusion tensor imaging [DTI]17–19 and susceptibility-weighted imaging20) have proven to be especially useful in the pediatric population because they demonstrate alterations in white matter connections that cannot be detected by conventional structural techniques.21 However, a "normal" structural scan during the acute phase of injury does not rule out subsequent functional damage. During the year after injury, the brain can undergo significant hemodynamic and biochemical changes that may result in neurobehavioral dysfunction.8
This considered, functional neuroimaging has significant potential to provide a more accurate diagnosis of neurologic damage and clinical outcome. In contrast to structural neuroimaging, functional neuroimaging allows researchers to study neural function across the whole brain and provide a map of the pattern of neural activity. Other techniques such as electroencephalography (EEG) or event-related potentials also provide measures of brain function but provide poor spatial-resolution sensitivity, particularly with respect to subcortical structures. In addition to its ability to reveal physiologic dysfunction in regions that appear structurally intact on a CT or MRI scan, functional neuroimaging may serve to assess reorganization that often occurs to compensate for severe neurologic damage. Furthermore, because of its ability to depict brain activity during cognitive tasks, functional neuroimaging can help to clarify how children and adults differ in terms of recovery mechanisms, thus enabling neuroscientists to design treatments tailored to meet the unique needs of pediatric patients.
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FUNCTIONAL NEUROIMAGING TECHNIQUES |
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TOPABSTRACTASSESSMENT OF PEDIATRIC BRAIN...FUNCTIONAL NEUROIMAGING...DIAGNOSIS AND CLINICAL OUTCOME...MECHANISMS OF RECOVERY FROM...MECHANISMS OF RECOVERY AFTER...CONCLUSIONSREFERENCES |
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Currently, functional neuroimaging techniques that are commonly used to measure metabolic or hemodynamic changes in the brain include functional MRI (fMRI), proton magnetic resonance spectroscopy (1H-MRS), positron emission tomography (PET), and single-photon emission CT (SPECT). These techniques differ in methodology and level of invasiveness. With the usual precautions of excluding subjects carrying metal, fMRI and 1H-MRS are noninvasive. Whereas fMRI uses a blood oxygen level–dependent (BOLD) signal to index neural activation, 1H-MRS measures the relative concentration of metabolites (eg, N-acetyl-aspartate [NAA], creatine/phosphocreatine [Cre], cytosolic choline compounds [Cho]) in a given volume of brain tissue. PET and SPECT involve radiation exposure resulting from the use of a radiolabeled tracer/ligand to measure cerebral blood flow or other specific chemical elements such as neurotransmitter levels, receptors, or enzymes. In addition, magnetoencephalography and quantitative EEG are 2 noteworthy brain-mapping techniques that can be used to characterize magnetic or electrical shifts that occur after brain trauma. However, these techniques are not commonly used as the primary means of examining pediatric patients with brain injury. For a comprehensive review of the underlying principles, advantages, and limitations of the various functional neuroimaging techniques, refer to the work by Ernst and Rumsey.22
Here we review the recently published studies that have used functional neuroimaging to evaluate pediatric patients with brain injury. First, we discuss 7 studies that highlight the relative advantages and limitations of functional neuroimaging with regard to initial assessment, identification of chronic pathologic changes, prediction of clinical outcome, and treatment design. We then address past and present principles of neural plasticity, which clarify mechanisms underlying differences in recovery from similar neurologic damage between children and adults. Finally, we review 6 studies that used functional neuroimaging to elucidate mechanisms of recovery and neurophysiological reorganization after pediatric brain injury.
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DIAGNOSIS AND CLINICAL OUTCOME AFTER PEDIATRIC BRAIN INJURY |
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TOPABSTRACTASSESSMENT OF PEDIATRIC BRAIN...FUNCTIONAL NEUROIMAGING...DIAGNOSIS AND CLINICAL OUTCOME...MECHANISMS OF RECOVERY FROM...MECHANISMS OF RECOVERY AFTER...CONCLUSIONSREFERENCES |
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The following 7 studies highlight the ability of functional neuroimaging techniques to assess acute neural abnormalities, identify chronic pathology, and predict clinical outcome in the aftermath of pediatric brain injury (see Table 1).
Seghier et al19 used BOLD fMRI and DTI to examine a 3-month-old infant with perinatal stroke involving the left visual pathways. DTI revealed the absence of the optic radiation in the left hemisphere. In accordance with these structural findings, fMRI during visual stimulation revealed negative BOLD activation in the visual cortex of the intact right hemisphere and no activation in the infarcted left hemisphere. This innovative study demonstrated how a combination of structural and functional techniques can be used to elucidate structure-function relationships after pediatric brain injury. Such findings have the potential to provide valuable guidelines for early surgical interventions.
Goshen et al23 and Emanuelson et al24 compared the efficacy of SPECT to that of conventional structural neuroimaging techniques in the evaluation of pediatric patients during the year after brain injury. Goshen et al23 used SPECT with technetium-99m-exametazime (99Tcm-HMPAO, which assays regional cerebral blood flow), EEG, CT, and MRI to examine 28 patients (aged 15 months to 16 years; mean: 8.9 years) presenting with chronic clinical sequelae of brain injury. SPECT was performed, on average, 3 months after the injury. Six patients underwent repeated follow-up scans, for a total of 35 SPECT studies evaluated retrospectively. SPECT abnormalities were defined qualitatively by degree of regional gray matter perfusion (normal, absent, decreased, or increased).
Overall results indicated that SPECT was a more sensitive method than CT, EEG, or MRI for detecting neural lesions. Although all patients had clinical symptoms, 15 of 32 CT scans and 4 of 10 MRI scans were read as normal, compared with only 3 of 35 SPECT studies. The EEG results were generally abnormal (80%) but provided nonspecific evidence of background-activity disturbance. When pathology was found by using CT, the results were generally in agreement with SPECT findings. However, CT findings were often less well defined and not as discretely localized as SPECT findings. SPECT was found to be particularly sensitive in detecting abnormalities in the basal ganglia and cerebellar regions, with a 3.6:1 detection rate in the basal ganglia and a 5:1 detection rate in the cerebellum compared with CT. Furthermore, a significant correlation was observed between the SPECT findings and clinical status, particularly in patients suffering from motor dysfunction. This study concluded that SPECT can be helpful in assessing the extent of brain lesion during the chronic stage of pediatric brain injury, when there is often no clear-cut relationship between anatomic and clinical findings.
Emanuelson et al24 examined 20 pediatric patients (aged 3.9–18.4 years; mean: 14.4 years) by using SPECT with 99Tcm-HMPAO and CT. The patients, who suffered brain injury after a traffic accident, a fall, anoxia, or surgical complications, were divided into 2 groups (mild injury and severe injury) on the basis of GCS score. CT scans (acquired at a mean of 9 days after the trauma) and SPECT results (acquired at a mean of 10 months after the trauma) were analyzed retrospectively, and the findings were related to clinical data at discharge and follow-up 5 years after injury. Clinical measures included the GCS, the Glasgow Outcome Scale, the Kriel Outcome Scale,25 and telephone interviews. With respect to neurologic outcome, CT and SPECT revealed similar results in the patients with severe injury, but in the group of mildly injured children, the number of affected lobes indicated by SPECT was significantly higher than those indicated by CT. SPECT was also a better predictor of clinical outcome on discharge and at a 5-year follow-up. Overall, SPECT seemed to be a more sensitive method than CT for detecting minor abnormalities in brain physiology and predicting functional outcome in cases of mild pediatric brain injury.
Sutton et al26 used 1H-MRS to assess pediatric patients with brain injury to study biochemical changes that occurred immediately after the injury and make treatment recommendations. In the first part of the study, 17 patients (aged 1 month to 15 years; average age: 4.75 years) were evaluated by using MRI. Causes of brain injury included motor vehicle accidents, a fall, and child abuse. On the basis of the results of the MRI scan, the patients were placed into 1 of 3 groups that defined the nature of their injury: contusion, traumatic cerebral infarction, or diffuse axonal injury. 1H-MRS scans were acquired after the MRI scans, 48 to 72 hours postinjury. 1H-MRS spectra indicated an increase in brain tissue lactate/total creatine ratio in regions of traumatic infarction and contusion compared with regions of diffuse axonal injury and healthy brains.
Lactate is an acidic byproduct of glycolysis that is present in small, usually undetectable amounts in the brain of healthy children and adults (lactate levels in infants are naturally higher and may be detectable by 1H-MRS).2,27 If ischemia occurs as the result of injury and the amount of oxygen in the brain decreases, lactate levels will rise. The accumulation of too much lactate results in tissue acidosis, which may cause additional brain damage.28 Thus, when treating pediatric patients suffering from infarctions and contusions, Sutton et al26 suggest the use of buffering agents such as tromethamine to reduce the amount of tissue lactate. Clinical trials conducted by Marmarou et al29 and Wolf et al30 confirmed that tromethamine is a safe and effective way to counteract acidosis in the brain of injured adults. However, to date, no studies have been published examining the efficacy of tromethamine in the treatment of pediatric patients with brain injury.
Ashwal et al2 and Holshouser et al27 assessed the predictive value of 1H-MRS in determining outcome of pediatric brain injury. Ashwal et al2 studied a group of 53 patients: 26 infants (aged 1–17 months; mean: 7 months) and 27 children (
18 months; mean: 8.5 years) with acute nonaccidental (n = 21) or other forms (n = 32) of injury. Patients were evaluated by using clinical measures (including the GCS and the PCPCS, a 15-point MRI scaling system [based on the location and extent of the injury]), and 1H-MRS spectra (acquired at a mean of 5 days postinjury in infants and 8 days postinjury in children). 1H-MRS indicated that metabolite ratios were abnormal (lower NAA/Cre or NAA/Cho, higher Cho/Cre) in patients who had a poor outcome (severe disability, persistent vegetative state, and death). Lactate was detected in 91% of the infants and 80% of the children who had poor outcomes; none of the patients with good outcome (no, mild, or moderate disability) had detectable lactate levels. Thus, the presence of lactate alone was able to accurately predict the 6- to 12-month outcome in 96% of the infants and 96% of the children. In contrast, the clinical variables alone were able to accurately predict the 6- to 12-month outcome in only 77% of the infants and 86% of the children.
Holshouser et al27 compared the effectiveness of short-echo-time (time to echo [TE]: 20 milliseconds) and long-echo-time (TE: 270 milliseconds) 1H-MRS methods in evaluating pediatric brain injury. The advantages of the short-TE method include better signal-to-noise ratios and the ability to detect metabolites other than lactate (eg, glutamate/glutamine ratios). The main advantage of the long-TE method is the reduced interference (resulting from underlying signals of other metabolites) in the detection of lactate. Whereas both methods have been used successfully to examine the developing brain after injury,31,32 the 2 methods are rarely used to comparatively examine the same group of pediatric patients with brain injury.
Many of the 70 patients examined by Holshouser et al27 were also included in the Ashwal et al2 sample. The patients were divided into 3 age groups: 19 neonates (aged 3 days to 1 month; mean: 11 days), 28 infants (aged 1–17 months; mean: 8 months), and 23 children (aged 20 months to 18 years; mean: 6 years). Causes of brain injury included cardiac arrest, near drowning, encephalopathy, and surgical complications. Patients were evaluated by using clinical measures (including the GCS and the PCPCS) and 1H-MRS spectra (acquired at a mean of 9 days postinjury in neonates, 4 days postinjury in infants, and 6 days postinjury in children). The short- and long-TE methods were equally predictive (91% in children and 96% in infants) of long-term outcome in children >1 month of age. However, the long-TE method produced a higher percentage of correct outcome predictions (91%) than the short-TE method (79%) in neonates.
Considering the importance of an accurate early prediction of outcome in the development of a treatment plan and family counseling, collective results from the studies conducted by Ashwal et al2 and Holshouser et al27 support the value of 1H-MRS in the evaluation of pediatric brain injury. However, the usefulness of 1H-MRS as an assessment tool in the acute stages of brain injury is limited by the fact that signal distortion prevents reliable probing of brain regions affected by contusion or hemorrhage.
Worley et al15 examined the effectiveness of PET with 18-fluorodeoxyglucose (which measures regional cerebral glucose metabolic rates) in predicting the outcome of pediatric brain injury. Patients included 22 children and adolescents (aged 4 months to 19 years; mean: 7 years) with severe traumatic, nonpenetrating brain injury caused by traffic accidents or abuse. All patients were evaluated by using clinical measures (GCS and the Rancho Los Amigos Cognitive Level Scale, scores combined to form the summary outcome score) and a PET scan (acquired at a median of 55 days postinjury; range: 18–643 days). One subset of the patients (n = 16) also received a CT or MRI within 24 days of the PET scan, and another subset of patients (n = 11) received a second PET scan at the point of outcome (a median of 28 months after the first PET scan). Regional cerebral metabolic rates of glucose were significantly correlated with clinical outcome only when the PET scan was acquired earlier than 12 weeks postinjury. Overall, PET scores were not more accurate than CT or MRI results in predicting clinical outcome. Future research is needed to delineate the critical postinjury time periods during which functional neuroimaging can optimally predict clinical outcome.
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MECHANISMS OF RECOVERY FROM BRAIN INJURY IN CHILDREN VERSUS ADULTS: THE KENNARD PRINCIPLE AND NEURAL PLASTICITY |
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TOPABSTRACTASSESSMENT OF PEDIATRIC BRAIN...FUNCTIONAL NEUROIMAGING...DIAGNOSIS AND CLINICAL OUTCOME...MECHANISMS OF RECOVERY FROM...MECHANISMS OF RECOVERY AFTER...CONCLUSIONSREFERENCES |
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In the 1930s, Margaret Kennard33 conducted systematic research on the effects of experimental cortical lesions in infant and adult monkeys and found that the behavioral consequences of similar lesions were less severe in infants. The results were coined the "Kennard principle," a term used to reflect the idea that recovery from brain damage will be more complete in the developing brain than in the adult brain. During the past decade, the Kennard principle has been supported by evidence of enhanced mechanisms of neural plasticity or capacity for repair during development,34–36 as well as evidence of enhanced reorganization after injury to the developing brain.37–39 However, the Kennard principle is not accepted unanimously. Certain types of brain damage have been found to be actually more severe if experienced during critical periods of neural development. Extensive reviews of this research40 conclude that plasticity, reorganization, and recovery after pediatric brain injury involves a complex interaction between 2 key endogenous factors: injury location and age at injury. With regards to injury location, the motor cortex has the largest potential for postlesional plasticity in children because of its capacity for interhemispheric and intrahemispheric compensation.41,42 On the other hand, injuries to the prefrontal cortex are likely to have long-term consequences because complex neural pathways may be disconnected prematurely.42,43 In their extensive review of neural plasticity, Payne and Lomber44 delineate specific features of the developing brain that facilitate its unique recovery from early lesions of the cerebral cortex.
The neurodevelopmental state of the brain plays a key role in determining the outcome of brain injury. Kolb et al43 postulated that the most detrimental time for cortical injury is the end of the gestational period (approximate age: 1 month), when massive cell migration occurs after completion of neurogenesis. Conversely, the least detrimental time for brain injury is at 1 to 2 years of age, a period of maximal dendritic and synaptic growth. Chapman and McKinnon42 noted that injury to the sensory and motor areas of the brain before 2 years of age may be particularly deleterious because neuronal myelination is still in progress. Furthermore, because myelination in the prefrontal region occurs throughout childhood,42,45,46 injury to this region at any premature age may inhibit the adaptability of the developing brain, resulting in severe neurobehavioral consequences.
In addition to these endogenous factors, outcome after brain injury may be influenced by exogenous factors such as the child's environment, psychosocial resources, and treatment type.43 Functional neuroimaging can serve to elucidate the complex interaction between these endogenous/exogenous factors and neurobiological outcome.
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MECHANISMS OF RECOVERY AFTER PEDIATRIC BRAIN INJURY |
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TOPABSTRACTASSESSMENT OF PEDIATRIC BRAIN...FUNCTIONAL NEUROIMAGING...DIAGNOSIS AND CLINICAL OUTCOME...MECHANISMS OF RECOVERY FROM...MECHANISMS OF RECOVERY AFTER...CONCLUSIONSREFERENCES |
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In the past decade, 6 studies have been conducted that use functional neuroimaging methods to explore the neurophysiological sequelae and recovery mechanisms that occur in the aftermath of pediatric brain injury (see Table 1). Collective results from these studies provide a better understanding of the neuroanatomical correlates of early functional reorganization and have helped to clarify which brain regions are most amenable to neurodevelopmental plasticity after injury to the developing brain.
Muller et al38 used [15O]water PET to explore brain reorganization for language after injury to the developing brain. Patients included 21 children and adolescents (aged 6–22 years; mean: 12.5 years) with early unilateral lesion (left-hemispheric lesion, n = 12; right-hemispheric lesion, n = 9). Lesion etiology included epilepsy, Sturge-Weber syndrome, tumor, stroke, perinatal hemorrhage, meningitis, and encephalitis. During the PET scan, cerebral blood-flow changes were recorded as the patient completed a repetitive listening task. Findings showed little evidence of intrahemispheric reorganization in the left-hemispheric lesion group, although they indicated a rightward shift of language activation in the perisylvian and temporoparietal regions. In the right-hemispheric lesion group, regional cerebral blood-flow pattern reflected an overall greater number of activated regions as well as a stronger subcortical and cerebellar language involvement than in the left-hemispheric lesion group. In accordance with these results, the authors concluded that there are both subtractive (ie, functional depression in areas normally involved in language) and additive (ie, recruitment of nonconventional regions at and around the lesion site) effects of early unilateral lesion on developing brain function.
Liegeois et al,47 Cioni et al,48 Holloway et al,39 Booth et al,49 and Stiles et al50 each used fMRI to explore neural reorganization after injury to the developing brain. Liegeois et al47 studied 10 children (aged 7–18 years) with intractable epilepsy resulting in early lesion to the left hemisphere to determine the effects of age of seizure onset, lesion location (ie, proximity to the classical Broca's and Wernicke's language areas), and handedness on the reorganization of language. A lateralization index (based on the number of voxels activated in the left and right inferior frontal gyri during the performance of a verb-generation task) was designed to characterize the fMRI data. Results demonstrated bilateral or right language lateralization in 5 of the 10 patients. Interestingly, lesions remote from the classical language areas were associated with nonleft language lateralization in 4 of 5 of the cases. Findings did not yield any significant associations between age of seizure onset or handedness and lateralization index scores.
Cioni et al48 examined sensorimotor cortical reorganization in 2 pairs of monozygotic twins. One member of each twin had suffered from a focal brain injury during the early stages of development. This focal injury was diagnosed as an intraventricular hemorrhage/periventricular infarction in twin 1 at the age of 3 days and was expressed as acute hemiplegia/aphasia in twin 2 at 3 years of age. fMRI scans were performed on the 2 sets of twins at the ages of 11 and 20 years, respectively, at which time the injured twin continued to suffer minor sensorimotor consequences of the early brain injury. During the fMRI, the twins completed a motor (finger movement) and a sensory (palm/finger brushing) task using their right and left hands. Tasks performed with the recovered hand of the injured twin activated the undamaged areas adjacent to the injury site and the ipsilateral sensorimotor cortex. Bilateral activation of the primary sensorimotor cortex was never observed in the healthy co-twin controls. On the basis of these results, the authors postulated that functional reorganization after brain injury was likely to depend on increased activity in healthy portions of the sensorimotor cortex that were adjacent to the injury site as well as increased activity in corresponding regions of the intact hemisphere.
Holloway et al39 also used fMRI to explore reorganization of sensorimotor function in 8 patients (aged 8–19; mean: 12 years) who had undergone hemispherectomy for relief from seizures. The patients were categorized according to age of disease onset (congenital disease, n = 4; acquired disease, n = 4). During the fMRI scans (acquired at least 1 year postsurgery), patients performed a passive movement task. Two of the 8 patients (1 with congenital disease and 1 with acquired disease) showed activation in the sensorimotor cortex of the remaining hemisphere with passive movement of the hemiplegic hand. The location of this activation was similar to that found on movement of the normal contralateral side of the brain. Results from behavioral measures (finger-tapping, peg-moving, simultaneous stimulation, and joint-position-sense tasks) indicated that patients with congenital disease showed generally better residual sensory and motor function in the hemiplegic limb than patients with acquired disease. Such functional abilities, however, were not necessarily correlated with findings of ipsilateral fMRI activations.
The population size in this study was too small to examine the effects of age of disease onset on sensorimotor reorganization. However, the findings did raise questions for additional research regarding the relationship between age of disease onset, age of surgery, and functional outcome in pediatric patients with seizures. Although this study had several uncontrolled variables (eg, nature of hemispherectomy [functional and structural] and time span between surgery and the scan), the data acquired suggested that fMRI can serve as an effective, noninvasive means of investigating functional reorganization in hemispherectomized children.
Booth et al49 used fMRI to study cognitive function and postulate mechanisms of reorganization in children who had suffered perinatal strokes or periventricular hemorrhages during the first year of life. Participants (aged 9–12 years) included 7 healthy children and 6 pediatric patients (5 with left-hemisphere injury and 1 with right-hemisphere injury). While laying in the scanner, participants completed 2 cognitive tasks: auditory sentence comprehension and mental rotation of alphanumeric stimuli. In general, data from both tasks indicated that a lesion to the left hemisphere was associated with organization to homologous areas in the contralateral hemisphere. However, all patients retained some activation in the intact portion of the damaged hemisphere, and the degree of shift to the contralateral hemisphere was found to be related to the size of the lesion. In addition, the patients showed more anterior cingulate activation than the healthy children during the mental rotation task. These results suggest that early lesions may prompt the recruitment of alternative brain areas typically involved in other cognitive processes and that the degree of recruitment may depend on the size and location of the lesion.
Stiles et al50 used fMRI to study the effects of early focal brain injury on the development of spatial analytic processing. Subjects included a 13-year-old male with injury to the left hemisphere (that resulted in compromised ability to encode parts of spatial patterns) and a 15-year-old male with injury to the right hemisphere (that resulted in impaired pattern integration). During the fMRI scan, the patients completed 2 tasks that assessed global and local spatial analytic processing. For each patient, processing of both global and local level of spatial-pattern information was strongly lateralized to the contralesional hemisphere. fMRI results were compared with those acquired previously from healthy subjects matched for gender and age. Similar to the findings of Booth et al,49 these results suggest that after early focal brain injury, the developing brain has the capacity to establish alternative patterns of neural arbitration for basic cognitive functions.
Collective results from the 4 aforementioned studies support the use of fMRI as both a diagnostic and therapeutic tool because it can be used to systematically record the trajectories of reorganization as a function of type of injury (ie, lesion size and location) and age, thus guiding rehabilitative interventions. fMRI can also serve as a valuable aid in determining the effectiveness of experimental treatment paradigms. For example, Werth and Seelos51 used fMRI to characterize visual function in cerebrally blind children with varying degrees of restitution after a novel type of systematic visual-field training. Additional fMRI-based research on neural reorganization in children after brain injury may demonstrate windows of opportunity for "aggressive" drug treatment and behavioral therapy. In addition, future fMRI studies will be likely to provide researchers with a better understanding of disparities in neural plasticity and potential for reorganization in adults and children suffering from brain injury. It is important to note, however, that the ability of functional neuroimaging to expand our current understanding of recovery from brain injury depends on the development of reliable functional brain maps of healthy children. Thus, it is necessary to accumulate more "normative" data to accurately characterize benign disparities in plasticity and reorganization.
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CONCLUSIONS |
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TOPABSTRACTASSESSMENT OF PEDIATRIC BRAIN...FUNCTIONAL NEUROIMAGING...DIAGNOSIS AND CLINICAL OUTCOME...MECHANISMS OF RECOVERY FROM...MECHANISMS OF RECOVERY AFTER...CONCLUSIONSREFERENCES |
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Compared with conventional structural neuroimaging techniques, functional neuroimaging methods provide a more accurate picture of the neurophysiological sequelae of brain injury and have a better predictive value of clinical outcome in pediatric patients with brain injury. However, additional functional neuroimaging research is warranted to better understand the characteristics and mechanisms of neural plasticity and neural reorganization in both children and adults. Such research is important to assist not only in diagnostic and prognostic assessments but also in the prescription and monitoring of rehabilitation programs.
A word of caution concerns the unique ethical and methodical difficulties associated with the conduct of functional neuroimaging research in children.22 Because PET and SPECT imaging involves exposure to ionized radiation, the use of this technology is currently limited to adults and pediatric patients for whom the clinical benefit outweighs the risks involved. Therefore, data from healthy control children can generally not be obtained with these nuclear medicine techniques.
Although fMRI is a noninvasive procedure that does not involve exposure to radiation, its use in the pediatric population presents several unique methodologic issues. To obtain optimal fMRI data, children must lie still in a small, enclosed space. Children who are unable to lie still may require sedation, which can affect the quality of acquired data.52 The study of 3 young children with Sturge-Weber syndrome by Bernal and Altman17 provides an excellent example of how fMRI parameters can be adjusted to minimize the effects of sedation on the data collected. In addition, the unfamiliar hospital environment and the noise generated by the scanner can be a source of anxiety for pediatric patients. Such anxiety may be attenuated by allowing the child to watch videos demonstrating the procedure or scheduling a simulation scan before the actual procedure. A notable anatomic confound of fMRI is the fact that as children develop, the ratio of gray to white matter decreases. To date, the degree to which the amount of myelination in various brain regions affects the magnitude of activation has not been quantified.18
Finally, a common limitation in interpreting scans of children who have suffered a brain injury is the absence of a premorbid functional neuroimaging evaluation. Careful experimental designs can mitigate this problem. Despite these limitations, functional neuroimaging modalities, as they become more widely available, can provide unprecedented potential to enhance our ability to diagnose, treat, and better understand the neurophysiological sequelae of pediatric brain injury.
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FOOTNOTES |
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Accepted Sep 23, 2005.
Address correspondence to Monique Ernst, MD, PhD, National Institutes of Health, National Institute of Mental Health/Mood and Anxiety Disorders Program, 15K North Dr, Bethesda, MD 20892-2670. E-mail: ernstm{at}mail.nih.gov
The authors have indicated they have no financial relationships relevant to this article to disclose.
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TOPABSTRACTASSESSMENT OF PEDIATRIC BRAIN...FUNCTIONAL NEUROIMAGING...DIAGNOSIS AND CLINICAL OUTCOME...MECHANISMS OF RECOVERY FROM...MECHANISMS OF RECOVERY AFTER...CONCLUSIONSREFERENCES |
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