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Pediatric Imaging |
1 From the Department of Radiology, Miami Children’s Hospital, 3100 SW 62nd Ave, Miami, FL 33155. Received November 29, 2000; revision requested January 17, 2001; revision received February 27; accepted March 23. Address correspondence to N.R.A. (e-mail: nolan.altman@mch.com).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Forty children between 2 months and 9 years old were examined and grouped according to age. Children were selected from patients referred to undergo brain MR imaging. Patients received pentobarbital (3.0–7.0 mg per kilogram of body weight) or chloral hydrate (50–75 mg/kg). The functional MR imaging study was performed at the end of the examination. Paradigms consisted of flashing lights at 8 Hz displayed on special goggles and a prerecorded mother’s voice presented through headphones. Activation maps were obtained from a paired t test with a P value of .0005 (uncorrected).
RESULTS: The visual stimulus produced statistically significant negative values in the rostral aspect of the primary visual area (28 [90%] of 31 patients). The auditory paradigm activated either temporal or frontal areas in 26 (68%) of 31 patients. There was more frontal activation in the older children.
CONCLUSION: Visual and auditory cortices can be activated in children who have been sedated. Visual responses show negative values in the rostral visual cortex, independent of age. Auditory activation is seen in temporal and frontal lobes.
Index terms: Brain, 13.99, 13.919 • Brain, function, 13.91 • Brain, MR, 13.121411, 13.121412 • Magnetic resonance (MR), functional imaging, 13.121419 • Magnetic resonance (MR), in infants and children, 13.121419
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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During examination with functional MR imaging, however, the patient’s cooperation to remain motionless and to understand and perform the task is required. These requirements have led to the restricted use of the examination in infants and young children. Development of passive paradigms and use of sedatives would avoid these obstacles, allowing the pediatric population to benefit from procedures that have proved worthy in adult presurgical planning, such as language mapping. Common language mapping paradigms, however, rely on the assumption that complete language acquisition has been achieved. This assumption is not valid in pediatric patients younger than 4 years in whom the asymmetry for verbal material is not yet well established (3).
Auditory and visual stimulation do not require patient cooperation, since they can be presented passively. Data concerning functional MR imaging activation in infants and young children who are receiving sedatives or anesthetics are limited (4–6). To our knowledge, there are no reports of the standardization of auditory and visual activation in healthy children. To understand the development of language, the young child must be examined, and an examination requires sedation. Localization of the modules of language recognition in the developing brain is a challenging task and may be best explored with functional MR imaging. The purpose of our study was to localize areas of activation related to age of sedated infants and to development of children’s brains with use of passive auditory and visual tasks with functional MR imaging.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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An abnormal finding at MR imaging examination was also cause for exclusion from the study, except in one patient with craniopharyngioma and two patients with benign macrocephaly of infancy. In all patients younger than 12 months old, a follow-up telephone call was made 6–12 months after the examination to verify normal neurologic development, and an audiologic evaluation was performed when possible (six patients). Two patients were excluded from the study. One child developed attention deficit hyperactivity disorder. The other patient was excluded due to technical failure in the postprocessing procedure.
The 38 remaining patients were assigned to three groups, according to the well-known ages of brain maturation and language acquisition stages (3,7): Group 1 (age range, 1–12 months; rapid brain myelinization) included 11 patients with an average age of 6.36 months. Group 2 (age range, 13 months to 4 years; slow brain residual myelinization and main language acquisition time) included 14 patients with an average age of 2.2 years. Group 3 (age, older than 4 years; 95% of adult brain maturation) included 13 patients with an average age of 6.5 years.
MR imaging was performed in healthy volunteers who were 10–14 years old who were awake and listening to the mother’s voice through a recording used in the study. In two of these volunteers, flashing lights with the eyes open and closed also were used as a stimulus. These children were evaluated initially to verify the task paradigms and postprocessing procedures that were used for the study group.
Stimuli and Imaging
A radiologist (N.R.A.) administered sedatives to the patients. Pentobarbital (3–7 mg per kilogram of body weight) in a single bolus was used in 25 patients. Chloral hydrate (50–75 mg/kg) was administered orally in nine patients. For patients 2, 21, and 35, agents including pentobarbital, chloral hydrate, or alprazolam were used. An anesthesiologist administered propofol to patient 26. All patients received 6% O2 by face mask for the duration of the procedure. The requested MR imaging examination was performed, and afterward the functional study was performed if the patient remained sedated. This resulted in the functional MR imaging examination being performed between 45 and 90 minutes after the sedative was administered.
Two paradigms, flashing lights and a recording of mother’s voice, were used in random order. The visual stimulus (flashing lights at 8 Hz) was delivered through closed eyes by using a 3 x 3 light-emitting diode array mounted in goggles (model SIOVSB; Grass Instruments, West Warwick, RI). The auditory stimulus was delivered through generic headphones connected with insulated tubing to a pair of generic 40-W speakers located inside an aluminum box placed close to the magnet. The stimulus consisted of the mother speaking to the child by using familiar and endearing words; by recalling relatives, pets, and events; and by singing familiar songs. Mothers were encouraged to use intonation and infant-directed prosody, according to the theory of "motherese" (8–10), which previously demonstrated that infants are able to segment clauses from motherese cues but not for directed speech. The speech was prerecorded in an isolated room during 2 minutes, and the mothers were given a list of the previously mentioned prompts and were instructed to speak at a normal volume. The volume was adjusted by the examiner so it was consistent for all the groups.
MR imaging was performed with a 1.5-T unit (Signa Horizon LX platform; GE Medical Systems, Milwaukee, Wis) with birdcage, quadrature, and transmit-receive head coils designed for whole-brain imaging. A series of 16 localizer images were obtained in the sagittal plane. Ten transverse section locations were selected parallel to a plane defined by a line between the basal aspects of the frontal and occipital lobes for MR imaging and functional MR imaging studies. The MR images were obtained with T1 spin-echo sequences, with repetition time msec/echo time msec of 300/14, field of view of 240 mm, matrix of 256 x 256, 6-mm section thickness, and 2-mm gap.
The functional images with the same thickness and gap were obtained with gradient-echo single-shot echo-planar MR imaging, with 3,750/60, flip angle of 60°, field of view of 240 mm, and a matrix of 64 x 64. The experiment consisted of 48 time points (sets) of 10 images, with two extra sets at the beginning of the series, used to obtain the steady state of transverse magnetization. The 48 sets were classified into six epochs, three in the off mode (baseline condition) and three in the on mode (activated condition). Starting in the off mode, the experiment proceeded, switching every 30 seconds. Thus, each section was imaged 48 times, which resulted in 240 image pairs for comparisons.
The functional MR imaging data were processed off line by using computer software (MEDX, version 3.0; Sensor Systems, Sterling, Va) (11). Time-point images were first analyzed to detect motion, by comparing the center of areas of signal intensities of the total of images acquired, by using the intensity-weighted method module provided with the computer software. The images were spatially smoothed with a Gaussian kernel of full width at half maximum of 10 mm to reduce the noise in the images. Signal normalization was applied to normalize the signal of each voxel and to remove the effects of signal drift.
Parametric statistical maps were obtained in each series by using a paired two-tailed t test. Activation was defined as positive in those voxels in which the signal intensity P values were less than .0005 (uncorrected), with a z-score threshold of 3.47, on the condition that the same study showed clusters of voxels fulfilling two criteria: (a) z score greater than 3.0 and (b) cluster extent at an 
value of less than .1. With these settings, the probability of a false-positive finding for a 3-voxel cluster was .031 (12).
For the visual paradigm, the t test analysis was performed two ways, first by using the off mode and then the on mode as a control to assess the signal intensity of the negative values expected in this paradigm, as seen in a previous investigation (5). With the auditory paradigm, only the off mode was used as the control condition. Anatomic localization was performed by means of superimposing the functional images on T1-weighted images obtained in the same patient at the same section location.
For each paradigm, areas of activation were quantified by number of voxels and were lateralized with the computer. Anatomic localization was then determined (N.R.A., B.B.). The difference between regions of activation, for each of the paradigms, was lateralized and assigned a lobe with the computer.
Statistical Analysis
The Fisher exact test was used to evaluate the differences in visual activation between the functional MR imaging postprocessing algorithms of the off-on and on-off modes. Nonparametric Kruskal-Wallis tests were used to evaluate visual and auditory paradigms for all the age groups, on the basis of the differences in the total number of voxels activated per task and per group. P values were calculated, and a value of less than .05 was considered to indicate a statistically significant difference. The effects of sedatives were also analyzed by using the Fisher exact test to determine whether there was a difference between pentobarbital and chloral hydrate in regard to activation. Statistical analyses were performed by using statistical software (DATADESK; Data Description, Ithaca, NY; SAS, SAS Institute, Cary, NC). Descriptive statistics were used in the small number of subjects in the different subgroups analyzed.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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No statistically significant difference was found regarding types of sedatives used with respect to activation (visual, P > .99; auditory, P > .99).
The youngest patient (patient 1) demonstrated activation in the motor cortex bilaterally with the auditory paradigm. This 2-month-old boy would suck only during the on-mode epochs.
The four older awake volunteers demonstrated activation of primary and secondary auditory areas with predominance of the left hemisphere. In two patients, there was activation of the Broca area. Flashing lights produced positive values in the primary visual areas, with less signal intensity with the eyes closed. Negative values were scattered and observed in parietal and temporal lobe areas.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The purpose of this study was to determine areas of activation in the healthy developing child’s brain with use of visual and auditory tasks. Findings in this study suggest that there is a potential for performing functional MR imaging in infants and young children. These findings may be used as a baseline against which findings associated with pathologic conditions may be contrasted.
The visual paradigm consistently elicited negative values in the occipital lobe in all three age groups. This finding has been reported previously (4,5), though only in children as old as 1
years. The negative values may be due to the reduction of the oxyhemoglobin-deoxyhemoglobin ratio in the occipital lobe as a consequence of increased metabolic rate. The visual cortex in young children appears to have increased oxygen extraction during visual stimulation to an extent that surpasses the physiologic cerebral blood flow responses (13). The relative increase of deoxyhemoglobin increases the dephasing of the local spins, which reduces the signal intensity. To allow consistent display with the functional MR imaging postprocessing software, these negative signals are mathematically switched to positive values (Fig 5).
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The auditory paradigm was designed to invoke the most powerful response. Mother’s voice, and particularly motherese for the preverbal infants, was assumed to provide the best auditory stimulus for children (10–18). The mothers sang and used words or sentences containing names of relatives, favorite toys, pets, television programs, and the like, so activation of other cognitive areas would be expected. Sedation and machine noise may limit the response of the primary auditory area. Despite these limitations, activation was observed in 26 (68%) of 38 patients. The predominant activation of the temporal lobes is important in terms of predicting early language localization and lateralization. Previous study findings demonstrated functional asymmetry in simple nonlanguage auditory tasks. Findings of other investigators (14–16) of a "right ear advantage" are possibly due to left hemisphere dominance. This dominance not only depends on verbal stimulus (14,17) but also is seen with pure-tone tasks in right-handed subjects (18).
Language hemispheric dominance, assessed with functional MR imaging, has been demonstrated in children as young as 7 years old who were performing spelling and word-generation tasks (19). In a functional MR imaging study of six children between 6 and 10 years old (four right-handed and two left-handed), Ulualp and co-workers (20) did not find significant asymmetry of the activation with pure tones. Review of their data, however, demonstrates greater activation in the left hemisphere in three and equal activation in two female patients, with a greater activation in the right hemisphere in one of the left-handed subjects. To our knowledge, no study findings address the relationship of localization and lateralization for passive paradigms with sedation in infants and young children.
Sedation does not appear to preclude evaluation of auditory activation. Different neuronal areas that process complex sounds have been demonstrated in the nonprimary auditory cortex of anesthetized rhesus monkeys with use of cortical electrodes (21).
The frontal activation with the auditory paradigm observed in this study also has been previously reported. Right frontal lobe activation from auditory stimulus while sleeping has been shown, in a study conducted in adults, with implanted cortical electrodes with use of plain tones as stimuli (22). Mesial frontal activation also has been related to arousal systems (23). These findings indicate that the frontal lobe may serve as a kind of idle circuitry involved in preparing the body to react, as a type of species-protective mechanism, during sleep. There appears to be a maturational issue, because the frontal activation was least apparent in the youngest age group.
The motor activation observed in patient 1 is a well-established reflex observed in infants, named "habituation-dishabituation of high-amplitude sucking." The sucking reflex is provoked by an auditory stimulus that vanishes (habituation) shortly after starting the repetition of a given syllable. The response can be reinitiated (dishabituation) with a change of the syllable. This response implies linguistic discrimination, which is present in infants as early as 2 months old (24,25). The areas activated correspond to the cortical oral motor areas.
Sedation was variable because we used different types of medications. Infants and children who weighed less than 10 kg were sedated with chloral hydrate, and the majority of the remaining patients were sedated with pentobarbital. The medication was administered in as low a dose as possible to produce light sedation and to facilitate activation; however, it was not possible to give each child equal doses, since the individual response was variable. Pentobarbital reduces cerebral blood flow 20%, in patients with brain trauma (26), at doses that are much higher than those used for pediatric sedation. To our knowledge, there are no studies in which cerebral blood flow was measured in humans with these lower doses. However, on the basis of these reported observations, these effects are not marked if the procedure is performed 45 minutes after the sedative was administered (5), as was the case in all our subjects. Our policy was to perform the functional MR imaging immediately after the regular requested procedure was accomplished. This usually resulted in the examination being performed at least 45 minutes after a sedative was administered.
The use of sedation has disadvantages and advantages. Sedation may limit functional statistical analysis. We chose the cluster detection procedure as a technique to compensate for the low P values assigned for the signal intensities, since these were not corrected for multiple comparisons. In any activated case, at a threshold of a z score of 3.47, the cluster detection technique was prescribed to include values greater than 3.0 with extension larger than 5 voxels. Still, some false-positive values could be considered as activated, but this probability is less than .031 (12).
Advantages of sedation include the lack of patient motion, which allows more accurate statistical analysis. There is also a pure-rest cognitive state during the off-mode epochs, which can never be obtained when the child is awake. For these reasons, we think that activation was demonstrated in our study when initially this may not have been expected.
In conclusion, we demonstrated brain activation in sedated infants and children by using visual and auditory stimuli with functional MR imaging. Visual areas have a characteristic pattern of activation. Auditory stimulus activates temporal and frontal lobe areas. Comparison of patterns of activation among the three groups revealed differences in the frontal and temporal lobe activation for the auditory paradigm. The frontal and left temporal lobe areas showed more activation as the brain developed. This may be due to language development or possibly an arousal response, but it is clearly a maturational phenomenon. Findings of this study suggest new avenues for investigation of cognitive processes in infants and children. The further understanding of how language is established in the developing brain is necessary before evaluation of language and learning disorders can be performed. It is our hope that with further studies these puzzling problems may be elucidated.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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  A. M. Patel, L. D. Cahill, J. Ret, V. Schmithorst, D. Choo, and S. Holland Functional Magnetic Resonance Imaging of Hearing-Impaired Children Under Sedation Before Cochlear Implantation Arch Otolaryngol Head Neck Surg, July 1, 2007; 133(7): 677 - 683. [Abstract] [Full Text] [PDF]
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 G. Dehaene-Lambertz, S. Dehaene, and L. Hertz-Pannier Functional Neuroimaging of Speech Perception in Infants Science, December 6, 2002; 298(5600): 2013 - 2015. [Abstract] [Full Text] [PDF]
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