Книги по МРТ КТ на английском языке / Functional Neuroimaging in Child Psychiatry Ernst 1 ed 2000

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Swanson, J. M., Castellanos, F. X., Murias, M., LaHoste, G. and Kennedy, J. (1998b). Cognitive neuroscience of attention deWcit hyperactivity disorder and hyperkinetic disorder. Curr. Opin. Neurobiol., 8, 263±71.

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3

Functional magnetic resonance imaging

Guinevere F. Eden and Thomas A. ZeYro

Introduction

Investigating the neural basis of cognitive development necessarily requires sensitive measures of brain activity that may be used to obtain repeated observations of subject populations over an extended period of time. MRI methods allow rapid and noninvasive determination of both brain structure and brain function, characteristics that are of particular importance in studies involving children. These imaging techniques employ a combination of static and modulated magnetic Welds to obtain local estimates of chemical concentrations in diVerent brain regions. Most commonly, both structural and functional images are derived from proton signals reXecting the local environment of water molecules in various tissue types. The variable environment in diVerent tissue types results in corresponding intensity variations in reconstructed brain images, referred to as tissue contrast. In structural images, the variable tissue contrast provides a means to visualize the spatial distribution of gray matter, white matter, and cerebrospinal Xuid throughout the brain. In functional imaging, additional small modulations of signal intensity occur because of changes in tissue blood Xow and oxygenation.

Signal intensity changes can be recorded as a function of time and their relation to behavior examined with a variety of signal processing techniques that enhance the behavioral task-related signal change while suppressing undesirable physiologic noise arising from head motion, respiratory artifact, or global changes in cerebral blood Xow. In the simplest case, signal intensity in a control condition is subtracted from signal intensity recorded during task performance in order to compute an estimate of taskrelated brain activity. This process is repeated over the entire brain to derive a ªmapº of task-related brain activity. In more complex circumstances, the resulting map may

reXect the correlation of signal change with some aspect of task performance or behavioral state. The Wnal fusion of these maps with high-resolution structural imaging provides neuroanatomic localization of brain function in a structural context, allowing comparisons of functional neuroanatomy among diVerent individuals or subject groups.

Physiologic basis of fMRI

Most functional MRI (fMRI) studies utilize techniques based on the BOLD-contrast (blood oxygenation leveldependent contrast) eVect (Belliveau et al., 1991; Kwong et al. 1992; Ogawa et al., 1992; Turner et al. 1993). This technique utilizes rapid imaging, usually echo planar, of the brain to record the hemodynamic consequences of neuronal activity. Neuronal activity is thought to be associated with concomitant changes in blood Xow and oxygenation that result in local changes in the relative proportions of oxyhemoglobin and deoxyhemoglobin, molecules that have diVering magnetic susceptibilities. Thus, task-related changes in neuronal activity trigger a series of events that Wnally result in local changes in magnetic susceptibility that may be captured with rapid MRI techniques. Of note is the fact that these hemodynamic changes are delayed and dispersed in time relative to their neuronal antecedents, properties that limit the temporal resolution of this technique but which may be exploited advantageously in some experimental designs. The goal of analysis of functional MRI (fMRI) time series is to extract the best estimate of neuronal activity from the recorded hemodynamic signal. As discussed below, this process is made diYcult by a host of instrumental and physiologic artifacts encountered in fMRI data acquisition and analysis (Cohen, 1996; Turner and Jezzard, 1993). For references concerning the physiologic

45

46G. F. Eden and T. A. ZeYro

basis of the BOLD contrast eVect see Cohen (1996) and Turner and Jezzard (1993).

Safety considerations

All human structural and functional neuroimaging techniques carry some risk for the individual being studied. Although the hazards associated with fMRI examinations in children and adults are extremely low, it is worthwhile brieXy to consider the areas of possible danger to the subject.

The Wrst source of possible hazard is the system's static magnetic Weld.While there is no evidence of adverse eVects from exposure to lower Weld strengths, whole-body exposure at 5 tesla (T) can aVect blood Xow through the circulatory system (Tenforde and Budinger, 1985). After being exposed to the even higher Weld strength of 10T, some subjects reported discomfort (Beischer, 1962). At the Weld strengths utilized for most functional neuroimaging studies (1.5±4T), there have been no reports of signiWcant physiologic eVects, with the exception of a sensation of mild dizziness reported by subjects executing rapid head movements in the higher 4T Welds.

Other hazards presented by the static magnetic Weld involve potentially adverse aVects on implanted metallic objects or devices. Cardiac pacemakers become inoperative at Weld strengths of 0.5mT or above. Therefore, any patient with implanted cardiac or neural stimulation devices should not be scanned. All persons should be screened prior to entering the magnet room. The Wrst step is to take a careful history, inquiring about the possible presence of cardiac pacemakers, neural stimulators, aneurysm clips, cochlear implants, hip prostheses, hair implants, shrapnel, or a history of metalworking. The interview should be followed by an examination with a magnetometer to conWrm the absence of ferromagnetic material on or in the subject. As the static magnetic Weld may attract metallic objects from a distance, care should also be taken to keep all ferromagnetic materials outside the magnet room. Metallic objects can easily become dangerous projectiles near most commercial MR systems.

The second source of possible biohazard are the cryogens used to maintain the static magnetic Weld. The liquid nitrogen and helium employed in superconducting magnets are very cold and can cause immediate tissue damage following contact. Under extremely unlikely circumstances, during a ªquenchº, it is possible for the system's cryogen to change state and become gaseous, posing a threat of asphyxiation. Commercial MR systems all have an emergency ventilation system to handle this exigency.

A third source of potential hazard to subjects are the system's gradients, which generate distortions in the static magnetic Weld allowing spatial localization of the MR signal changes. Echo-planar imaging sequences are accompanied by high-amplitude gradient ringing, characterized by high sound energy in a narrow frequency band. Although there have been no reports of auditory system damage in subjects participating in fMRI experiments, it would seem reasonable to err on the side of caution and equip subjects with attenuating earplugs. Under some circumstances, gradients may also induce electrical currents in the body. During echo-planar imaging experiments, this phenomenon may lead to peripheral nerve stimulation, particularly involving the trigeminal or facial nerves. Limiting the maximal rate and amplitude of gradient Weld changes can avoid these eVects.

The last source of potential hazard stems from radiofrequency energy deposition in the body. Limiting the amount of radiofrequency energy deposition can prevent elevations of body temperature to levels that cause damage to local tissues or systemic physiologic eVects (International Non-Ionizing Radiation Committee, 1991). The measure of radiofrequency power used in human imaging systems is called the speciWc absorption rate (SAR). Safe levels for SAR for infants, adults, and individuals with compromised thermoregulatory systems can be obtained from the MR system manufacturer.

In general, structural and functional brain imaging using commercial MR imaging systems has an excellent safety record. With proper attention to the above cited considerations, investigators should feel comfortable that functional neuroimaging in children and adults poses no signiWcant biohazard.

Pediatric studies using fMRI

Although fMRI has been employed in over 700 studies of the adult brain published to date, its utilization in studying children and human development is only just beginning. Functional MRI was Wrst used in a pediatric study to monitor focal seizures in a 4-year-old boy (Jackson et al., 1994). Here fMRI was used to identify those areas showing activity during clinical seizures. More recently, fMRI has been employed clinically to study language function in children. Hertz-Pannier and colleagues used fMRI to map language dominance in children between ages 8.8 and 18 years with partial epilepsy (Hertz-Pannier et al., 1994, 1997). A word generation task was used to activate the frontal lobes, and the magnitude of signal change was used to calculate language asymmetry indices. The results were

Functional magnetic resonance imaging	47

in agreement with intra-carotid amobarbital (amobarbitone) testing performed in these children for presurgical evaluation. The data showed clear activation of the left frontal areas of the brain during overt or covert production of words in response to the presentation of letters or words. A further report showed that both a word Xuency task and single word reading successfully resulted in task-related signal changes in a 9-year-old boy (Benson et al., 1996). However, more complex tasks, such as generating the opposite meaning of a word or generating the verb form of a noun, were unsuccessful in generating signal changes, thus underscoring the quintessential importance of task selection.

From these early studies, it appeared that children could tolerate the MRI environment for clinical purposes. Whether the same procedures that are applied in cognitive studies of adults can be utilized to study children outside of the clinical setting is of both practical and empirical importance. Casey and colleagues have addressed this issue by studying the same tasks in children and adults (Casey et al., 1997b). One major diYculty in comparing children and adults arises from diVerences in task performance across the two age groups. A similar problem can also occur in clinical studies when controls may be compared with a group of patients whose task performance is unmatched. Steps can be taken to account for these behavioral diVerences by controlling for them in the analysis procedures. When diVerences in task performance are taken into account, neuroimaging studies have shown similar patterns of cortical activity in adults and children during equivalent tasks.

From a developmental point of view, one might expect similar cortical localization for a given task in children and adults. However, should diVerences be observed between age groups, there is an open question regarding how to best quantify these diVerences in order to reveal developmental changes. For example, diVerences might be quantiWed in terms of spatial extent or amplitude of task-related signal change. Many pediatric studies have focused on frontal areas of the brain (inferior frontal and medial frontal gyri), albeit with diVerent aims and diVerent behavioral tasks. Word generation, working memory, and attention (e.g., continuous performance) tasks have been utilized to activate frontal areas in the brains of children. A study investigating working memory has identiWed developmental changes measured by greater MR signal (per cent signal change) in children with increasing age (from 9 years and 7 months to 11 years and 7 months) (Casey et al., 1995). As discussed in Chapter 9, the adult data for this same task show a much lower signal compared with that of the pediatric group. This suggests that the age-related

signal increase during development in childhood must be followed by a decrease, producing the lesser signal change associated with this task in adulthood. This initial Wnding is intriguing because it suggests complex developmental patterns. However, to resolve these changes, a large number of children across a wider age range will need to be studied. Furthermore, other aspects of the data will need to be considered: quantitative measures of developmental changes could involve the number of voxels or the extent of activation. Interestingly, measures of magnitude of activation in frontal cortex have shown that children display a greater volume of activation compared with adults during an attention task (Casey et al., 1997b). It is clear that expansion of these studies to include larger numbers of children will yield important information on the relationship between behavioral performance and physiologic signal changes in the developing brain compared with that of the mature adult brain. This knowledge will provide an understanding of normal development of cognition and sensorimotor processing and the necessary base with which to tackle many serious clinical problems.

Indeed, one of the most important applications of pediatric fMRI studies lies in clinical studies. For example, epilepsy constitutes one of the most common brain disorders (1±2% of the general population). Noninvasive application of fMRI in presurgical planning has already provided a powerful tool for the advancement of preoperative evaluation for epilepsy surgery (Jackson, 1994). It also promises to be of great importance in unraveling the mechanisms of developmental disorders such as dyslexia, as well as other prevalent disorders such as attentiondeWcit hyperactivity disorder (ADHD). One preliminary report of children with developmental dyslexia undergoing fMRI studies has demonstrated signiWcantly less activation in inferior parietal areas and the inferior frontal gyrus of children with dyslexia compared with those without reading problems (Frost et al., 1997). These Wndings are in agreement with functional neuroimaging data in adults (Rumsey et al., 1992, 1997b; Shaywitz et al., 1998). Singlesubject analysis of such data in larger numbers will eventually contribute substantial information to the understanding of this heterogeneous and complex learning disorder.

Data acquisition

Clearly a number of limitations imposed by the MR environment need to be taken into consideration when conducting functional neuroimaging with MRI. Any equipment utilized for stimulus presentation or recording

48G. F. Eden and T. A. ZeYro

of the subject's response must be nonferrous. Since the advent of fMRI there have been many advances in equipment design to address this obstacle, and, therefore, this issue will not be discussed in great detail here. However, as a pragmatic aid, an appendix at the end of this chapter lists manufacturers of commercial products that have been optimized for the MRI environment and are commonly used in fMRI experiments. It contains a list of devices used for visual and aural stimulus presentation and response collection and is intended as a guide for those who wish to set up an fMRI experiment.

Practical issues when scanning children

In addition to the already rigorous limitations of the MR environment, further hurdles need to be overcome to ensure that tasks can be presented and responses elicited from young subjects in an uncontrived manner. Making compromises to the ideal experimental situation is an all too familiar situation with fMRI, which often does not allow faithful replication of the ªidealº behavioral or psychophysical situation employed outside of the magnet. With children, tasks that may be suitable for adults may be problematic. Children of younger ages do not have the cognitive and motor skills of adults, and the complexity of their motor responses are more limited. The number and position of buttons available during button-press responses to stimuli should, therefore, be limited; in fact, a maximum of two possible buttons used for response is recommended. Furthermore, while lying down in the scanner, the subject is unable to see his or her hands. This lack of visual guidance during button-press responses adds a further degree of diYculty to the task. The experimenter also cannot expect the child to report accurately whether the stimulus is maximally perceptable, or to give input regarding the necessity of adjustments such as focusing a visual display or increasing the volume of an auditory stimulus. Finally, a child's comfort must be taken into account to a greater degree than required for adult subjects when choosing the mode of stimulus presentation. For instance, a rear-projection screen viewed through a mirror is often used for visual stimulus presentation. It is also possible to project stimuli directly into certain types of goggles. However, we believe that the screen holds a greater advantage than the goggles because it avoids close proximity and hence possible discomfort to the face. Goggles might also require the child to maintain fusion. By maximizing the child's comfort and minimizing apprehension, one hopes to minimize head motionrelated artifacts stemming from the child's anxiety-related head movement.

Subject exclusion

It is very common in the USA, and increasingly in other countries, for children and adolescents between the ages of 8 and 18 to be wearing braces on their teeth. While physicians often obtain structural scans of people who wear braces for clinical purposes, the oral cavity causes substantial inhomogeneity eVects, resulting in large distortions to the facial area. For fMRI, these artifacts are extensive in the inferior portions of the brain and may result in unusable data. Consequently, children with braces are excluded from fMRI studies. As in adult studies, children with other forms of ferrous material in their body need to be excluded from study participation.

Subject preparation

The probability that a child can successfully complete a scanning protocol with little or no head movement and discomfort can be greatly increased by carefully preparing the individual. Just as in the adult population, if a child is put at ease and has a good understanding of what to expect when placed in the magnet, fewer complications will arise from anxiety, confusion, or discomfort. Having the child Wrst perform the task outside of the magnet will ensure that the child is fairly automated on the task. It is also useful to teach the child what else should be expected during the scan. Listening to a recording of the scanner noise eliminates some of the surprise and anxiety associated with the gradient noise. It is beneWcial to have younger children lie in a mock scanner environment prior to the real scan. Some sites have even utilized a magnet for the sole purpose of subject training (Slifer et al., 1993). At some sites, it is feasible to have children visit the scanner before the experiment so that the child can become acclimated. In general, we have found it useful to have children come in for two separate visits. On day one, the child becomes familiarized with the investigators during screening procedures. They are engaged in projects related to the brain (such as coloring pictures of the brain) and they undergo a short anatomic scan at the end of their visit. The child leaves with his Wrst MRI exposure and a picture of his own brain. On day two, the investigator will have acquired relevant behavioral screening data and an anatomic scan used for coregistration with the functional data acquired during the child's visit. Some investigators choose to perform a short functional run during the Wrst visit to be used only for practice purposes and then discarded.

Pediatric protocols often have the option of parental presence in the MR room. While this has the beneWt of comforting the child, it increases the likelihood that the

Functional magnetic resonance imaging	49

child will move his head in order to see the parent, thereby disrupting the imaging protocol. Often it is more useful to assess the situation rather than to follow a strict rule in this regard.

Monitoring of subject responses in the MR environment

The majority of published fMRI studies have employed motivated adults, often investigators, in whom reliable task performance can be obtained throughout the duration of a scan. For children entering this environment, it is important to monitor their behavior during the task in order to ensure task compliance and comfort levels. Pressing a button in response to a stimulus is one useful way of monitoring task performance. This can be practiced before a scan.

As described above, there has been particular interest in language studies using fMRI. In pediatric studies, the commitment of diVerent cortical areas to language and how they change during language acquisition is of great interest. Word pronunciation is often avoided or minimized out of concern that it introduces head motion. Further, there are susceptibility artifacts associated with changes in the size of the oral cavity that occur during articulation. Being located relatively close to the base of the brain, movement of this space can cause artifacts around the base of the temporal lobes. However, particularly in children, there are concerns that failure to respond overtly can lead to noncompliance. There is additional concern about studies that do not allow for pronunciation when studying language, because the signal changes can be modulated by response type. That is, responding overtly or covertly dramatically changes the resulting activation patterns (Bookheimer et al., 1995; Rumsey et al., 1997a). One way to circumvent this problem is to have subjects voice the response very carefully by whispering, or to use acquisition techniques that to some degree minimize this problem (see below).

Minimization of head motion

The scarceness of pediatric fMRI reports in the literature is undoubtedly a consequence, in part, of diYculty of obtaining data free of motion artifact from children. Also, there are concerns with respect to subjecting children to this noisy and conWned environment. Studies performed to date report data exclusion or repeated scanning of children because of head motion in 10% (Casey et al., 1997b) to 37% of the children scanned (Hertz-Pannier et al., 1997). One study of children and adults performing the same tasks

reported that head motion in children was no greater than that of the adults (Casey et al., 1997b). As might be expected, most investigators' experience has shown that the longer the duration of the scan, the more likely it is that the subject will move their head more frequently and to a larger extent. In studies performed to date, the duration of scans in children lasted about 1h and were, therefore, not very diVerent to the time engaged during adult protocols.

In general, it is clear that head motion is likely to be one of the greatest obstacles to successful application of fMRI in children; this may be a more serious issue in children with certain clinical conditions. Training children to lie as still as possible in preparation for the scan minimizes interscan head motion. For young children (younger than 10 years), it is beneWcial to have them practice lying still in a mock scanner. In this approach, individuals are placed in a device that resembles a magnet or in an old decommissioned magnet. The child can become familiarized to the conWned environment of the magnet and practice lying still. This can be achieved either by observing the child or by actually measuring his or her head movement using, for example, a light-emitting diode device. The experimenter should go through a checklist with the child, instructing the child on what will happen through the course of the experiment. Older children might then switch roles with the investigator and ªteachº the experimenter how to behave.

Acoustic interference

The gradient noise during fMRI data acquisition causes a measurable signal increase in the auditory cortex. During fMRI experiments, stimulation of the auditory cortex may result from the constant noise (usually around 90dB) generated by the gradients. While this potent auditory stimulant may result in neuronal activity in the auditory system, it may also cause a reduction of activity in other sensory areas. There is some evidence that modality-speciWc sensory stimulation causing activation in one sensory cortical area can induce decreases elsewhere. SigniWcant decreases in regional cerebral blood Xow have been detected with positron emission tomography (PET) in auditory areas during a visual task (Haxby et al., 1994). In this case, the striking reduction observed in the primary and secondary auditory cortex could result from selective attentional processes, reducing the response to unattended auditory stimuli while enhancing the response in visual areas. It has been demonstrated that these cortical decreases in blood Xow are associated with nonselective attention during the performance of a visual task (Shulman et al., 1997). Close examination revealed that

50 G. F. Eden and T. A. ZeYro

this modulation is inconsistently localized across cortical areas and is unpredictable across studies, with the nature of the modulations in the auditory cortex being dependent on the nature of the task. For example, left hemisphere decreases were seen with nonlanguage tasks and right hemisphere reductions were observed during linguistic tasks. While certain areas (auditory cortex, insula, and parietal operculum) appear to show response decreases, it is not currently understood what governs these decreases and why they are not occurring systematically. These Wndings suggest that the auditory stimulation induced by fMRI is likely to promote modulations in areas not generally thought to be modulated by auditory stimuli. (Fiez et al., 1995; Shulman et al., 1997).

More direct evidence has been obtained from fMRI studies, indicating that the eVect of the MRI acoustics is complex. During visual and motor tasks, subjects were exposed to stimuli in noise reduced and noisy conditions (Cho et al., 1998). The resulting task-related BOLD signals diVered signiWcantly. During motor activity, the acoustic noise enhanced the motor signal, but during visual stimulation the signal from visual cortex was reduced. These Wndings emphasize the earlier cautions expressed in the PET literature. In fMRI, the gradient noise can potentially induce such decreases in areas outside of auditory cortex, contaminating estimation of task-related changes in those areas. Such signal modulation has recently been demonstrated to be nonspeciWc with respect to task and spatial location (Cho et al., 1998).

Investigation into this complex relationship observed in adults has not been extended to pediatric studies. It is not known whether the inXuence of acoustic stimulation on the brain is the same in children as in adults, regardless of whether it has an attentional or physiologic explanation. Studies involving language or sound processing are especially likely to be polluted by the external noise, and few studies have successfully been able to eliminate the noise by insulation or other approaches. In traditional data acquisition procedures, the gradient noise occurs equally in the control and task conditions. Assuming that the signal change resulting from this gradient noise is linearly additive with task-related signal change, it should be possible to subtract the noise eVects. Therefore, data-analysis techniques reliant upon image subtraction, such as the t- test, will be insensitive to this source of noise. Although it is reasonable to assume that linear additivity for gradient noise might hold for many cortical regions, it is less likely that this assumption is reasonable for cortical areas known to be responsive to auditory stimuli.

One way to circumvent the exposure to the gradient noise caused by the magnet is to interleave data acquisi-

tion periods with task performance. This behavior interleaved gradient (BIG) technique takes advantage of physiologic hemodynamic delay and dispersion in order to collect image data under relatively quiet conditions. In our studies, we employ an approach in which the gradients are oV during periods of task execution and then immediately switched on to acquire data. Detection of the task-related signal change relies on the presence of a hemodynamic lag of 5±8s between neuronal activity and the resulting BOLD contrast response. We recently validated this technique using an externally paced Wnger movement task known to induce large signal changes in motor areas (Eden et al., 1999). Six subjects performed an index Wnger tapping task with the dominant hand at a rate of 2Hz paced by a large Xashing green star. Finger tapping alternated with periods of rest, during which the subject viewed a red star, Xashing at the same rate. Multislice echo-planar image (EPI) acquisition was used (time to echo (TE) 43ms; time to repetition (TR) 12s; matrix 64!64; Weld of view (FOV) 256mm; 40 axial slices; thickness 4mm; cubic voxels 4mm; 50 time points per run). Two runs were performed in each of the following four acquisition modes.

1Acquired after task, BIG. Data were acquired after the task and involved 8s of tapping during which no data were acquired, followed by a 4s interval during which one whole-head volume was acquired.

2Acquired during task (control). Rest and task were alternated as in the previous condition but the acquisition began during the second half of the task period, thereby providing a control for the assumed hemodynamic lag.

3Acquired concurrently 1. This employed the traditional block design of continuous task periods alternating with rest periods.

4Acquired concurrently 2. The same procedure was used as in (3) but it was controlled for diVerences in the number of movements produced over the total scans by

changing the tapping rate.

Fifty time points were collected for each condition. Using MEDx (Sensor Systems, Sterling VA), the image data were corrected for head motion and for global and local intensity variations. Task and rest periods were compared using the t-statistic that was then transformed to a Z-score. The Z-map was then searched for local maxima.

The resulting statistical maps revealed task-related changes in primary motor cortex, primary somatosensory cortex, premotor cortex, the supplementary motor area, the cingulate motor area, thalamus, and anterior cerebellum. Comparisons of the Z-maps generated from the movement minus rest condition for the four acquisition modes listed above revealed that activations in primary motor cortex were similar or higher when data acquisition occurred

Functional magnetic resonance imaging	51

Fig. 3.1. Task description of an experiment assessing the validity of the behavior interleaved gradient (BIG) technique. BIG takes advantage of physiologic hemodynamic delay and dispersion in order to collect image data under relatively quiet conditions (Eden et al. 1999).

following task completion, as is the case for BIG. Figure 3.1 summarizes the experimental procedures for BIG.

Interleaving task performance and data acquisition allows task performance under relatively quiet experimental conditions (Eden et al., 1999; Edmister et al., 1999). Task performance periods of 8s were suYciently long to yield excellent statistical results. This technique is useful when the experiment requires maximal acoustic isolation of the subject. It is also advantageous when speech is required, as articulation, with its attendant motion artifacts, will not occur during periods of data acquisition.

Rate-related eVects

There is now a signiWcant body of literature from the Weld of PET and MRI describing the eVects of stimulus presentation rate or stimulus duration on regional cerebral blood Xow (Fox and Raichle, 1984; Price et al., 1994, 1996) or fMRI signal (van Meter et al., 1995; Binder et al., 1997; Dhankhar et al., 1997; Rees, et al., 1997). Rate-related changes have been studied with both types of imaging, but the observations reported vary with the nature of the experiment. The eVect

of exposure duration has been systematically studied with PET during oral reading (Price et al., 1994) and listening to words (Price et al., 1992). This latter experiment revealed a linear relationship between the rate of aurally presented words and regional cerebral blood Xow bilaterally in portions of the superior temporal gyrus, including primary auditory cortex, and right posterior superior temporal gyrus. However, posterior portions of the left superior temporal gyrus (Wernicke's area) failed to show this linear rate dependence. In a comparison of reading aloud versus lexical decision (Price et al., 1994) bilateral posterior temporal and inferior parietal areas, or Brodmann's area (BA) 39, as well as cingulate gyrus and left hippocampus were signiWcantly more active during reading aloud compared with silent reading (lexical decision). However, this was only the case when words were presented for durations of 150ms. These diVerences disappeared when stimuli were presented at a longer duration (1000ms). Together these Wndings suggest that responses in these superior temporal and inferior parietal areas are modulated by presentation rates.

Functional MRI studies investigating stimulus response rate have not entirely agreed with the PET studies. While

52G. F. Eden and T. A. ZeYro

the PET data show a linear dependency on rate in auditory cortex, BOLD signals in this area appear to be nonlinear (Binder et al., 1994; Rees et al., 1997). By comparison, the nonlinear behavior observed in Wernicke's area measured with PET was shown to be linear in an fMRI study (Dhankhar et al., 1997). These discrepancies might be related to subtle between-study diVerences or to the inherent characteristics of the BOLD response, such as the relationship between BOLD and deoxyhemoglobin concentration (Binder et al., 1994; Rees et al., 1997). As with the relationship between neuronal activity and the BOLD response, the nonlinearity of the BOLD contrast is not yet fully understood. In practice this means that investigators will need to take greater care in situations in which rate and exposure duration make a signiWcant contribution to the outcome of the study. In pediatric studies, it is likely that children of diVerent ages will exhibit diVerent reaction times, as they become more proWcient at a task. Depending on the experimental design, reaction time variability can inXuence the rate at which the experiment is conducted. For younger children with a signiWcantly lower response rate (and, therefore, lower frequency of responses over a given time period), it is important to identify the role of rate-related modulation of the signal. Failing to do so might confound data in which diVerences are identiWed in two age groups but obscured by rate eVects. One possible solution to this problem is to map the regions that show parametric rate modulation in a group of controls in a separate study. Having determined which brain areas exhibit rate modulation for a given task, it will be possible to interpret more carefully any between-group diVerences seen in the context of between-group rate diVerences. If a particular region can be shown to not exhibit rate modulation over the range of rates used in the experiment, then it would be less likely that the performance rate diVerences between groups accounted for the diVering patterns of task-related activation.

Event-related fMRI

Recently, a new experimental approach has been introduced that analyzes the hemodynamic response to single events, cognitive, perceptual or motor. This approach is referred to as event-related or single-trial fMRI (Buckner et al., 1996; Friston et al., 1998). It takes advantage of the fact that averaging of the hemodynamic response to brief events may be used to identify regional changes in taskrelated brain activity. Among the advantages of eventrelated techniques is the ability to avoid subject expectancy by randomizing the order of diVerent trial types. During analysis, the trials are sorted by type and

then averaged to enhance signal contrast-to-noise. Elaboration of this basic method allows correction or modulation of the MR signal by previous or successive events using deconvolution techniques Wrst developed in the context of event-related potential signal processing.

In pediatric studies, event-related experimental designs might be of particular value because the investigator may want to sort the trials depending on the nature of the response given by the child. Children are more likely to exhibit less stable task performance on all but the simplest sensorimotor tasks. Consequently, in any epoch during the scanning sessions, trials in which the correct response was made will be intermixed with trials in which incorrect responses occurred, making statistical contrasts between behavioral epochs less sensitive. The greater response variability observed in these younger individuals might be partially ameliorated by eliminating trials in which incorrect responses occurred. Selection and averaging of only the trials in which the child made a correct response might allow more sensitive detection of event-related signal change. Moreover, application of overlap correction methods using deconvolution will allow collection of data in less time, an important consideration for pediatric imaging.

Data analysis

The analysis of functional neuroimaging data may be described as a series of processes beginning with image reconstruction and ending with visualization of fused structure/function for individual subjects and groups of subjects. The outcome of the statistical analysis is greatly determined by the acquisition parameters and experimental procedures described above. In addition, because of the time required to acquire each slice using EPI, there is a trade-oV between spatial resolution, temporal resolution, and brain coverage. Therefore, using thinner slices requires a larger number of slice acquisitions to cover the same brain volume. Because the time to acquire each slice is Wxed, more time is required for increased spatial resolution orthogonal to the slice orientation. These spatiotemporal constraints on data acquisition have important consequences pertaining to the success of the data analysis phase of experiments.

In the previously described pediatric neuroimaging studies (Hertz-Pannier et al., 1994; Jackson et al., 1994; Casey et al., 1995, 1997a; Benson et al., 1996), all investigators focused their attention on the frontal areas of the brain and, for this reason, restricted data acquisition to the frontal lobes. This was presumably done to achieve shorter

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data acquisition times, a decided advantage in pediatric studies. A particular disadvantage of this approach is that a partial brain volume makes adequate head motion correction diYcult, as the realignment algorithms beneWt from the presence of data covering a larger three-dimen- sional volume.

Image artifacts

Image artifacts can result from both instrumental and physiologic sources. Some of these artifacts can be corrected with improved reconstruction techniques and others require image processing of the reconstructed images. Geometric image distortion is a particularly troublesome artifact, as its degree may adversely aVect subsequent stages of data processing. SpeciWcally, low spatial distortion is required for optimal performance of rigidbody head motion correction algorithms. The spatial accuracy of EPI data is strongly inXuenced by the accuracy of the shimming procedure employed prior to data acquisition. Although most 1.5T MR imaging systems have adequate facilities for automated shimming, the more profound susceptibility artifacts occurring at higher static Weld strengths are more diYcult to correct using automated procedures.

Rigid-body and parenchymal motion

Despite taking the time to prepare children as described above, it is not possible to completely immobilize subjects during functional imaging procedures. Systems that are best at reducing interscan motion (e.g., bite-bars) are not suitable for use in many pediatric populations. The head motion between scans is the principal source of error variance in fMRI time series. This motion may arise from either translation/rotation of the head or brain parenchymal motion resulting from cardiac or respiratory pulsations.

Translational or rotational motion of the head results in misregistration of sequentially collected brain volumes, resulting in signal intensity changes related to changing partial volume eVects. Although the motion is global, the eVects of the motion are regionally speciWc, being most prominent in regions of variable tissue contrast. Examples include boundaries between gray matter and cerebrospinal Xuid. This may result in an easily appreciated ªrimº artifact around the edge of the brain in statistical maps generated from time series with excessive interscan motion. If peak-to-peak rigid-body motion exceeds 10±30% of the image voxel width, statistical maps are likely to exhibit statistical artifacts. Therefore, assuming con-

stant head motion, statistical map artifact will increase with increasing spatial resolution and decreased voxel width. Linear realignment techniques are eVective in correcting this source artifact in statistical images.

Even in the absence of rigid-body head motion, regionally varying parenchymal motion of the brain can produce signiWcant artifacts in statistical parametric maps. This parenchymal motion results from an interaction between the viscoelastic properties of the brain tissue and local pressure changes induced by arterial and venous pressure modulations of cardiac and respiratory origin (Poncelet et al., 1992). This motion is most pronounced in the midline structures and reduces the sensitivity to task-related changes in these areas. Because it varies throughout the brain, parenchymal motion cannot be adequately modeled by rigid-body transformations. An additional complication arises because this motion results in MR signal changes at frequencies above the sampling rates customarily employed in EPI functional imaging, usually one sample each 2 to 5s. The average heart rate is one per second and therefore it will not be properly sampled. This physiologic aliased noise can be reduced by designing digital Wlters that attenuate the MR signal at the appropriate frequencies (Biswal et al., 1996). Another promising approach to this problem is to utilize cardiac gating. In this method, MR signal acquisition is synchronized with the cardiac impulse, assuring that each time point is collected in the same phase of the cardiac cycle. This technique has made possible the detection of auditory task-related changes in subcortical structures (Guimaraes et al., 1998).

Motion detection and correction

Prior to attempting any realignment, it is important to assess the magnitude of interscan head motion. This may be accomplished by viewing an animation of the time series, by computing the translational motion of the center-of-intensity of the volumes comprising the time series, or by computing a voxel-wise variance map. Examination of an animated slice from a time-series is an excellent method with which to obtain a rapid qualitative estimate of interscan head motion. Computing the motion of the image volume center-of-intensity is more computationally demanding but results in quantitative estimates of motion. The translational moments in each dimension (x, y, or z) may be further processed to obtain scalar estimates of motion for the entire time series, including meansquare error or three-dimensional path length. Regionally speciWc motion artifacts may be detected by computing the signal variance across the temporal dimension for each voxel in the image volume. In the resulting map, areas of