PEDIATRICS Vol. 120 No. 5 November 2007, pp. e1245-e1254 (doi:10.1542/peds.2006-2596)
ARTICLE |
Altered Resting Cerebral Blood Flow in Adolescents With in Utero Cocaine Exposure Revealed by Perfusion Functional MRI
a Department of Radiology and Neurology, Center for Functional Neuroimaging, University of Pennsylvania, Philadelphia, Pennsylvania
b Divisions of Neonatology
c Biostatistics and Epidemiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. Animal studies have clearly demonstrated the effects of in utero cocaine exposure on neural ontogeny, especially in dopamine-rich areas of cerebral cortex; however, less is known about how in utero cocaine exposure affects longitudinal neurocognitive development of the human brain. We used continuous arterial spin-labeling perfusion functional MRI to measure the effect of in utero cocaine exposure on resting brain function by comparing resting cerebral blood flow of cocaine-exposed adolescents with non–cocaine-exposed control subjects.
PATIENTS AND METHODS. Twenty-four cocaine-exposed adolescents and 25 matched non–cocaine-exposed control subjects underwent structural and perfusion functional MRI during resting states. Direct subtraction, voxel-wise general linear modeling, and region-of-interest analyses were performed on the cerebral blood flow images to compare the resting cerebral blood flow between the 2 groups.
RESULTS. Compared with control subjects, cocaine-exposed adolescents showed significantly reduced global cerebral blood flow. The decrease of cerebral blood flow in cocaine-exposed adolescents was observed mainly in posterior and inferior brain regions, including the occipital cortex and thalamus. After adjusting for global cerebral blood flow, however, a significant increase in relative cerebral blood flow in cocaine-exposed adolescents was found in anterior and superior brain regions, including the prefrontal, cingulate, insular, amygdala, and superior parietal cortex. Furthermore, the functional modulations by in utero cocaine exposure on all of these regions except amygdala cannot be accounted for by the variation in brain anatomy.
CONCLUSIONS. In utero cocaine exposure may reduce global cerebral blood flow, and this reduction may persist into adolescence. The relative increase of cerebral blood flow in anterior and superior brain regions in cocaine-exposed adolescent participants suggests that compensatory mechanisms for reduced global cerebral blood flow may develop during neural ontogeny. Arterial spin-labeling perfusion MRI may be a valuable tool for investigating the long-term effects of in utero drug exposure.
Key Words: in utero cocaine exposure • ASL perfusion fMRI • cerebral blood flow • frontal lobe • adolescence
Abbreviations: IUCE—in-utero cocaine exposure • ASL—arterial spin labeling • fMRI—functional MRI • CBF—cerebral blood flow • BOLD—blood oxygen-dependent level • ROI—region of interest • VBM—voxel-based morphometry • COC—cocaine-exposed adolescent • CON—non–cocaine-exposed control • TR—repetition time • FDR—false-discovery rate
In utero cocaine exposure (IUCE) and its potential cognitive and psychological sequelae have been major health-related concerns since the late 1980s in the United States. Although theories and models from animal experiments have clearly demonstrated some alterations and deficits of cortical development induced by IUCE, especially in the dopamine-rich areas of cerebral cortex,1,2 the effect of IUCE on human subjects remains unclear. On one hand, evidence from previous studies has shown different degrees of harmful IUCE effects in the newborn, such as premature birth, birth asphyxia, brain hemorrhage, growth retardation, and neurobehavioral deficits.3,4 On the other hand, a review of IUCE effect in early childhood failed to find any consistent association between IUCE and physical growth or cognitive developmental deficits.5 Currently, there is still no clear answer regarding the extent to which IUCE may have an enduring impact on the neurocognitive development of children. The inconsistency of the IUCE effect on human subjects may be because of the complex methodologic issues involved in conducting longitudinal studies with the diverse human population. The unavoidable imprecision in ascertaining the gestational timing and dose of cocaine to which the fetus was exposed, the occurrence of concurrent substance use other than cocaine, the socioeconomic status and family mental health history, some limited sample sizes, and the lack of long-term follow-up may all contribute to the inconsistency.
Recent advances in brain imaging and cognitive neuroscience have led to growing interest in integrating neuroimaging methods and neurocognitive framework into the study of IUCE effects. Using different imaging techniques, such as functional or structural MRI, diffusion tensor MRI, magnetic resonance spectroscopy, electroencephalography, or event related potential, previous studies6–11 have provided emerging evidence suggesting that IUCE may affect the frontal lobe, which may be reflected in neurocognitive impairments in attentional and arousal regulatory systems, as well as executive function.12–14
Longitudinal studies of cortical development from childhood through adulthood in healthy normal brains have demonstrated that maturation of high-order association cortices occurs later than low-order sensory cortices, such as the maturational changes of the prefrontal cortex during late adolescence.15 In addition, animal studies on nonhuman primates16,17 suggest that the behavioral effects of IUCE might not be manifested until adulthood. However, to date, few studies have investigated the impact of IUCE on human brain activity during adolescence. Our group has followed a cohort of in utero cocaine-exposed and nonexposed participants since their birth in the late 1980s or early 1990s.18–21 These participants, who are now entering early-to-middle adolescence, provide an opportunity to investigate the effects of IUCE on neurocognitive function in the adolescent brain.
To this end, the present study used arterial spin-labeling (ASL) perfusion functional MRI (fMRI) and measured resting cerebral blood flow in 2 groups of adolescents, with and without IUCE, with the aim of noninvasively exploring the effects of IUCE on resting cerebral activation patterns in the adolescent brain. ASL perfusion MRI offers absolute quantification of cerebral blood flow (CBF; ie, milliliters of blood per 100 g of tissue per minute) that is normally coupled with neural activity by using magnetically labeled arterial blood water as an endogenous tracer.22 Previous studies have shown excellent reproducibility over long-term time periods and less between-subject variability of ASL perfusion compared with blood oxygen-dependent level (BOLD) fMRI.23–25 ASL may be particularly advantageous for pediatric neuroimaging, because it is entirely noninvasive and provides improved image quality compared with adult images because of several physiologic properties of a child brain.25,26 We were particularly interested in the effect of IUCE on the frontal lobe and the reciprocally connected limbic structures. Therefore, we defined a priori regions of interest (ROIs) of frontal lobe and the limbic structures including the cingulate cortex, caudate, insula, and amygdala. The occipital lobe and thalamus were also included as the lower-order sensory processing regions for comparison with the frontal lobe. To explore any possible association between the influences of IUCE on resting brain CBF and on brain anatomy, perfusion fMRI was combined with optimized voxel-based morphometry (VBM), a quantitative morphometrical analysis of structural MRI to compare the gray matter volume between groups.27–29
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METHODS |
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Participants
A total of 49 adolescent participants, including 25 cocaine-exposed adolescent (COC) participants and 24 non–cocaine-exposed control subject (CON) participants, were recruited from a cohort of exposed and nonexposed participants who have been followed since their birth (1989–1992). Full details of enrollment have been reported previously.18 Written consent was obtained according to institutional review board approval from the Children's Hospital of Philadelphia. Subjects selected for MRI met the following criteria: they were right handed, had no metal appliances, and were on no medications. Because of concerns for possible confounding effects of gender and IQ, we further selected exposed and nonexposed children by gender and by group quartiles of 4-year Wechsler Preschool and Primary Scale of Intelligence-Revised scores. We did not perform drug screens before the fMRI scan. However, all of the subjects in the cohort have drug screens at the time of the annual visit, and there was no difference between the COC and CON groups. All of the participants were born at a single inner-city hospital to mothers of low socioeconomic status. The COC cohort was heavily cocaine exposed during gestation with 24 of 25 having been exposed in all 3 trimesters and 19 of 25 mothers of the COC cohort having used frequently (once or more per week; median: 117 days of exposure and a minimum of 2 trimesters of pregnancy); conversely, the mothers in the CON cohort denied cocaine use, and both mother and child had urine samples (peripartum and natal, respectively) that were negative for cocaine metabolites.
Among the COC group, 8 mothers reported using cigarettes, alcohol, and marijuana; 7 mothers reported using cigarettes and alcohol; 5 mothers reported using cigarettes and marijuana; 4 mothers reported using cigarettes; and 1 mother reported using marijuana; in the CON group, only 1 mother reported using cigarettes, and no mothers reported using alcohol or marijuana. The numbers of mothers using cigarettes, alcohol, or marijuana in the 2 groups are listed in Table 1. Children were included if they were born at 
34 weeks' gestational age (range: 34–42 weeks; see Table 1). Children were excluded if they were <34 weeks' gestational age, had an Apgar score of 
5 at 5 minutes of age, or had fetal alcohol syndrome or any syndrome known to be associated with developmental delay. Participants had cranial ultrasounds performed as soon after birth as possible. Three of the control children did not have scans because they were not medically necessary, and infants were discharged before the scan could be performed. Participants also had a neurologic examination at 6.5 years of age by a developmental pediatrician masked to group status who used a standard neurologic examination (cranial nerves, optic fundus, deep-tendon reflexes, tone, gross motor strength, range of motion, gait, plantar responses, sensation, and an articulation screen) and an examination for soft signs (finger to nose, rapid pronation-supination, heel-to-toe walking, balance on 1 foot with eyes closed, and hop) to evaluate the children.20
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Imaging Acquisition
A continuous ASL technique was conducted on a Siemens 3.0-T Trio whole-body scanner (Siemens AG, Erlangen, Germany) using a standard transmit/receive head coil for perfusion fMRI scans. ASL was implemented with a 0.16-g/cm gradient and 22.5-mg radiofrequency irradiation applied 8 cm beneath the center of the acquired slices. Control/labeling was interleaved using an amplitude-modulated version of the labeling pulse based on a sinusoid function.30 The tagging/control duration was 1.6 seconds. Interleaved images with and without labeling were acquired using a gradient echo-planar imaging sequence. A delay of 1.2 seconds was inserted between the end of the labeling pulse and image acquisition to reduce transit artifact. Acquisition parameters were as follows: field of vision, 22 x 22 cm2; matrix, 64 x 64; repetition time (TR)/echo time, 4000 milliseconds/17 milliseconds; and flip angle, 90°. The resting perfusion scanning protocol lasted 320 seconds with 80 acquisitions. Sixteen slices (6-mm thickness with 1.5-mm gap) were acquired from inferior to superior in sequential order. Before the perfusion scan, high-resolution anatomic images were obtained by a three-dimensional magnetization-prepared rapid acquisition of gradient echo sequence with TR/inversion time/echo time at 1620 milliseconds/950 milliseconds/3 milliseconds, flip angle at 15°, 160 contiguous slices of 1-mm thickness, field of vision at 192 x 256 mm2, and matrix at 192 x 256. The total length of scan time lasted
1 hour, including the perfusion scan, anatomic scan, and other scans for BOLD imaging and diffusion tensor imaging (data not reported here).
Functional Imaging Data Analysis
Functional and structural MRI data processing and analysis were conducted primarily with the statistical parametric mapping software (SPM2 [Wellcome Department of Cognitive Neurology, United Kingdom], implemented in Matlab 6 [Math Works, Natick, MA]), with some modifications for perfusion analysis (see http://cfn.upenn.edu/perfusion/software.htm).
For each subject, functional images were first realigned to correct for head motion and coregistered with the anatomic image. Perfusion-weighted image series were then generated by pairwise subtraction of the label and control images, followed by conversion to absolute CBF image series based on a single-compartment continuous arterial spin-labeling perfusion model.30 Thus, the resulting CBF data sets contained 40 acquisitions with an effective TR of 8 seconds. One mean CBF image was generated for each individual subject, normalized to a 2 x 2 x 2-mm3 subject-based Montreal Neurologic Institute template generated from the optimized VBM (see "Structural Imaging Data Analysis" below), and smoothed in space with a three-dimensional, 8-mm full-width-at-half-maximum Gaussian kernel. Global CBF was calculated and compared by a 2-sample t test. The mean CBF images for each group were averaged, and a voxel-wise direct subtraction was performed to obtain a straightforward comparison between the 2 groups without statistical processing. Voxel-wise population comparisons (analysis of covariance) using the general linear model were also conducted on these individual CBF images with covariates to account for the age and gender variability. Comparisons were conducted on both absolute CBF (without global CBF correction) and relative CBF (with an additional covariate of global CBF to account for the variability in global CBF). Contrasts were defined as the difference between 2 groups (COC – CON). Areas of significant activation and deactivation associated with the contrasts were identified for the mapwise significance level of false-discovery rate (FDR),31 corrected P value of <.05, and cluster size >100 voxels.
The ROIs were determined a priori to be the frontal lobe, occipital lobe, insula, caudate, cingulate, amygdala, and thalamus. These structures were defined from an automated anatomic-labeling ROI library.32 For each subject, the quantitative CBF values in each ROI were read out by the statistical parametric mapping Marsbar toolbox.33 The relative CBF values were calculated as the ratio of regional CBF to global CBF. Two-sample t tests were performed on these values to explore the difference between the regional CBF of the 2 groups. With our sample size of 24 COC subjects and 25 CON subjects, using a significance level of 
= .05, we could detect an effect size of .8 SDs with 80% power in 1 a priori ROI.
Structural Imaging Data Analysis
The high-resolution structural images of all 49 of the participants were analyzed using the optimized VBM protocol described in previous studies.29 The VBM approach provides a sophisticated automated method to measure gray matter volume differences between 2 groups. A study-specific T1 brain template was created for spatial normalization, and study-specific probability maps were created to optimize the segmentation of each subject's image. The customized T1 template, gray matter, white matter, and cerebrospinal fluid images were used for the optimized VBM procedure. The spatially normalized segments of each subject's gray matter images were modulated for volume analysis and smoothed in space with a three-dimensional, 8-mm full-width-at-half-maximum Gaussian kernel. Two-sample t tests were performed on the global volumes of gray matter, white matter, and cerebrospinal fluid. The individual modulated gray matter images were entered into the whole brain voxel-wise general linear model with 3 covariates to account for the age, gender, and total gray matter volume variability. Areas that showed significant difference between the 2 groups were identified for the mapwise significance level of the FDR-corrected P value <.05 and cluster size >100 voxels. The gray matter volumes of the above ROIs were calculated. To investigate any possible association between the influences of IUCE on brain anatomy and on resting CBF, multivariate regression analyses were performed on regional absolute CBF in each ROI, using IUCE, total gray matter volume, and regional gray matter volume in each ROI as the independent covariates.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The study demographics of all 49 of the participants are shown in Table 1. The COC and CON groups were similar (all P values at >.05) except for poly-substance exposure in COC (all P values at <.001). The quantitative resting CBF images averaged from the COC group and CON group, as well as the CBF differences, are shown in Fig 1. Both resting CBF images visualized the perfusion signal in all of the brain regions with good sensitivity and illustrated clear contrast between gray and white matter in the perfusion intensity. The global CBF intensities were significantly lower for the COC group than the CON group (10.1% decrease; P = .047; Fig 3B). The direct subtraction of the CBF image of the COC group from that of the CON group revealed robust CBF decreases in widespread posterior and inferior brain regions (Fig 1C). These regions included the occipital cortex and thalamus and extended to the cerebellum, fusiform, posterior hippocampus, and inferior temporal cortex. Sparse CBF increases were observed in small anterior frontal, cingulate, and parietal regions.
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The results from the voxel-wise analysis are shown in Fig 2 and listed in Table 2. Without correction of the global CBF difference, significant CBF decreases were found in a large posterior and inferior brain region that were similar to the finding from direct subtraction (Fig 2A). However, with correction of global CBF, significant relative CBF increases were found in multiple anterior and superior brain regions, including bilateral medial and dorsal frontal cortex, insula-putamen, cingulate, and parietal cortices. The regional CBF results for the ROI analyses are shown in Fig 3. Significant absolute CBF (Fig 3B) decreases in the COC group were observed in the occipital lobe (19.8% decrease; P = .004) and the thalamus (21.1% decrease; P = .003), whereas significant relative CBF (Fig 3C) increases were seen in the frontal lobe (9.3% increase; P = .001), cingulate cortex (12.2% increase; P < .001), insula (10.2% increase; P < .001), and amygdala (12.2% increase; P = .004). These ROI results confirmed the voxel-wise results. However, no absolute or relative CBF difference was found in the caudate (both P > .05).
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From morphometrical analyses, there were no group differences in the total volumes of gray matter, white matter, or cerebrospinal fluid (all P > .1; data not shown). The voxel-wise comparison revealed no significant differences between the gray matter volumes of the 2 groups when using the whole-brain mapwise corrected threshold. The ROI analyses revealed no group differences except that the relative regional gray matter volume (percentage of total gray matter volume) was significantly decreased in caudate (5.1% decrease; P = .02), and the absolute and relative regional gray matter volumes were both significantly increased in amygdala (6.2% and 7.0% increase; both P < .02) in the COC group. With the regional gray matter volume and total gray matter volume included in the multiple regression analyses of the CBF data, the IUCE effect was still significant for absolute resting CBF reduction in the thalamus and occipital lobe (both P < .01), as well as for relative resting CBF increase in the frontal lobe, cingulate cortex, insula, thalamus, and occipital lobe (all P < .05; Table 3).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Capitalizing on the several advantages of perfusion fMRI and our longitudinal cohort followed since birth, the present study measured resting brain CBF in a relatively large group of adolescent participants with and without IUCE and suggests several important findings with respect to the effects of IUCE on the developing human brain during adolescence.
The first finding of the present study is the reduced global CBF in prenatally cocaine-exposed participants compared with nonexposed participants. Reduction of cerebral glucose metabolism and CBF in the human brain is a well-established neurologic consequence of cocaine abuse in adults.34–38 Cocaine use can lead to both a global CBF decrease and regional hypoperfusion. To quantify the effects of cocaine use on global CBF, Wallace et al39 used single photon emission computed tomography and reported an 30% decrease in absolute whole-brain CBF at the time of peak cocaine subjective effects. Similarly, Johnson et al35,36 also used single photon emission computed tomography and reported an 8% to 10% decrease in whole-brain blood flow for intravenous cocaine administration compared with recently abstinent cocaine-dependent subjects. In addition, Gollub et al40 reported a 14% decrease in CBF to cortical gray matter 15 to 30 minutes after infusion of cocaine using flow-sensitive alternating inversion recovery MRI. In the present study, IUCE was associated with a 10% reduction in global CBF, consistent with these values reported previously. A previous study with adult subjects has demonstrated that cocaine has potent effects of cerebral vasoconstriction, and chronic exposure may alter cerebrovascular reactivity and permanently decrease CBF.41 Reduced global CBF in subjects with IUCE suggests that chronic exposure in utero may have similar effects on the fetus, and these effects may persist into adolescence.
The second finding of this study is the altered distribution of resting CBF in participants with IUCE compared with control subjects. The direct subtraction of quantitative CBF, the voxel-wise general linear modeling, and the ROI analyses all consistently showed a reduction in absolute CBF, primarily in posterior and inferior brain regions, including the occipital lobe, thalamus, and posterior temporal lobe. However, frontal, cingulate, insula, and caudate regions showed little absolute CBF differences. The occipital lobe is the cortical center for visual processing, and the thalamus is the subcortical center for receiving and projecting visual and other sensory signals to cortex. Specifically, 1 previous study2 has demonstrated systematically underdeveloped gray matter cellular structure in the occipital lobe of primates with IUCE. In adult human subjects with chronic cocaine abuse, Lee et al42 reported an enhanced BOLD signal in occipital regions in response to photic stimulation, which may reflect inefficient neuronal processing of visual information. The present results are in line with and further extend these findings in terms of IUCE-reduced resting brain function of visual occipital processing in adolescents.
Third, after correction for global CBF differences, the relative CBF was significantly higher in frontal, cingulate, insula, amygdala, and parietal regions in participants with IUCE, that is, relatively more CBF was distributed to the frontal and superior brain regions than the posterior and inferior brain regions. These frontal, cingulate, and parietal regions serve as the neural substrates mediating attention and arousal regulation, which are higher-order association cortices, the development of which is far from complete by childhood.43–46 The changes in relative CBF in these regions are consistent with the view that IUCE-induced changes may affect attention processing.14,47,48 That CBF relatively increased in the late-maturing frontal regions but decreased in the early maturing occipital regions in the cohort with IUCE may reflect the compensatory mechanisms involved in the brain development.
Interestingly, we observed significant relative CBF increases in amygdala and insula but not in caudate. These brain structures are both critical for processing emotion and for linking emotion to behavior. The amygdala and insula are well known for their critical roles in the processing of aversive and unpleasant affects, such as fear, disgust, and pain.49–51 The observed CBF enhancement in amygdala and insula is consistent with the evidence showing the IUCE effect on negative affects.10,12,13 The caudate is well known to be involved in the processing of positive affects, such as reward.52 That there were no CBF changes in caudate may provide impetus for future studies to examine the neurologic basis associated with the possible different alterations in negative and positive affects in children with IUCE.
In addition to investigating the resting CBF difference between the 2 groups, the present study also used morphometrical analysis to explore the possible effects of IUCE on the brain anatomy of adolescent participants. The results demonstrated no significant effect of IUCE on the whole brain or regional gray matter volume, with the exceptions of increases in absolute and relative amygdala volume and decrease in relative caudate volume revealed by ROI analysis. The less significant anatomic differences between exposed and nonexposed participants suggest either a dissociation of the IUCE effect on brain function or brain anatomy or a higher sensitivity of perfusion fMRI than morphometrical analysis. Furthermore, the relative volume difference observed in the caudate was confirmed by the voxel-wise analysis of the same data using a more sensitive method, symmetric diffeomorphisms, for brain structural analysis.53 When including the regional gray matter volume and total gray matter volume in the multivariate regression analyses, the IUCE effect was still significant for absolute CBF changes in the occipital cortex and thalamus, as well as for relative CBF changes in the frontal cortex, insula, and cingulate cortex. These findings suggest that CBF alterations in these regions in participants with IUCE cannot be accounted for by variations in gross brain anatomy. However, the IUCE effect on the absolute and relative CBF in amygdala was not significant when adjusting amygdala anatomic differences, suggesting that IUCE may affect the structure and function of amygdala in a similar way, or structural change of amygdala may be the reason for increased amygdala CBF. These results raised interesting issues for further research regarding the relationship and the temporal order of the IUCE effects on brain function and anatomy.
There were several limitations in our study. First, drug-abusing adults rarely use cocaine in isolation and usually combine cocaine with other potential neuroteratogens, such as alcohol, tobacco, and marijuana; thus, the interpretation of the effect of drugs in humans often is confounded. In the present study, the COC cohort was also exposed to multiple drugs, and there were robust differences of poly-drug exposure between the COC and CON cohorts; thus, the present findings might be confounded by concurrent exposure of tobacco, alcohol, and marijuana in mothers. To minimize this confounding effect, we separated the COC group by each kind of drug exposure and performed additional comparisons between the COC and CON groups by only exposed subjects without a given type of drug exposure (eg, to minimize the effect of alcohol exposure, we compared the COC and CON groups using only subjects without alcohol exposure). We also performed comparisons between the subjects with and without a given type of drug exposure within the COC group (eg, we compared the COC subjects without alcohol exposure with the COC subjects with alcohol exposure). Results from these additional analyses showed similar patterns, suggesting that the altered resting CBF patterns observed in adolescents were associated with IUCE rather than poly-drug use. Future studies with better control of confounding variables in a larger cohort will be needed to elucidate the independent effect of IUCE on brain function and development.
Second, the subjects were pubescent or peripubescent, thus, hormonal changes, especially in female subjects, might interact with the IUCE. However, the analyses including only male subjects yielded similar results, suggesting that the present effects are unlikely to be related to the pubescent hormonal changes.
Finally, all of the subjects were from families of low socioeconomic status, and their IQ scores were mildly low. Whether IUCE affects children of high socioeconomic status and normal IQ the same way and how environmental enrichment and parental nurturance interact with IUCE during brain development remain open to future studies.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We used ASL perfusion fMRI and noninvasively quantified resting CBF in adolescent participants with and without IUCE, demonstrating that IUCE reduces global CBF and alters CBF distribution in the adolescent brain. To our knowledge this is the first study to investigate the impact of IUCE on resting brain function in adolescence. The observed global CBF reduction suggests that the IUCE effect on blood flow may persist until adolescence or young adulthood. In light of reduced global CBF, the apparent increase in the distribution of CBF to more frontal and superior brain regions in exposed participants suggests that compensatory mechanisms may be involved during neurodevelopment. Whether and how these alterations in CBF will be reflected in behavior changes in adolescents and young adults with IUCE are the focus of an ongoing investigation.
Using neuroimaging techniques to image brain structure, function, and metabolites in longitudinally followed exposed and nonexposed control children has emerged as one of the major research directions in the study of prenatal drug exposure.54 This current study and previous reports6–11,54 show the promise of neuroimaging studies to enhance our understanding of how maternal drug abuse affects neurobehavior in their offspring. Perfusion fMRI will be a valuable tool for imaging the long-term effects of drug use during pregnancy in neurodevelopment, given its excellent stability over time.
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ACKNOWLEDGMENTS |
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This research was supported in part by National Institutes of Health Human Brain Project MH072576 and HD049893, National Science Foundation grant BCS-0224007, the Thrasher Research Fund, National Institute on Drug Abuse grant DA14129, and National Institute of Child Health and Human Development grant MRDDRC-HD26979.
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FOOTNOTES |
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Accepted Apr 19, 2007.
Address correspondence to Hallam Hurt, MD, Division of Neonatology, Children's Hospital of Philadelphia, 3535 Market St, Philadelphia, PA 19104. E-mail: hurt{at}email.chop.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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