幼儿多动症之纹状体活性的微分模型

Differential Patterns of Striatal Activation in Young Children with and without ADHD Sarah Durston, Nim T. Tottenham, Kathleen M. Thomas, Matthew C. Davidson, Inge-Marie Eigsti, Yihong Yang, Aziz M. Ulug, and B.J. Casey Background: Cognitive control, defined as the ability to suppress inappropriate thoughts and actions, is compro- mised in attention-deficit/hyperactivity disorder (ADHD). This study examines the neural basis of this deficit. Methods: We used a paradigm that incorporates a para- metric manipulation within a go/nogo task, so that the number of go trials preceding a nogo trial is varied to tax the neural systems underlying cognitive control with increasing levels of interference. Results: Using this paradigm in combination with event- related functional magnetic resonance imaging (fMRI), we show that children without ADHD have increased suscep- tibility to interference with increasing numbers of go trials preceding a nogo trial, but children with ADHD have difficulty even with a single go trial preceding a nogo trial. In addition, children with ADHD do not activate frontos- triatal regions in the same manner as normally developing children, but rather rely on a more diffuse network of regions, including more posterior and dorsolateral pre- frontal regions. Conclusions: Normal immature cognition may be char- acterized as being susceptible to interference and sup- ported by the maturation of frontostriatal circuitry. ADHD children show a slightly different cognitive profile at 6 to 10 years of age that is paralleled by a relative lack of or delay in the maturation of ventral frontostriatal circuitry. Biol Psychiatry 2003;53:871–878 © 2003 Society of Bi- ological Psychiatry Key Words: ADHD, development, striatum, response inhibition, event-related fMRI, parametric Introduction Attention-deficit/hyperactivity disorder (ADHD) is acommon and impairing neuropsychiatric disorder with onset in childhood. It is thought to affect 3% to 5% of all school-aged children and is characterized by age- inappropriate symptoms of hyperactivity, inattentiveness, and impulsivity (Buitelaar 2002; Kaplan et al 1994). Converging evidence implies the involvement of dopami- nergic frontostriatal circuitry in ADHD. Anatomical im- aging studies using magnetic resonance imaging (MRI) have demonstrated subtle reductions in volume in regions of the basal ganglia and prefrontal cortex (e.g., Castellanos et al 1996, 2001; Filipek et al 1997), whereas functional studies have suggested that these regions may be hypoper- fused (e.g., Lou et al 1984). Cognitive functioning is mildly impaired in this disorder (for review, see Sergeant et al [2002]). In particular, cognitive control, the ability to inhibit inappropriate thoughts and actions, is affected. Several studies have shown that this impairment is related to the reduction in volume in frontostriatal regions (Casey et al 1997a; Semrud-Clikeman et al 2000), and functional studies have suggested that older children and adults with ADHD may activate these regions less than controls during tasks that require cognitive control (e.g., Bush et al 1999; Rubia et al 1999; Vaidya et al 1999). We recently showed that development of this ability is related to the maturation of ventral frontostriatal circuitry in a sample of normally developing children relative to adults (Durston et al 2002b). We manipulated task diffi- culty within a go/nogo paradigm by parametrically vary- ing the number of go trials preceding a nogo trial (Durston et al 2002a). Such manipulations allow for comparisons between groups on trials of similar performance. More importantly, this manipulation allows one to test the extent to which immature cognition is characterized by suscep- tibility to interference by varying the salience of the interfering information. Children demonstrated an in- creased susceptibility to interference compared to adults, as they made more errors overall. In addition, they displayed an increase in the number of errors they made to nogo trials as a function of the number of preceding go From the Sackler Institute for Developmental Psychobiology (SD, NTT, KMT, MCD, I-ME, AMU, BJC), Weill Medical College of Cornell University, New York, New York, Department of Child and Adolescent Psychiatry (SD), University Medical Center Utrecht, Utrecht, The Netherlands; Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York (I-ME); and Department of Psychiatry (YY) and Department of Radiol- ogy (AMU), Weill Medical College of Cornell University, New York, New York. Address reprint requests to Sarah Durston, Sackler Institute for Developmental Psychobiology, Weill Medical College of Cornell University, 1300 York Avenue, Box 140, New York NY 10021. Received August 16, 2002; revised November 14, 2002; accepted November 19, 2002. © 2003 Society of Biological Psychiatry 0006-3223/03/$30.00 doi:10.1016/S0006-3223(02)01904-2 trials as adults did, demonstrating that their ability to inhibit an action was sensitive to the preceding context; however, whereas in adults activation in ventral prefrontal regions increased with increasing interference, this cir- cuitry appeared to be maximally activated in children when suppressing a behavioral response regardless of the number of preceding responses. This pattern of ventral frontostriatal activity correlated with both age and perfor- mance, suggesting that changes in susceptibility to inter- ference are paralleled by maturation in underlying fron- tostriatal circuitry (Durston et al 2002b). In the present study, we used our go/nogo paradigm in combination with event-related functional magnetic reso- nance imaging (fMRI) to investigate the effect of increas- ing interference on both behavior (the suppression of the button press involved in the go response) and magnetic resonance (MR) signal in young children with ADHD and group-matched controls. We predicted that children with ADHD would demonstrate increased susceptibility to interference compared to control children, as the develop- ment of this ability is thought to be impaired in these children. Therefore, we hypothesized that children with ADHD would make more errors overall to nogo trials than control children. Second, we hypothesized that these differences would be paralleled by less efficient or focal patterns of frontostriatal activity than in children without ADHD. Methods and Materials Subjects A total of 14 right-handed children completed the study1, including 7 healthy controls (mean age � 8.68 [1.51] years, range 6.2–10.3 years, 1 female) and 7 children meeting DSM-IV criteria for ADHD (mean age � 8.55 [1.59] years, range 6.6–10.8 years, 1 female; 3 inattentive subtype, 4 combined subtype) (American Psychiatric Association 1994). A structured interview was used to establish diagnosis in the ADHD children and to confirm absence of diagnosis for the controls (Schedule for Affective Disorders and Schizophrenia for School-Age Chil- dren–Parent Version) (Orvaschel 1994). ADHD children with comorbid disorders other than opposition defiance disorder (ODD) and conduct disorder (CD) were excluded. The Conners rating scale (Conners 1969) and the Child Behavior Checklist (CBCL) (Achenbach and Edelbrock 1983) were used to inven- tory ADHD symptomatology. Subjects were screened for any contraindications for MRI. All ADHD subjects were on stimulant medication, which they withheld from taking the day of the MRI. We obtained written assent from all subjects before scanning and written consent from a parent or legal guardian. The procedure was approved by the institutional review board at Weill Medical College of Cornell University. Ten children were excluded from the imaging study after having participated in a scanning session (including 7 subjects with ADHD) due to excessive motion in the scanner or technical problems; however, we were able to analyze the behavioral data for the larger sample of children (14 children with ADHD and 10 control children). Paradigm The subject’s task was to press a button in response to visually presented stimuli but to avoid responding to a rare nontarget. The task consisted of five runs, which lasted 3 minutes and 56 seconds each. Each run contained a total of 57 trials, with 75% go trials, resulting in a total of 70 nogo trials, including 20 of each type (with 1, 3, or 5 preceding go trials) per subject. Foil trials (nogo trials after 2 or 4 go trials) were included to prevent learning of the pattern, but these trials were not included in the analysis. The order of presentation of the different types of nogo trials was pseudorandomized. To make the task more interesting for children, characters from the Pokemon cartoon series were used as stimuli. Stimulus duration was 500 milliseconds and the interstimulus interval was 3500 milliseconds (total trial length � 4000 milliseconds). Scan Acquisition Echo planar imaging (EPI) blood oxygenation level dependent (BOLD) images were acquired in 24 axial slices on a 1.5 T GE Signa scanner (Advanced NMR, Wilmington, MA), covering most of the brain (repetition time [TR] � 2000, echo time [TE] � 40, 64 � 64, 4-mm slice thickness, 3.125 � 3.125 mm in-plane resolution). Anatomical spin echo images were also collected (TR� 500, TE�min, 256� 256, field of view [FOV] � 20, 4-mm slice thickness) in the same locations as the functional slices. Stimuli were presented using the integrated functional imaging system (IFIS) (MRI Devices Corporation, Waukesha, WI) that uses a liquid crystal display (LCD) video display in the bore of the MR scanner and a fiberoptic response collection device. Scanning sessions lasted no longer than 1 hour. The functional images were collected in 20–25 minutes, while the anatomical images were collected within a similar time frame. The participants were shown cartoons during the anatom- ical scans to prevent boredom and restlessness. Analysis Automated Image Registration (AIR) version 3.08 (Woods et al 1992) was used for motion correction, image smoothing (2 mm), and cross registration of data. Cross registration was checked by visual inspection of an overlay of each subject’s brain with the brain chosen as the standard. There were no differences in variance between groups in MR signal. Foil trials were not included in the analyses. NeuroImaging Software (Laboratory for Clinical Cognitive Neuroscience, University of Pittsburgh and Princeton University) was used to perform a series of voxelwise, multifactorial analyses of variance (ANOVAs), beginning with a 14 (subjects) � 2 (condition: go vs. nogo) design, averaging 1 At least three runs of the paradigm with less than one voxel of movement. Runs with too much motion were replaced with runs from the same subject to keep the number of runs per subject constant. At least one run was replaced for three subjects. 872 S. Durston et alBIOL PSYCHIATRY 2003;53:871–878 across all runs, to look for common patterns of activation between groups. Secondly, a 14 (subjects) � 2 (group) � 2 (condition: go vs. nogo) ANOVA was performed to look for differences in pattern of activation between groups. Post hoc analyses were performed for each group separately. For each trial type, two 2-second scans were included in the analyses taken at the peak of the hemodynamic response (4 and 6 seconds after stimulus presentation), yielding 40 data points per trial type per subject. In each analysis, regions of three or more contiguous voxels (p � .05 for each voxel in the cluster) were identified (Forman et al 1995). To separate clusters that had more than one maximum with contiguous voxels, analyses were also performed at more conservative p-values, ranging from p � .005 to p � .01 to examine whether these regions were behaving similarly by comparing their response over go trials and the three levels of nogo trials. If they did not display the same pattern, they were treated as separate clusters. Images were warped into stereotaxic space using Analysis of Functional Neuroimages (AFNI) (Cox 1996) to localize regions of activity, based on the coordinate system of the Talairach atlas (Talairach and Tournoux 1988). Only correct trials were analyzed. A post hoc scan by scan analysis similar to one we have used previously (Casey et al 2000; Durston et al 2002b) was performed on brain regions identified as having significant signal change by the omnibus group � condition ANOVA to test for a differential response between groups on the three different types of nogo trials. Correlations between MR signal change, age, and accuracy were calculated for regions that differentiated the two groups. Results Behavioral Results Across all subjects that participated in the behavioral study, children with ADHD made significantly more errors on nogo trials (mean accuracy � 90.4 [8.1]% for controls; 79.1 [14.4]% for ADHD; t � 2.43, p � .032). Differences in reaction time (RT) and accuracy on go trials did not reach significance (mean RT � 677 [112] milli- seconds for controls; 758 [102] milliseconds for ADHD; t � 1.87, p � .09; mean accuracy � 97.8 [1.8]% for controls; 95.8 [3.7]% for ADHD; t � 1.71, p � .12). For the group of children with usable imaging data, there were no differences between the children with and without ADHD in reaction time (mean RT � 678 [140] millisec- onds for controls; 719 [133] milliseconds for ADHD; t � .02, p � .99) or accuracy (for go trials: mean accuracy � 97.8 [1.8]% for controls; 95.8 [3.7]% for ADHD; t � .71, p � .49; for nogo trials: mean accuracy � 86.4 [8.8]% for controls; 74.9 [9.6]% for ADHD; t � 1.19, p � .26.); however, the number of errors made on the nogo trials increased as a function of the number of preceding go trials for the control children (10.2%, 17.2%, 17.9%, r � .90, p � .02) but not for the children with ADHD (15.6%, 22.7%, 21.7%, r � .79, p � .07). Thus, ADHD children’s performance on nogo trials preceded by only one go trial was more similar to control children’s performance on nogo trials preceded by as many as three to five go trials (see Figure 1). Average motion was no different between groups used in the final analysis (x � .02 mm, y � .00 mm, and z � .42 mm for controls; x � .23 mm, y � .01 mm, and z � 1.10 mm for ADHD; t � 1.3, p � .22 for x; t � .1, p � .92 for y; t � 1.91, p � .09 for z). fMRI Results EFFECTS OF CONDITION (GO TRIALS VS. NOGO TRI- ALS). Significant regions of activation for the ANOVAs comparing go to nogo trials across groups are summarized in Table 1. The most robust activation for the 14 (subjects) � 2 (condition) ANOVA was in the left primary motor cortex (Brodmann Area [BA] 4), where MR signal in- creased for go trials (motor response) compared to nogo trials (no motor response). MR signal increased for nogo trials compared to go trials for regions in the right inferior parietal lobe and bilateral posterior cingulate gyrus and posterior hippocampus (see Table 1). EFFECTS OF GROUP BY CONDITION. In the 14 (sub- jects) � 2 (group) � 2 (condition) ANOVA, only one region in the left caudate nucleus displayed more activa- tion for control children than for children with ADHD. In contrast, children with ADHD displayed more activation in a number of regions, including the right superior frontal gyrus (BA 10), the right middle frontal gyrus (BA 9/46), the right inferior parietal lobe (BA 40), the bilateral posterior cingulate gyrus (BA 31), the bilateral precuneus (BA 7), the right superior temporal gyrus (BA 22), and the bilateral occipital cortex (BA 18) (see Table 1). EFFECTS OF CONDITION FOR CONTROL CHILDREN. The results from the individual group ANOVAs are summarized in Table 2. Control children showed an increase in MR signal in the left primary motor cortex for go trials compared to nogo trials. For nogo trials, MR Figure 1. Percentage of errors on nogo trials as a function of the number of preceding go trials (mean � SE). ADHD, attention- deficit/hyperactivity disorder. Differential Patterns of Striatal Activation 873BIOL PSYCHIATRY 2003;53:871–878 signal increased relative to go trials in the inferior frontal gyrus (BA 44/45), caudate nucleus, right globus pallidus, anterior cingulate gyrus (BA 32), right middle frontal gyrus (BA 8), and right inferior parietal lobe (BA 40) (see Table 2 and Figure 2). EFFECTS OF CONDITION FOR CHILDREN WITH ADHD. Children with ADHD showed an increase in MR signal in the left primary motor cortex for go trials compared to nogo trials similar to the controls. For the comparison of nogo trials relative to go trials, they showed an increase in activation in the right superior frontal gyrus (BA 10), right inferior parietal cortex (BA 40), bilateral posterior cingulate gyrus (BA 31), bilateral precuneus (BA 7), and bilateral occipital cortex (BA 18) (see Table 2 and Figure 3). POST HOC ANALYSES. The post hoc scan by scan analysis revealed no effect of preceding context on MR signal in any region for either group. Correlations between MR signal change, age, and accuracy were not significant for any region in this sample. Discussion In this study, we show that, behaviorally, children with and without ADHD are susceptible to behavioral interfer- ence during performance of a go/nogo task, with children Table 1. Regions Activated in Comparisons Including All Subjects Area Brodmann Area Side Talairach Maximum F Condition (go versus nogo) for All Subjects Primary Motor 4 left (�35, �15, 49) 40.37 Posterior Hippocampus bilateral (21, �46, 0) (�20, �47, 0) 9.98 Inferior Parietal Lobe 40 right (53, �32, 26) 8.20 Posterior Cingulate Gyrus 31 bilateral (8, �49, 35) (�8, �46, 35) 6.60 Group by Condition (go versus nogo) More Activation in Control Subjects Caudate Nucleus left (�10, 25, �5) 8.73 More Activation in ADHD Subjects Superior Frontal Gyrus 10 right (11, 57, 21) 23.92 Occipital Cortex 18 bilateral (�20, 84, 3) (14, 87, �1) 17.95 Inferior Parietal Lobe 40 right (28, �42, 24) 16.89 Precuneus 7 bilateral (5, �53, 48) (�3, �55, 48) 13.89 Superior Temporal Gyrus 22 right (38, �35, 4) 12.68 Middle Frontal Gyrus 46 right (41, 30, 25) 9.73 Posterior Cingulate Gyrus 31 bilateral (19, �43, 28) (�7, �49, 26) 9.61 Middle Frontal Gyrus 9/46 right (53, 17, 25) 9.49 Activation is greater for nogo trials than for go trials in all areas except primary motor cortex, where activation is greater on go trials. ADHD, attention-deficit/hyperactivity disorder. Table 2. Regions Activated in Comparisons for Individual Groups Area Brodmann Area Side Talairach Maximum F Condition (go versus nogo) for Control Children Primary Motor 4 left (�25, 22, 54) 180.04 Inferior Parietal Lobe 40 right (60, �25, 27) 39.06 Middle Frontal Gyrus 8 right (33, 35, 39) 34.43 Caudate Nucleus right (8, 25, �5) 29.00 Inferior Frontal Gyrus 44/45 left (�43, 23, 38) 18.27 Caudate Nucleus left (�15, 4, 16) 12.66 Globus Pallidus right (25, �6, �6) 11.58 Anterior Cingulate Gyrus 32 medial (�2, 2, 25) 6.58 Condition (go versus nogo) for ADHD Children Superior Frontal Gyrus 9/10 right (17, 50, 22) 78.48 Posterior Cingulate Gyrus 31 bilateral (19, �35, 31) (�16, �43, 35) 33.37 Primary Motor 4 left (�32, 16, 54) 26.71 Inferior Parietal Lobe 40 right (48, �45, 25) 17.08 Occipital Cortex 18 bilateral (18, �82, �1) (�13, 82, 6) 16.45 Precuneus 7 bilateral (12, �40, 45) (�11, �38, 42) 10.21 Activation is greater for nogo trials than for go trials in all areas except primary motor cortex, where activation is greater on go trials. ADHD, attention-deficit/hyperactivity disorder. 874 S. Durston et alBIOL PSYCHIATRY 2003;53:871–878 with ADHD being more susceptible to our parametric manipulation. Using the same task, we previously showed that children and adults differ in their susceptibility to interference (with children making more errors overall), but that both age groups showed a behavioral effect of preceding context, with a greater number of false alarms on nogo trials that were preceded by more go trials (D