اساس عصبی کنترل توجه پایدار و گذرا در بزرگسالان جوان مبتلا به ADHD

Abstract Differences in neural activation during performance on an attentionally demanding Stroop task were examined between 23 young adults with ADHD carefully selected to not be co-morbid for other psychiatric disorders and 23 matched controls. A hybrid blocked/single-trial design allowed for examination of more sustained vs. more transient aspects of attentional control. Our results indicated neural dysregulation across a wide range of brain regions including those involved in overall arousal, top-down attentional control, response selection, and inhibition. Furthermore, this dysregulation was most notable in lateral regions of DLPFC for sustained attentional control and in medial areas for transient aspects of attentional control. Because of the careful selection and matching of our two groups, these results provide strong evidence that the neural systems of attentional control are dysregulated in young adults with ADHD and are similar to dysregulations seen in children and adolescents with ADHD.

. Results 3.1. Behavioral results 3.1.1. Participant characteristics Unpaired t-tests indicated that participants with ADHD exhibited significantly elevated symptoms of ADHD in childhood and as young adults, as would be expected (see Table 1). In contrast, the two groups did not differ significantly on measures of Full Scale, Verbal, or Performance IQ estimated from the Matrix Reasoning and Vocabulary subtests, and there were no group differences on measures of reading or mathematics achievement. Overall, the analysis of our samples indicates they are well matched with regards to overall intellectual ability, but the ADHD group shows clear evidence of attentional dysfunction and significant functional impairment. Table 1. Descriptive characteristics of the Control and ADHD samples. Group t Control, M (SD) ADHD, M (SD) Descriptive characteristics Age 19.0 (0.9) 20.0 (1.7) 2.61* DSM-IV ADHD symptomsa Childhood Inattention 0.8 (1.0) 7.4 (2.0) 14.07*** Hyperactivity-impulsivity 1.0 (1.3) 6.8 (1.8) 12.55*** Current Inattention 0.9 (1.2) 6.6 (2.3) 11.81*** Hyperactivity-impulsivity 1.5 (1.2) 5.0 (2.2) 6.46*** WAIS-III estimated IQ scores Performance 113.5 (10.5) 114.4 (8.7) 0.31 Verbal 113.3 (10.5) 118.9 (12.7) 1.64 Full scale 113.4 (8.3) 116.6 (7.2) 1.42 WJ-III Reading and spelling Letter word ID 105.1 (8.9) 101.3 (9.8) 1.40 Word attack 100.4 (9.7) 100.3 (9.4) 0.05 Spelling 106.9 (7.9) 103.6 (8.5) 1.29 Math Calculations 110.7 (13.5) 106.2 (16.0) 0.93 Math fluency 102.3 (11.2) 95.5 (11.6) 1.93 Percent impaired χ2 Control, N (%) ADHD, N (%) Domain of functioning Global impairment (past 12 months) 5 (22%) 19 (83%) 17.1*** Management of responsibilities 0 (0%) 15 (65%) 22.3*** Academic functioning 1 (4%) 13 (57%) 14.8*** Social relationships 0 (0%) 16 (70%) 24.5*** Driving 2 (9%) 8 (35%) 4.6* Occupational functioning 2 (9%) 11 (48%) 8.7** Significant impairment in 1 or more domains 5 (22%) 23 (100.0%) 29.6*** Significant impairment in 2 or more domains 0 (0%) 19 (83%) 32.4*** * p < .05, ** p < .01, *** p < .001. a Parent and self-report ratings were combined to create the total symptom counts by coding each symptom as present if endorsed by either the parent or the participant (see Lahey et al., 2004). Table options 3.2. Stroop task 3.2.1. Reaction time An ANOVA on mean reaction time with a between-subjects factor of GROUP (ADHD, Control), BLOCK (congruent, neutral, incongruent) and TRIAL TYPE (block-specific, neutral frequent) yielded a significant three-way GROUP by BLOCK by TRIAL TYPE interaction (F(2,88) = 5.96, p < .005), which was driven entirely by block-specific trials (TRIAL by GROUP F(2,88) = 7.87, p < .001) and not by the neutral frequent trials (TRIAL by GROUP F(2,88) = .393, p = .69) (see Fig. 1A). Interference and facilitation were calculated as a percentage of RT on neutral trials. For across-block analyses, mean RT for all trials within a block were used (e.g., interference: mean RT for the incongruent block − mean RT for the neutral block/mean RT for the neutral block), while for within-block analysis, RT for the block-specific trials were compared to RT for the neutral frequent trials within that block (e.g., mean RT for the neutral frequent trials in the congruent block − RT for the congruent trials in the congruent block/RT for the neutral frequent trials in the congruent block). Thus, interference represents the percentage increase to which RT is slowed on incongruent trials relative to neutral trials. Likewise, facilitation represents the percentage increase to which RT is speeded on congruent trials relative to neutral trials. Both interference and facilitation index the degree to which individuals have difficulty complying with task demands and pay attention to the word rather than the ink color. Behavioral performance on the Stroop task for individuals with ADHD and ... Fig. 1. Behavioral performance on the Stroop task for individuals with ADHD and controls. (A) Reaction time and (B) accuracy. Performance is shown for each group separately for each of the three blocks. Within each block, performance on block-specific trials (left) as well as performance on neutral frequent trials (right) is shown. Errors bars represent plus and minus on standard deviation. Figure options Because meta-analyses suggest that poor performance on the Stroop task is often observed in individuals with ADHD (van Mourik et al., 2005 and Willcutt et al., 2005), the results were surprising as they revealed that interference was significantly greater for the control group than for the ADHD group both across blocks (t = 2.93, df = 44, p < .005) (ADHD: 9.8%, Controls: 15.5%) and within block (t = −2.40, df = 44, p < .025) (ADHD: 17.9%, Controls: 26.5%). In consideration of the fact that the ADHD group showed less interference, this measure was used as a covariate in specific fMRI analyses noted below to determine whether group differences in activation still existed even when behavioral performance was taken into account. Compared to controls, the ADHD group exhibited marginally increased facilitation across blocks (ADHD: 1.7%. Controls: −0.6%) (t = 1.90, df = 44, p = .064 two-tailed) and significant greater facilitation within blocks (ADHD: .5%, Controls: −4.3%) (t = 2.76, df = 44, p < .01). MacLeod and MacDonald have argued that facilitation (i.e., faster responses on congruent than neutral trials) indexes the degree to which individuals do not comply with task demands on congruent trials. Rather than identifying the ink color on these trials, individuals “cheat” on a certain proportion of congruent trials and read the word. Because reading is faster than ink color identification, their responses are speeded in comparison to neutral trials, on which no such cheating is possible. Hence, individuals with ADHD appear do not appear to be complying with task demands. In contrast, the control group is actually slowed by congruent trials compared to neutral trials, which is not without precedence ( Nealis, 1973 and Schulz, 1979). Finally, the degree to which the ink color interfered with processing, as defined by the sum of interference and facilitation, was shown not to differ between the two groups via an independent sample t-test (t = −1.72, df = 44, p > .05). 3.3. Accuracy An ANOVA on mean accuracy with the between-subject factor of GROUP (ADHD, Control) and the within-subject factors of BLOCK (congruent, neutral, incongruent) and TRIAL TYPE (block-specific, neutral frequent) yielded no effects or interactions with the factor of GROUP (see Fig. 1B). 3.4. Imaging results 3.4.1. Group differences in activation 3.4.1.1. Blocked analyses 3.4.1.1.1. Conditions vs. fixation The contrast of each block (i.e., congruent, incongruent, neutral) vs. fixation calculated separately was used to examine brain mechanisms engaged when ink color identification must be selected over word reading. Similar group differences emerged across all three types of blocks (see Table 2). Individuals with ADHD showed significantly less activity in left posterior DLPFC (BA 8/6) and left middle DLPFC (BA 9/46) than controls (see Fig. 2A). Table 2. Clusters that yielded significant differences between groups for blocked activity vs. fixation baseline. Region BA Max Z No. of voxels x y z Z value for each group individually Neutral vs. fixation baseline Control > ADHD *Middle frontal gyrus (L) 46 3.69 140 −42 30 24 CTRL 5.03 ADHD n.s. 2.42 *Precentral gyrus (L) 6 3.40 77 −50 4 36 CTRL 6.32 ADHD 3.52 ADHD > Control *Posterior cingulate (R) 23 4.59 1140 8 −46 20 CTRL −2.74 ADHD 2.59 *Insula (R) 13 3.54 802 34 −26 12 CTRL n.s. −2.10 ADHD 2.78 *Superior temporal gyrus (R) 22 3.61 408 60 −10 2 CTRL −3.22 ADHD n.s. 1.06 22 3.09 103 42 −58 12 CTRL −3.93 ADHD n.s. −0.07 *Superior temporal gyrus (L) 41 3.14 277 −46 −26 4 CTRL n.s. −2.41 ADHD n.s. 2.37 *Superior frontal gyrus (L) 8 3.94 338 −14 46 46 CTRL −4.27 ADHD n.s. 1.59 *Lingual gyrus (L) 17 3.68 266 −2 −94 −4 CTRL 2.90 ADHD 4.97 *Precuneus (L) 19 3.20 123 −34 −82 38 CTRL −4.34 ADHD n.s. 0.34 Medial frontal gyrus (R) 10 3.10 113 6 54 14 CTRL −3.48 ADHD n.s. 0.46 *Inferior frontal gyrus (R) 47 3.40 112 26 16 −28 CTRL −4.07 ADHD n.s. −0.75 Congruent vs. fixation baseline Control > ADHD *Middle frontal gyrus (L) 46 3.32 154 −46 32 28 CTRL 4.65 ADHD 2.70 *Middle frontal gyrus (L) 8 3.62 152 −48 6 40 CTRL 5.33 ADHD 2.77 ADHD > Control *Superior temporal gyrus (R) 22 3.39 269 60 −4 −2 CTRL −4.15 ADHD n.s. −0.64 *Superior temporal gyrus (L) 41 3.36 215 −40 −34 8 CTRL −4.32 ADHD n.s. −0.61 *Cingulate gyrus (R) 31 3.11 96 4 −48 30 CTRL −4.87 ADHD n.s. −2.17 Incongruent vs. fixation baseline Control > ADHD *Middle Frontal Gyrus (L) 9 3.29 54 −46 32 30 CTRL 4.80 ADHD n.s. 2.72 ADHD > Control * Insula (R) 13 3.37 571 44 −14 6 CTRL −4.31 ADHD n.s. −0.22 *Insula (L) 13 3.21 224 −40 −22 6 CTRL −5.63 ADHD −3.94 *Posterior cingulate (R) 29 3.39 469 6 −48 6 CTRL −4.66 ADHD n.s. −2.10 *Superior temporal gyrus (R) 22 3.26 254 42 −60 12 CTRL −3.90 ADHD n.s. 0.65 Superior temporal gyrus (L) 38 3.18 178 −34 0 −28 CTRL −4.89 ADHD n.s. −2.36 *Lingual (L) 18 3.48 153 0 −92 −2 CTRL n.s. 2.55 ADHD 5.34 Inferior occipital gyrus (R) 17 3.11 110 16 −90 −6 CTRL 3.68 ADHD 4.80 * Clusters sizes are also significant at p < .05 (Z = 1.96) when the behavioral covariate of mean RT for the relevant block (e.g., RT across all trials in the incongruent block) is included as a covariate. Table options On the other hand, individuals with ADHD showed more activity than controls across all three contrasts in a number of regions including the right insula, left and right superior temporal gyri, and posterior cingulate cortex. Inspection of the maps individually for each group revealed that individuals with ADHD did not deactivate these regions relative to fixation baseline as much as controls. Deactivation of the insula and superior temporal gyri may occur as a means to preclude linguistic processing of the word, while deactivation of posterior cingulate, a region considered part of the default network, may aid in meeting attentional demand. In sum, these findings suggest that compared to controls, young adults with ADHD show less engagement of brain regions that support top-down attentional control to task-relevant processes, show less disengagement of regions that process task-irrelevant material, and less disengagement of the default network. 3.5. Contrasts across conditions The control group showed more activity in posterior regions related to attentional control for the contrast of congruent > neutral blocks (left precuneus) and incongruent > neutral blocks (left inferior parietal lobule) (see Table 3). ADHD individuals exhibited more activity in right middle frontal gyrus for the contrast of incongruent > neutral and incongruent > congruent trials. This region often seems to become activated to meet increased attentional demand (e.g., Milham et al., 2003a and Milham et al., 2003b), and as such this finding may indicate that ADHD individuals need to recruit more brain regions than controls to meet similar attentional demands. The alternative possibility that engagement of this region by ADHD individuals undergirds their reduced behavioral interference is unlikely because when the degree of behavioral interference in RT is used as a covariate, these group differences remain. Table 3. Clusters that yielded significant differences between individuals with ADHD and controls in comparisons across blocks. Region BA Max Z No. of voxels x y z Z value for each group separately Congruent > neutral Control > ADHD Precunues (L) 7 3.38 116 −6 −60 32 CTRL n.s. 2.44 ADHD n.s. −1.72 Incongruent > neutral Control > ADHD *Supramarginal gyrus (L) 40 3.31 81 −58 −50 34 CTRL 4.32 ADHD n.s. 1.53 ADHD > Control *Cuneus (R) 7 3.22 140 2 −76 30 CTRL n.s 0.50 ADHD 4.75 *Middle frontal gyrus (R) 46 3.47 83 48 40 20 CTRL n.s. 1.03 ADHD 4.77 Incongruent > congruent ADHD > Control ∧Middle frontal gyrus (R) 46 3.18 72 54 34 18 CTRL n.s. −1.32 ADHD 3.09 * Clusters sizes are also significant at p < .05 (Z = 1.96) when interference (mean RT to all trials in the incongruent block − mean RT to all trials in the neutral block/mean RT to all trials in the neutral block) is considered as a covariate. ∧ Also significant at p < .05 (Z = 1.96) when the difference between interference and facilitation (mean RT to all trials in the neutral block − mean RT to all trials in the congruent block/mean RT to all trials in the neutral block) is included as a covariate. Table options 3.6. Single-trial analyses 3.6.1. Within block analyses The purpose of the single-trial within-block analysis was to examine the response to transient attentional demands that cannot be controlled via a static top-down attentional set across a block of trials. Because the single-trial contrasts compare trial types within a block, any attentional set for the block will be equivalent across the two trial types and hence will not contribute to any observed differences. The results from these analyses are presented in Table 4. Table 4. Clusters that yielded significant differences between individuals with ADHD and controls in the single-trial comparisons within block. Region BA Max Z No. of voxels x y z Z value for each group separately Incongruent > neutral (inc) Control > ADHD *Right thalamus 3.44 748 6 −22 0 CTRL 4.51 ADHD n.s. .70 *Cingulate gyrus (R) 24 3.16 138+ 6 14 28 CTRL 4.39 ADHD n.s. 1.25 Congruent > neutral (con) Control > ADHD ∧Inferior parietal lobule (L) 40 3.8 546 −38 −58 46 CTRL 4.05 ADHD n.s. −.22 Neutral block-specific > neutral frequent neutral Control > ADHD Parahippocampal gyrus (R) 30 3.33 459 24 −50 8 CTRL 2.46 ADHD n.s. −2.22 Lingual gyrus (R) 18 3.25 115+ 28 −76 −10 CTRL n.s. 1.57 ADHD −2.96 Clusters sizes marked with + are corrected for multiple comparisons within an a priori Stroop mask; other regions are corrected for multiple comparisons within a whole-brain search. * Remains significant at p < .05, Z = 1.96 when covariate of interference (RT incongruent trials within the incongruent block − RT neutral trials within the incongruent block/RT neutral trials within the incongruent block) is used as a covariate. ∧ Remains significant at p < .05, Z = 1.96 when covariate of facilitation (RT neutral trials within the congruent block − RT congruent trials within the congruent block/RT neutral trials within the congruent block) is used as a covariate. Table options The results indicate that brain activation also differs between ADHD individuals and controls in the face of transient attentional demands. For the contrast of incongruent > neutral trials within the incongruent blocks, controls exhibited more activity than individuals with ADHD in two regions, the thalamus and anterior cingulate cortex (BA 24) directly above the callosum (see Fig. 2B). As the thalamus serves to activate cortical regions, we speculate that contributions of this region to phasic increases to attentional demand are smaller in ADHD individuals. The lack of anterior cingulate cortex activity in the ADHD group is consistent with reports by others of atypical activation in adults with ADHD in this portion of the cingulate (Bush et al., 1999). An analysis including the degree of behavioral interference as a covariate indicated that these group differences remained, indicating that the smaller degree of behavioral interference in the ADHD was unlikely to be generating these group differences. Regions of significantly greater activity for controls than individuals with ... Fig. 2. Regions of significantly greater activity for controls than individuals with ADHD. (A) Blocked activity: regions of mid- and posterior dorsolateral prefrontal cortex in the contrast of congruent blocks vs. fixation blocks. (B) Single-trial activity: regions of the anterior cingulate cortex and thalamus in the contrast of incongruent trials vs. neutral trials within the incongruent block. Figure options The contrast of congruent > neutral trials within the congruent block revealed that controls but not individuals with ADHD activated a large region of the inferior parietal lobe (BA 40), spanning the intraparietal sulcus, which has been heavily implicated in attentional control. We speculate that for controls, top-down control is relatively low on congruent blocks, so intraparietal regions are recruited on congruent trials to help deal with the increased attentional demand (relative to neutral trials within the block). In contrast, based on the blocked analysis and their increased behavioral facilitation, individuals with ADHD are not complying with task demands, and may be reading the word on a certain proportion of congruent trials. Hence, congruent trials are not likely to engage these attentional control regions. The contrast of neutral infrequent vs. neutral frequent trials within the neutral block yielded marginally more activation in controls for a set of posterior regions including the right parahippocampal, right lingual and bilateral fusiform gyri, and right cuneus. These finding suggests more sensitivity on the part of the controls to stimulus-specific perceptual characteristics of the lower frequency of occurrence of the neutral infrequent items. In sum, these data suggest that certain portions of the brains of individuals with ADHD are not as sensitive as controls to the transient increase in attentional demands that occur on a trial-by-trial basis, including regions of posterior cortex sensitive to the perceptual characteristics of an item, thalamic regions most likely involved in cortical arousal, and portions of the dorsal anterior cingulate cortex, which we have previously argued are involved in late-stage selection (Milham & Banich, 2005). 3.7. Analyses of trial types in different blocks In the within-block single-trial analyses discussed above, the neutral frequent trials serve as our baseline. To examine whether this baseline was similar across blocks, we performed an across-block comparison of activation to the neutral frequent trials using the orthogonalization procedures within FSL. This procedure allowed us to calculate the event-related activity for neutral frequent trials independent of activity common to all trials within the block from which they were drawn (e.g., incongruent trial). What remains then is the transient response to these item types. These analyses suggested that there were minimal differences in activation between the groups for the neutral frequent trials across blocks (see Table 5). Table 5. Clusters that yielded significant differences between individuals with ADHD and controls in the single-trial comparisons across block. Region BA Max Z No. of voxels x y z Z value for each group separately Neutral frequent (inc) > neutral frequent (neut) Control > ADHD Hippocampus (L) 3.37 173 −34 −18 −16 ADHD n.s 2.11 Control 2.62 Substantia nigra (R) 3.18 171 14 −14 −12 ADHD n.s. −2.37 Control n.s. 2.13 Neutral frequent (Inc) > neutral frequent (cong) Control > ADHD Substantia nigra (R) 3.65 789 10 −28 −16 ADHD n.s. −2.04 Control 3.02 Incongruent–congruent Control > ADHD Inferior frontal gyrus (R) 47 3.06 112+ 48 16 −6 ADHD n.s. .27 Control 4.00 Clusters sizes marked with + are corrected for multiple comparisons within an a priori Stroop mask; other regions are corrected for multiple comparisons within a whole-brain search. Table options We similarly examined event-related activity for incongruent > congruent trials, orthogonal of the effect of block. Controls activated a region of right inferior frontal gyrus, implicated in inhibitory control (Aron, Robbins, & Poldrack, 2004) significantly more for incongruent than congruent trials, a difference that was absent for individuals with ADHD. This region did not yield a group difference in the blocked contrast, suggesting this region becomes involved in transient rather than sustained aspects of attentional control.