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Stroop interference, hemodynamic response and aging: An event-related fMRI study
Neurobiology of Aging 28 (2007) 937–946
Stroop interference, hemodynamic response and aging: An event-related fMRI study Stefan Zysset ∗ , Matthias L. Schroeter, Jane Neumann, D. Yves von Cramon Max-Planck-Institute for Human Cognitive and Brain Science, Leipzig, Germany Received 13 July 2005; received in revised form 14 April 2006; accepted 3 May 2006 Available online 12 June 2006
Abstract In a Stroop interference task, subjects are required to name the color of a word, while ignoring the meaning of the word. The increase in time taken to name the color name if the underlying word is incongruent to the color is called Stroop color-word interference effect. With increasing age, reaction time (RT) is slowed. In an functional magnetic resonance imaging (fMRI) study we investigated the effects of aging (subjects from 22 to 75 years of age) on the performance in the color-word matching Stroop task and on the hemodynamic response. The present study shows that middle-aged adults were generally slowed but no increased interference effect occurred. Further, middle-aged adults showed increased activations in several task-related regions, mainly in the inferior frontal junction (IFJ) area (bilaterally) and the presupplementary motor area. For the middle-aged subjects, regions in the inferior frontal gyrus (IFG), the basal putamen and the occipital lobe were additionally recruited, indicating a stronger dependence on compensatory strategies. Further, middle-aged subjects showed generally a greater magnitude of the hemodynamic response, resulting in greater percent signal changes. © 2006 Elsevier Inc. All rights reserved. Keywords: Stroop interference; Aging; fMRI; Hemodynamic response; General slowing
1. Introduction The Stroop effect [44] is one of the best-known effects in cognitive psychology. It accounts for cognitive interference, which occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute. Naming the ink color of a color word takes much longer than naming the color of a patch of color or reading out a color word. The difference in reaction time (RT) is the so-called Stroop interference effect (for a review see [27]). Virtually everyone who can read shows a robust Stroop effect from early age on. The Stroop task is [44] is probably the classic paradigm to study cognitive control [10] and the Stroop effect seems a good measure for frontal lobe function and inhibitory processes, a construct repeatedly invoked to explain cognitive deficits associated with aging (e.g. [20]). ∗ Corresponding author at: Max-Planck-Institute for Human Cognitive and Brain Sciences, Stephanstrasse 1a, D-04I03 Leipzig, Germany. Tel.: +49 341 99 40 167; fax: +49 341 99 40 221. E-mail address: [email protected] (S. Zysset).
0197-4580/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2006.05.008
The Stroop task is an ideal tool for studying typical and atypical development of executive processes and has been used in several studies to investigate aging processes [25,31,1,38,42]. Clinical and recent neuroimaging studies showed the relevance of the medial and lateral frontal cortex for Stroop interference [50,31,29,13,55]. With increasing age, reactions times in the Stroop task are usually slowed. While some studies show that the interference effect increases as well [24,52], other studies argue that the apparent age-sensitivity of the Stroop interference effect appears to be merely an artifact of general slowing [51,49]. The inhibition theory of cognitive aging claims that increased interference effects exhibited by older adults find their origin in defective inhibitory mechanisms. The specific inhibitory mechanism that might be implicated is that of ‘restraint inhibitory control’, or the ability to restrain stimuli from “seizing control of thought and action effectors ([21], p. 654)”. In a meta-analysis of 20 behavioral studies comparing younger and older adults on the Stroop interference effect, Verhaegen and De Meersman [51] found no significant inter-
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ference effect, expressed as mean standardized difference, between the two age groups. They argue that the apparent age-sensitivity of the Stroop interference effect appears to be merely an artifact of general slowing. The same conclusions are taken by Uttl and Graf [49], who tested the color-word Stroop task with 310 subjects of ages between 19 and 83. The general conclusion is that age effects in Stroop interference are due to age-related slowing and no evidence is provided for a qualitative different kind of processing that declines with age. This concept is called the unspecific hypothesis of general slowing with increasing age, and is not limited to inhibitory processes, but to all cognitive processes [40]. A recent functional magnetic resonance imaging (fMRI) study of the Stroop task with elderly adults by Langenecker et al. [25] reported that with increasing age, numerous regions exhibited greater activations, including the left inferior frontal gyrus (IFG). In a study by Nielson et al. [33], older adults had significantly greater activations in multiple frontal regions, including the left IFG. Milham et al. [31] reported greater activations for younger subjects compared to elderly subjects, mainly in the left middle frontal gyrus (MFG), anterior cingulate, and superior parietal lobule, while older adults had greater activation compared to young adults in the IFG. A few studies reported that the activation pattern was comparable between young and elder subjects, but the volume of these activations is reduced with increasing age [19,39]. However, other studies observed additional activations for elderly subjects, mainly in the prefrontal cortex and in the contralateral hemisphere [8,9,33,18,19,28]. A quantitative comparison of the activation patterns resulting from fMRI studies to test hypotheses regarding agerelated changes relies on the assumption that the coupling of neural activity to the neuroimaging signal is not affected by aging. Differences in neuroimaging signal response between young and elderly adults can be mapped directly to differences in neural response, only if such coupling does not change with age [11,12]. Huettel et al. [23] showed that the amplitude and form of hemodynamic responses for young and elderly adults are similar. But elderly adults showed greater voxelwise noise leading to a smaller spatial extent of activation. An fMRI study by Nielson et al. [34] showed that although task performance and activation pattern differed, the underlying hemodynamic response was comparable between younger and older adults. In contrast, Taoka et al. [46] found the time lag of the hemodynamic response in fMRI to be prolonged with increasing age. In a blocked design study, the latency of the trailing edge of the hemodynamic response tends to increase with age [38]. In summary, one can assume that with normal, healthy aging, the neuronal coupling remains intact, even if the temporal dynamic might change. The basic aim of the present fMRI study was to compare the neural processes and the hemodynamic response underlying the color-word Stroop interference task for healthy young and middle-aged adults. For this, a single trial version of the paradigm used in previous fMRI-studies [55,36,32] and func-
tional near-infra-red studies [43,41] was applied to test adults of varying age. The use of a single trial design allowed us to characterize the hemodynamic response in accordance with age. Further, changes in reaction time and the interference effect were investigated. 2. Method 2.1. Subjects Forty-seven healthy subjects (24 women) of different age were tested. Subject’s age ranged from 22 years up to 75 years, the mean age was 42 years. The subjects were divided in two groups according to age: a group of 23 young subjects (26.6 mean age; S.D. = 3.6; range 22–36 years of age) and a group of 24 middle-aged subjects (57.1 mean age; S.D. = 6.49; range 45–75 years of age). The two groups do not differ in the number of years of school (p = 0.2) and on the reading span (p = 0.92). Written informed consent from all subjects was obtained prior to the scanning session. All subjects had normal or corrected-to-normal vision, normal color vision and were native German speakers. The subjects were screened for neurological and psychiatric disorders and only healthy adults were included. Only 4 out of the 24 middle-aged subjects and none of the young adults were taking medication at the time of the study.1 Subjects were instructed about the task and were given a short practice session before entering the scanner. Once they felt comfortable with the task, subjects were positioned supine in the scanner. 2.2. Psychophysical procedures An adapted single trial version of the color-word interference task [44,55] was used. Subjects were told that they would see two rows of letters appear on the screen and were instructed to decide, via button-press, if the color of the top row letters corresponded to the color name written at the bottom row. During ‘neutral’ trials, the letters in the top row were ‘XXXX’ printed in red, green, blue or yellow, and the bottom row consisted of the color words ‘RED’, ‘GREEN’, ‘BLUE’ and ‘YELLOW’ printed in black (see Fig. 1). For ’incongruent’ trials, the top row consisted of the color words ‘RED’, ‘GREEN’, ‘BLUE’ and ‘YELLOW’ printed in a incongruent color to the color word (e.g. ‘green’ printed in red), in order to produce an interference between color word and color name. The bottom row consisted again of the color words ‘RED’, ‘GREEN’, ‘BLUE’ and ’YELLOW printed in black. The meaning of the letters or words (e.g. ‘XXXX’ or ‘GREEN’) at top was task irrelevant. In half of the trials in both conditions the color in the top row corresponded to the color name of the bottom row. ‘Hits’ and ‘foils’ were pre1 The medications taken were l-Thyroxin© , Allpurinol© , Kreon© , Enahexal© and Methohexal© .
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Fig. 1. Examples of single trials for the neutral and incongruent condition of the color-word matching Stroop task: ‘Does the color of the upper word correspond with the meaning of the lower word?’ For the upper two examples, the correct answer would be ‘NO’; for the lower two examples, the correct answer would be ‘YES’.
sented in random order to prevent subjects from developing response tendencies. Responses were given with index (YES) or middle (NO) finger of the right hand. To prevent subjects from focusing on the lower word and blurring out the top word, the top word was presented 100 ms before the lower word (see also [27,17]). By this, visual attention is shifted automatically to the top word. Hundred incongruent and 100 neutral trials were presented. Additionally, 40 none-events (empty-trials) were presented to improve statistical evaluation of the data [30], resulting in a total number of 240 trials. Trials were presented every 6 s on average and a variable stimulus-onset delay (0, 400, 800, 1200 or 1600 ms) was introduced in order to improve the temporal resolution [30]. Stimuli were presented with the VisuaStim XGA (Resonance Technology, Northridge, USA), a high-resolution visor (800 × 600 resolution) consisting of two small TFT-screen placed close to the subjects eyes. 2.3. MRI scanning procedure The experiment was carried out on a 3T scanner (Medspec 30/100, Bruker, Ettlingen). Twenty axial slices (19.2 cm FOV, 64 × 64 matrix, 4 mm thickness, 1 mm spacing), parallel to the AC-PC plane and covering the whole brain were acquired using a single shot, gradient recalled EPI sequence (TR 2000 ms, TE 30 ms, 90◦ flip angle). One functional run with 723 scans was measured, each scan covering the 20 slices. Prior to the functional run, 20 anatomical T1-weighted MDEFT [48,35] images (data matrix 256 × 256, TR 1.3 s, TE 10 ms) and 20 T1-weighted EPI images with the same spatial orientation as the functional data were acquired. 2.4. fMRI data analysis The fMRI data were processed with LIPSIA software [26]. This software package contains tools for preprocessing,
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registration, statistical evaluation and presentation of fMRI data. Functional data were corrected for motion using a matching metric based on linear correlation. To correct for the temporal offset between the slices acquired in one scan, a sine-interpolation based on the Nyquist-Shannon-Theorem was applied. A temporal highpass filter with a cutoff frequency of l/60 Hz was used for baseline correction of the signal and a spatial Gaussian filter with 5.65 mm FWHM was applied. To align the functional dataslices onto a 3D stereotactic coordinate reference system, a rigid linear registration with six degrees of freedom (three rotational, three translational) was performed. The rotational and translational parameters were acquired on the basis of the MDEFT and EPI-T1 slices to achieve an optimal match between these slices and the individual 3D reference data set. This 3D reference data set was acquired for each subject during a previous scanning session. The MDEFT volume data set with 160 slices and 1 mm slice thickness was standardized to the Talairach stereotactic space [45]. The same rotational and translational parameters were normalized, i.e., transformed by linear scaling to a standard size. The resulting parameters were then used to transform the functional slices using trilinear interpolation, so that the resulting functional slices were aligned with the stereotactic coordinate system. This linear normalization process was improved by a subsequent processing step that performs an additional non-linear normalization [47]. The statistical evaluation was based on a least-squares estimation using the general linear model for serially autocorrelated observations (see also [16,53,2,54]). The design matrix was generated with a synthetic hemodynamic response function, its two derivatives and a response delay of 6 s. The model equation, including the observation data, the design matrix and the error term, was convolved with a Gaussian kernel of dispersion of 4 s. FWHM. In the following, contrast maps were generated for each subject, differentiating between the neutral and incongruent conditions. As the individual functional datasets were all aligned to the same stereotactic reference space, a random-effects group analysis was performed [22]. The individual contrast images were used for a random-effects second-level analysis with an additional regressor coding the two age groups. Subsequently, t-values were transformed into Z-scores. To protect against false positive activations, only regions with a Z-score greater than 3.1 (p < 0.001, uncorrected) or 2.58 (p < 0.005, uncorrected), respectively, and with a volume greater than 216 mm3 (6 voxels) were considered [14,6]. Further, a timecourse analysis of the fMRI-signal was calculated (for details see [32]). Trial-averaged timecourses (stimulus-onset locked) were obtained on a voxel-by-voxel basis for each subject at a sampling rate of 200 ms. Activations for time points falling between two observed points were linearly interpolated from the weighted activations of their neighbors. The resulting timecourse of the null-event condition was subtracted from the timecourses of the neutral
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Fig. 3. Mean reaction times and error rates for the neutral and incongruent condition for the color-word matching Stroop task plotted for both age groups. Fig. 2. A typical trial-averaged timecourse of an activated voxel. The calculated parameters amplitude, slope, time-to-max and dispersion are represented in red.
and incongruent condition [7]. For each subject and the two conditions, four parameters were extracted from the averaged timecourse: (a) percent signal change; (b) slope of the hemodynamic response; (c) dispersion of the hemodynamic response; and (d) time to maximum. The minimum and maximum signal change were sought in the time range of 0–3 and 2–8 s, respectively. The percent signal change was calculated relating the minimum and maximum signal intensity (see Fig. 2). The slope represents the steepness between t-steep and t-flat (see Fig. 2). The dispersion was calculated as the fullwidth of the hemodynamic response at half the height. The time-to-max was the time in seconds when the maximum signal intensity was reached after onset of the stimulus. The resulting parameters (amplitude, slope, dispersion and timeto-max) were tested for age- and condition-related effects in regions of interest.
3. Results 3.1. Behavioral results For all subjects, reaction times and error rate were registered. Only the RTs of correct responses were analyzed. Fig. 3 shows the mean RT and error rate for both conditions and both age groups. A two-factorial ANOVA with condition (neutral and incongruent) as within effect and age (young and middleaged) as between effect was calculated for RT and error rate. For RT, a significant main effect for condition (F(1, 45) = 66.7; p < 0.001) and age (F(1, 45) = 29.4; p < 0.001) was found. The interaction between condition and age was not significant (F(1, 45) = 1.2; p = 0.27). Older adults are significantly slower than young adults on both the neutral and
incongruent conditions but the incongruent condition is no more affected by age than the neutral condition. For both conditions, very few errors (<5%) were produced. No significant effect for age could be found for the neutral (p = 0.55) or incongruent (p = 0.88) condition using a nonparametric test. 3.2. Imaging results First, the contrast of the incongruent against the neutral condition was calculated for each subject. The resulting individual interference contrast images were used for a randomeffects second-level analysis across all subjects contrasting between the middle-aged and young subjects. Further, the individual median RT of each subject was added as an additional covariate. The resulting activations for color-word interference contrast (incongruent vs. neutral) are shown in Fig. 4 and Table 1. The activations in relation to age and RT are reported in Fig. 5 and Table 2. The largest activations for the color-word interference contrast were along the inferior frontal sulcus (IFS, bilaterally), along the intraparietal sulcus (IPS, bilaterally), the posterior superior frontal gyrus, and the medial wall of the superior frontal gyrus (presupplementary motor area; preSMA). Further, the left and right anterior insula, posterior superior frontal gyrus (frontal eye fields; FEF), the precuneus, the fusiform gyrus (FG; bilaterally), the caudate nucleus, the putamen and the cerebellum were activated. The activations were more pronounced in the left hemisphere. That is, the volume of significantly activated voxels was about twice as big in the left hemisphere compared to the right hemisphere (73600 mm3 versus 36800 mm3 ). The pattern of activations corresponds to previously published data using the same color-word matching Stroop task with young subjects [55]. A negative signal change in relation to the interference contrast was detected in the posterior cingulate cortex. The largest age-related changes in relation to the interference contrast could be found in the left and right inferior
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Fig. 4. Interference-specific activations: main activations averaged across all subjects contrasting the incongruent condition against the neutral condition. The slices show the main activations in the left (x = −44) and right (x = 40) lateral cortex and the mid-sagittal plane (x = −5). Averaged Z-maps are mapped on to the reference brain used for non-linear normalization, Z-values are thresholded at Z = 3.1 (p < 0.001, uncorrected).
Table 1 Talairach coordinates, maximum Z-value of the local maxima for the incongruent vs. neutral contrast across all subjects, Z-values were thresholded at Z = 3.1 (p < 0.001; uncorrected) and activations reported have a minimum size of 216 mm3 (6 voxels) Interference-specific activations Anatomical region
Left hemisphere
Superior frontal gyrus (medial portion) Superior frontal gyrus posterior Inferior frontal junction Inferior frontal sulcus anterior Inferior frontal sulcus Intraparietal sulcus Precuneus Cingulate sulcus Anterior insula Fusiform gyrus anterior Fusiform gyrus posterior Putamen, pars postero-lateral Caudate nucleus Cerebellum, lobus posterior Posterior cingulate cortex
Right hemisphere
Z-max
Tal. coord.
Z-max
5.22 4.41 6.39 4.39
−5 14 46 −23 2 52 −44 17 28 −44 32 10
4.93 4.82 5.72
1 17 49 28 2 46 40 8 34
6.43 4.21
−32 −55 46 −8 −70 52
5.56 6.24 4.47 4.62 5.04 4.79 4.03
43 23 28 31 −46 43 10 −67 49 10 23 34 40 14 4 37 −64 −5 31 −85 −2
−35 23 7 −44 −67 −5 −29 −82 1 −17 −22 4 −11 −1 19 −11 −76 −11 −8 −55 22
5.78 5.50 5.22 3.53 3.42 3.99 −4.08
10 −73 −17 4 −52 28
3.42 −3.90
73602 mm3
Total activated volume
Tal. coord.
36801 mm3
Negative Z-values indicate that the neutral condition was more pronounced.
Table 2 Talairach coordinates, maximum Z-value of the local maxima for the age-related changes, Z-values were thresholded at Z = 2.58 (p < 0.005; uncorrected) and activations reported have a minimum size of 216 mm3 (6 voxels) Age-related changes Anatomical region
Superior frontal gyrus (medial section) Inferior frontal junction Inferior frontal gyrus Anterior lingual gyrus Putamen, pars postero-lateral
Left hemisphere Volume
Z-max
Tal. coord.
702 1188 3105 432 324
3.72 3.29 4.05 3.01 3.45
−8 23 49 −44 8 37 −47 23 10 −17 −67 7 −26 −16 −2
Total activated volume
Volume
Z-max
Tal. coord.
1242
3.69
46 11 40
1512
4.19
16 −52 4
5751 mm3
Total activated volume RT-related changes Inferior frontal gyrus (post) Fusiform gyrus posterior
Right hemisphere
1701
3.32 1701 mm3
2754 mm3
−32 −79 −5
621 405
3.73 3.02 1026 mm3
52 17 22 34 −76 −2
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Fig. 5. Age- and RT-related changes: the figures show the age-related (top) and RT-related (bottom) activations of the second-level analysis for age and RT. The two sagittal slices in the top row show main activations in the left (x = −44) and right (x = 40) frontolateral cortex for age-related changes. The axial and sagittal slice in the bottom row show the activation changes in relation to RT. Averaged Z-maps are mapped on to the reference brain used for non-linear normalization, Z-values are thresholded at Z = 2.58 (p < 0.005, uncorrected).
frontal junction area (IFJ), along the left inferior frontal gyrus and the anterior part of the right lingual gyrus (LG). The IFJ is located in the mid-dorsolateral prefrontal cortex around the junction of the inferior precentral sulcus and the inferior frontal sulcus (for an overview see [5,10]). The center of activation in the IFG was located in the triangular part of the IFG, reaching into the opercular part of the IFG and extended into the frontal operculum. Smaller agerelated changes were detected in the medial section of the superior frontal gyrus (preSMA) and the posterio-lateral part of the left putamen. The activated volume in relation to age was twice as large in the left then in the right hemisphere (see Table 2; left 5751 mm3 versus right 2754 mm3 ). The preSMA, the left and right IFJ and the putamen showed activations related to the interference contrast, but these contrasts were greater for the middle-aged subjects. On the contrary, the IFG and the LG showed no interference contrast specific activations, but these regions were additionally activated in the middle-aged group. This speaks in favor of a stronger involvement of verbal components used by middle-aged subjects. Further, RT related changes were found in the FG (bilaterally) and the right IFG (see Table 2). The IFG also showed interference related activations and the FG showed age-related changes of activity. It appears that slower
subjects depend more on a bilateral activation of the IFG. 3.3. Timecourse analysis To investigate the hemodynamic response and its changes related to aging, timecourses were extracted and analyzed for age-specific effects. Four parameters (amplitude, slope, dispersion and time-to-max) were calculated for each subject and both conditions as reported in the method section. The averaged timecourses for the regions showing age-related changes are shown in Fig. 6. What becomes obvious from these timecourses is that the middle-aged subjects have a larger hemodynamic response then the young adults. For the main regions reported in Table 2, the retrieved parameters were averaged for the two groups and conditions and tested for significance. The results of the statistical tests are shown in Table 3. The IFJ, the left IFG, the LG and the Putamen showed significant larger amplitude for the middle-aged subjects compared to young subjects. The time-to-max did not shift in any of the investigated regions in relation to the factor age. The dispersion increased only in the left IFG and the left IFJ in relation to age. As the time-to-max is not significantly shifted, it is not that the time-on-task is longer
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Fig. 6. Averaged timecourses: for the main regions of interest showing age-related the percent signal change was averaged across conditions and age groups.
for the middle-aged subjects, but the initial neural activity appears to be greater. It has been shown that the hemodynamic response is proportional to the average neural activity [4]. It appears that middle-aged subjects need more neural Table 3 Results of the two-factorial ANOVA (age-groups and conditions) for the four hemodynamic parameters amplitude, slope, dispersion and time-to-max Amplitude
Slope
Dispersion
Time-to-max
pSMA
Age Cond Int
0.069 0.092 n.s.
0.009 n.s. n.s.
n.s. n.s. n.s.
n.s. n.s. n.s.
IFJ left
Age Cond Int
0.0001 0.0001 0.014
0.0001 n.s. n.s.
0.066 0.039 n.s.
n.s. n.s 0.07
IFJ right
Age Cond Int
0.025 0.001 n.s.
0.002 n.s. n.s.
n.s. 0.02 n.s.
n.s. 0.004 n.s.
IFG left
Age Cond Int
0.049 0.0007 0.09
n.s. n.s. n.s.
0.037 0.07 n.s.
n.s. n.s. n.s.
LG left
Age Cond Int
0.06 n.s. n.s.
n.s. 0.1 n.s.
n.s. n.s. n.s.
n.s. n.s. n.s.
LG right
Age Cond Int
0.01 n.s. n.s.
n.s. n.s. n.s.
n.s. n.s. n.s.
n.s. 0.07 n.s.
Putamen
Age Cond Int
0.002 n.s. n.s.
0.09 n.s. n.s.
n.s. n.s. n.s.
n.s. n.s. 0.04
These parameters were extracted from the averaged timecourses. n.s. signifies a p-value > 0.1.
processing in order to achieve the same behavioral output, and by this the amplitude of the hemodynamic response is higher with increasing age. As expected, there were also significant effects on the amplitude in relation to the factor condition for regions showing an interference effect (pSMA, IFJ, IFG).
4. Discussion Three main conclusions can be drawn from the present study. (i) The middle-aged subjects were generally slowed, but did not produce a more pronounced interference effect. (ii) The same neural network was activated by young and middle-aged subjects; but with increasing age, additional, predominately left-sided, areas were recruited. (iii) Middleaged adults showed a greater magnitude of the hemodynamic response in most task-related areas compared to the younger adults. 4.1. Behavioral results The behavioral results show that middle-aged subjects are generally slowed in processing information, but no age dependent interference deficit could be observed. This finding is supported by the unspecific hypothesis of general slowing, which claims that a broad range of age effects on perceptual, cognitive and memory tasks are a consequence of an agerelated decline in processing speed [40,51,49]. No evidence is provided for a qualitative different kind of processing that declines with age. These behavioral findings speak against
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the specific inhibition deficit hypothesis, which claims that with increasing age, inhibitory processes are reduced, leading to increased Stroop interference effects [24,52]. 4.2. Age-related activation changes In relation to age, several regions showed greater activations with increasing age. PreSMA and the left IFJ, which showed interference-specific activations, revealed agerelated increases in activation. Both areas, together with the bilateral IPS, are the principal activations related to the Stroop effect [55]. Our results suggest that in order to solve the task, the neural activity becomes greater for middle-aged subjects. This is consistent with the findings of Langenecker et al. [25] who found greater activations in the IFG with increasing age. In their study, this region is labeled as part of the IFG (BA 6/9; −40 0 32), but corresponds well with the IFJ (−53 14 33) in the present study. Further, with increasing age, additional regions become activated which were not modulated by the interference contrast. These regions were the triangular and opercular part of the IFG and the anterior portion of the LG. The activation in the IFG is clearly distinct from the activation in the IFJ (see Fig. 5). It corresponds with findings of Milham et al. [31] who found age-related increases in activity in the IFG. The additional activation in this fronto-temporal network has been related to syntactical and phonological processing [3,15]. It appears plausible that with increasing age, compensatory verbal strategies become involved. Hence, for middle-aged subjects, the main interferencespecific regions become more activated, speaking in favor of a greater neural effort to solve the task. Additionally, regions not specifically related to interference become activated, namely regions related to semantic processes, verbal strategies and object/color identification. This corresponds to the compensatory-recruitment hypothesis which claims that additional brain regions might be brought on-line to enable optimal performance [37,18]. These additional regions and processes do not compensate for all age-related declines, and do not allow for an equal performance as for the young subjects. Reaction times are slightly slowed, but the task can be performed. 4.3. Hemodynamic response Surprisingly, middle-aged subjects showed a greater magnitude of the BOLD signal in the investigated ROIs. The time-to-max, however, remained unchanged with increasing age. As the time to peak is not significantly shifted, it is not due to time-on-task, but the underlying average neural activity seems to be greater with increasing age. This higher neural activity might be necessary in order to achieve a behavioral result similar to younger adults. Differences in neuroimaging signal response between young and middle-aged adults can be interpreted only if the underlying neural coupling is still intact [11,12]. The middle-
aged participants were generally healthy. In the present study, the shape of the hemodynamic response remains the same, as in the study by Nielson et al. [34]. It could be that neural coupling and the shape of the hemodynamic response is not affected in healthy aging for middle-aged subjects in regions involved in the Stroop task. But one has to consider, that the lack of age-related differences in some aspects of the hemodynamic response might be due to the younger ages of participants in this study. Whereas this study tested healthy subjects mainly under the age of 60, other studies that found age-related effects had average ages of the subjects greater then 60 or 65. Reductions in the hemodynamic response and changes in the shape might only occur with elder and old subjects or might be related to pathological, not-healthy aging processes.
5. Conclusion The present study shows that middle-aged adults were generally slowed but no disproportionate interference effect occurred. Further, middle-aged subjects showed greater activations in several task-related regions, mainly in the inferior frontal junction area and the presupplementary motor area. With increasing age, regions in the inferior frontal gyrus and the lingual gyrus were additionally recruited, indicating a stronger dependence on compensatory strategies. Further, middle-aged subjects had generally a greater amplitude in the hemodynamic response, resulting in greater percent signal changes.
Acknowledgments The authors would like to thank Anke Mempel, Mandy Naumann, Simone Wipper and Annett Wiedemann for their help with running the fMRI experiment, Anja Faustmann for her help with the data analysis and Heike Schmidt-Duderstedt for the assistance with the graphics.
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Stroop interference, hemodynamic response and aging: An event-related fMRI study Stefan Zysset ∗ , Matthias L. Schroeter, Jane Neumann, D. Yves von Cramon Max-Planck-Institute for Human Cognitive and Brain Science, Leipzig, Germany Received 13 July 2005; received in revised form 14 April 2006; accepted 3 May 2006 Available online 12 June 2006
Abstract In a Stroop interference task, subjects are required to name the color of a word, while ignoring the meaning of the word. The increase in time taken to name the color name if the underlying word is incongruent to the color is called Stroop color-word interference effect. With increasing age, reaction time (RT) is slowed. In an functional magnetic resonance imaging (fMRI) study we investigated the effects of aging (subjects from 22 to 75 years of age) on the performance in the color-word matching Stroop task and on the hemodynamic response. The present study shows that middle-aged adults were generally slowed but no increased interference effect occurred. Further, middle-aged adults showed increased activations in several task-related regions, mainly in the inferior frontal junction (IFJ) area (bilaterally) and the presupplementary motor area. For the middle-aged subjects, regions in the inferior frontal gyrus (IFG), the basal putamen and the occipital lobe were additionally recruited, indicating a stronger dependence on compensatory strategies. Further, middle-aged subjects showed generally a greater magnitude of the hemodynamic response, resulting in greater percent signal changes. © 2006 Elsevier Inc. All rights reserved. Keywords: Stroop interference; Aging; fMRI; Hemodynamic response; General slowing
1. Introduction The Stroop effect [44] is one of the best-known effects in cognitive psychology. It accounts for cognitive interference, which occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute. Naming the ink color of a color word takes much longer than naming the color of a patch of color or reading out a color word. The difference in reaction time (RT) is the so-called Stroop interference effect (for a review see [27]). Virtually everyone who can read shows a robust Stroop effect from early age on. The Stroop task is [44] is probably the classic paradigm to study cognitive control [10] and the Stroop effect seems a good measure for frontal lobe function and inhibitory processes, a construct repeatedly invoked to explain cognitive deficits associated with aging (e.g. [20]). ∗ Corresponding author at: Max-Planck-Institute for Human Cognitive and Brain Sciences, Stephanstrasse 1a, D-04I03 Leipzig, Germany. Tel.: +49 341 99 40 167; fax: +49 341 99 40 221. E-mail address: [email protected] (S. Zysset).
0197-4580/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2006.05.008
The Stroop task is an ideal tool for studying typical and atypical development of executive processes and has been used in several studies to investigate aging processes [25,31,1,38,42]. Clinical and recent neuroimaging studies showed the relevance of the medial and lateral frontal cortex for Stroop interference [50,31,29,13,55]. With increasing age, reactions times in the Stroop task are usually slowed. While some studies show that the interference effect increases as well [24,52], other studies argue that the apparent age-sensitivity of the Stroop interference effect appears to be merely an artifact of general slowing [51,49]. The inhibition theory of cognitive aging claims that increased interference effects exhibited by older adults find their origin in defective inhibitory mechanisms. The specific inhibitory mechanism that might be implicated is that of ‘restraint inhibitory control’, or the ability to restrain stimuli from “seizing control of thought and action effectors ([21], p. 654)”. In a meta-analysis of 20 behavioral studies comparing younger and older adults on the Stroop interference effect, Verhaegen and De Meersman [51] found no significant inter-
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ference effect, expressed as mean standardized difference, between the two age groups. They argue that the apparent age-sensitivity of the Stroop interference effect appears to be merely an artifact of general slowing. The same conclusions are taken by Uttl and Graf [49], who tested the color-word Stroop task with 310 subjects of ages between 19 and 83. The general conclusion is that age effects in Stroop interference are due to age-related slowing and no evidence is provided for a qualitative different kind of processing that declines with age. This concept is called the unspecific hypothesis of general slowing with increasing age, and is not limited to inhibitory processes, but to all cognitive processes [40]. A recent functional magnetic resonance imaging (fMRI) study of the Stroop task with elderly adults by Langenecker et al. [25] reported that with increasing age, numerous regions exhibited greater activations, including the left inferior frontal gyrus (IFG). In a study by Nielson et al. [33], older adults had significantly greater activations in multiple frontal regions, including the left IFG. Milham et al. [31] reported greater activations for younger subjects compared to elderly subjects, mainly in the left middle frontal gyrus (MFG), anterior cingulate, and superior parietal lobule, while older adults had greater activation compared to young adults in the IFG. A few studies reported that the activation pattern was comparable between young and elder subjects, but the volume of these activations is reduced with increasing age [19,39]. However, other studies observed additional activations for elderly subjects, mainly in the prefrontal cortex and in the contralateral hemisphere [8,9,33,18,19,28]. A quantitative comparison of the activation patterns resulting from fMRI studies to test hypotheses regarding agerelated changes relies on the assumption that the coupling of neural activity to the neuroimaging signal is not affected by aging. Differences in neuroimaging signal response between young and elderly adults can be mapped directly to differences in neural response, only if such coupling does not change with age [11,12]. Huettel et al. [23] showed that the amplitude and form of hemodynamic responses for young and elderly adults are similar. But elderly adults showed greater voxelwise noise leading to a smaller spatial extent of activation. An fMRI study by Nielson et al. [34] showed that although task performance and activation pattern differed, the underlying hemodynamic response was comparable between younger and older adults. In contrast, Taoka et al. [46] found the time lag of the hemodynamic response in fMRI to be prolonged with increasing age. In a blocked design study, the latency of the trailing edge of the hemodynamic response tends to increase with age [38]. In summary, one can assume that with normal, healthy aging, the neuronal coupling remains intact, even if the temporal dynamic might change. The basic aim of the present fMRI study was to compare the neural processes and the hemodynamic response underlying the color-word Stroop interference task for healthy young and middle-aged adults. For this, a single trial version of the paradigm used in previous fMRI-studies [55,36,32] and func-
tional near-infra-red studies [43,41] was applied to test adults of varying age. The use of a single trial design allowed us to characterize the hemodynamic response in accordance with age. Further, changes in reaction time and the interference effect were investigated. 2. Method 2.1. Subjects Forty-seven healthy subjects (24 women) of different age were tested. Subject’s age ranged from 22 years up to 75 years, the mean age was 42 years. The subjects were divided in two groups according to age: a group of 23 young subjects (26.6 mean age; S.D. = 3.6; range 22–36 years of age) and a group of 24 middle-aged subjects (57.1 mean age; S.D. = 6.49; range 45–75 years of age). The two groups do not differ in the number of years of school (p = 0.2) and on the reading span (p = 0.92). Written informed consent from all subjects was obtained prior to the scanning session. All subjects had normal or corrected-to-normal vision, normal color vision and were native German speakers. The subjects were screened for neurological and psychiatric disorders and only healthy adults were included. Only 4 out of the 24 middle-aged subjects and none of the young adults were taking medication at the time of the study.1 Subjects were instructed about the task and were given a short practice session before entering the scanner. Once they felt comfortable with the task, subjects were positioned supine in the scanner. 2.2. Psychophysical procedures An adapted single trial version of the color-word interference task [44,55] was used. Subjects were told that they would see two rows of letters appear on the screen and were instructed to decide, via button-press, if the color of the top row letters corresponded to the color name written at the bottom row. During ‘neutral’ trials, the letters in the top row were ‘XXXX’ printed in red, green, blue or yellow, and the bottom row consisted of the color words ‘RED’, ‘GREEN’, ‘BLUE’ and ‘YELLOW’ printed in black (see Fig. 1). For ’incongruent’ trials, the top row consisted of the color words ‘RED’, ‘GREEN’, ‘BLUE’ and ‘YELLOW’ printed in a incongruent color to the color word (e.g. ‘green’ printed in red), in order to produce an interference between color word and color name. The bottom row consisted again of the color words ‘RED’, ‘GREEN’, ‘BLUE’ and ’YELLOW printed in black. The meaning of the letters or words (e.g. ‘XXXX’ or ‘GREEN’) at top was task irrelevant. In half of the trials in both conditions the color in the top row corresponded to the color name of the bottom row. ‘Hits’ and ‘foils’ were pre1 The medications taken were l-Thyroxin© , Allpurinol© , Kreon© , Enahexal© and Methohexal© .
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Fig. 1. Examples of single trials for the neutral and incongruent condition of the color-word matching Stroop task: ‘Does the color of the upper word correspond with the meaning of the lower word?’ For the upper two examples, the correct answer would be ‘NO’; for the lower two examples, the correct answer would be ‘YES’.
sented in random order to prevent subjects from developing response tendencies. Responses were given with index (YES) or middle (NO) finger of the right hand. To prevent subjects from focusing on the lower word and blurring out the top word, the top word was presented 100 ms before the lower word (see also [27,17]). By this, visual attention is shifted automatically to the top word. Hundred incongruent and 100 neutral trials were presented. Additionally, 40 none-events (empty-trials) were presented to improve statistical evaluation of the data [30], resulting in a total number of 240 trials. Trials were presented every 6 s on average and a variable stimulus-onset delay (0, 400, 800, 1200 or 1600 ms) was introduced in order to improve the temporal resolution [30]. Stimuli were presented with the VisuaStim XGA (Resonance Technology, Northridge, USA), a high-resolution visor (800 × 600 resolution) consisting of two small TFT-screen placed close to the subjects eyes. 2.3. MRI scanning procedure The experiment was carried out on a 3T scanner (Medspec 30/100, Bruker, Ettlingen). Twenty axial slices (19.2 cm FOV, 64 × 64 matrix, 4 mm thickness, 1 mm spacing), parallel to the AC-PC plane and covering the whole brain were acquired using a single shot, gradient recalled EPI sequence (TR 2000 ms, TE 30 ms, 90◦ flip angle). One functional run with 723 scans was measured, each scan covering the 20 slices. Prior to the functional run, 20 anatomical T1-weighted MDEFT [48,35] images (data matrix 256 × 256, TR 1.3 s, TE 10 ms) and 20 T1-weighted EPI images with the same spatial orientation as the functional data were acquired. 2.4. fMRI data analysis The fMRI data were processed with LIPSIA software [26]. This software package contains tools for preprocessing,
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registration, statistical evaluation and presentation of fMRI data. Functional data were corrected for motion using a matching metric based on linear correlation. To correct for the temporal offset between the slices acquired in one scan, a sine-interpolation based on the Nyquist-Shannon-Theorem was applied. A temporal highpass filter with a cutoff frequency of l/60 Hz was used for baseline correction of the signal and a spatial Gaussian filter with 5.65 mm FWHM was applied. To align the functional dataslices onto a 3D stereotactic coordinate reference system, a rigid linear registration with six degrees of freedom (three rotational, three translational) was performed. The rotational and translational parameters were acquired on the basis of the MDEFT and EPI-T1 slices to achieve an optimal match between these slices and the individual 3D reference data set. This 3D reference data set was acquired for each subject during a previous scanning session. The MDEFT volume data set with 160 slices and 1 mm slice thickness was standardized to the Talairach stereotactic space [45]. The same rotational and translational parameters were normalized, i.e., transformed by linear scaling to a standard size. The resulting parameters were then used to transform the functional slices using trilinear interpolation, so that the resulting functional slices were aligned with the stereotactic coordinate system. This linear normalization process was improved by a subsequent processing step that performs an additional non-linear normalization [47]. The statistical evaluation was based on a least-squares estimation using the general linear model for serially autocorrelated observations (see also [16,53,2,54]). The design matrix was generated with a synthetic hemodynamic response function, its two derivatives and a response delay of 6 s. The model equation, including the observation data, the design matrix and the error term, was convolved with a Gaussian kernel of dispersion of 4 s. FWHM. In the following, contrast maps were generated for each subject, differentiating between the neutral and incongruent conditions. As the individual functional datasets were all aligned to the same stereotactic reference space, a random-effects group analysis was performed [22]. The individual contrast images were used for a random-effects second-level analysis with an additional regressor coding the two age groups. Subsequently, t-values were transformed into Z-scores. To protect against false positive activations, only regions with a Z-score greater than 3.1 (p < 0.001, uncorrected) or 2.58 (p < 0.005, uncorrected), respectively, and with a volume greater than 216 mm3 (6 voxels) were considered [14,6]. Further, a timecourse analysis of the fMRI-signal was calculated (for details see [32]). Trial-averaged timecourses (stimulus-onset locked) were obtained on a voxel-by-voxel basis for each subject at a sampling rate of 200 ms. Activations for time points falling between two observed points were linearly interpolated from the weighted activations of their neighbors. The resulting timecourse of the null-event condition was subtracted from the timecourses of the neutral
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Fig. 3. Mean reaction times and error rates for the neutral and incongruent condition for the color-word matching Stroop task plotted for both age groups. Fig. 2. A typical trial-averaged timecourse of an activated voxel. The calculated parameters amplitude, slope, time-to-max and dispersion are represented in red.
and incongruent condition [7]. For each subject and the two conditions, four parameters were extracted from the averaged timecourse: (a) percent signal change; (b) slope of the hemodynamic response; (c) dispersion of the hemodynamic response; and (d) time to maximum. The minimum and maximum signal change were sought in the time range of 0–3 and 2–8 s, respectively. The percent signal change was calculated relating the minimum and maximum signal intensity (see Fig. 2). The slope represents the steepness between t-steep and t-flat (see Fig. 2). The dispersion was calculated as the fullwidth of the hemodynamic response at half the height. The time-to-max was the time in seconds when the maximum signal intensity was reached after onset of the stimulus. The resulting parameters (amplitude, slope, dispersion and timeto-max) were tested for age- and condition-related effects in regions of interest.
3. Results 3.1. Behavioral results For all subjects, reaction times and error rate were registered. Only the RTs of correct responses were analyzed. Fig. 3 shows the mean RT and error rate for both conditions and both age groups. A two-factorial ANOVA with condition (neutral and incongruent) as within effect and age (young and middleaged) as between effect was calculated for RT and error rate. For RT, a significant main effect for condition (F(1, 45) = 66.7; p < 0.001) and age (F(1, 45) = 29.4; p < 0.001) was found. The interaction between condition and age was not significant (F(1, 45) = 1.2; p = 0.27). Older adults are significantly slower than young adults on both the neutral and
incongruent conditions but the incongruent condition is no more affected by age than the neutral condition. For both conditions, very few errors (<5%) were produced. No significant effect for age could be found for the neutral (p = 0.55) or incongruent (p = 0.88) condition using a nonparametric test. 3.2. Imaging results First, the contrast of the incongruent against the neutral condition was calculated for each subject. The resulting individual interference contrast images were used for a randomeffects second-level analysis across all subjects contrasting between the middle-aged and young subjects. Further, the individual median RT of each subject was added as an additional covariate. The resulting activations for color-word interference contrast (incongruent vs. neutral) are shown in Fig. 4 and Table 1. The activations in relation to age and RT are reported in Fig. 5 and Table 2. The largest activations for the color-word interference contrast were along the inferior frontal sulcus (IFS, bilaterally), along the intraparietal sulcus (IPS, bilaterally), the posterior superior frontal gyrus, and the medial wall of the superior frontal gyrus (presupplementary motor area; preSMA). Further, the left and right anterior insula, posterior superior frontal gyrus (frontal eye fields; FEF), the precuneus, the fusiform gyrus (FG; bilaterally), the caudate nucleus, the putamen and the cerebellum were activated. The activations were more pronounced in the left hemisphere. That is, the volume of significantly activated voxels was about twice as big in the left hemisphere compared to the right hemisphere (73600 mm3 versus 36800 mm3 ). The pattern of activations corresponds to previously published data using the same color-word matching Stroop task with young subjects [55]. A negative signal change in relation to the interference contrast was detected in the posterior cingulate cortex. The largest age-related changes in relation to the interference contrast could be found in the left and right inferior
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Fig. 4. Interference-specific activations: main activations averaged across all subjects contrasting the incongruent condition against the neutral condition. The slices show the main activations in the left (x = −44) and right (x = 40) lateral cortex and the mid-sagittal plane (x = −5). Averaged Z-maps are mapped on to the reference brain used for non-linear normalization, Z-values are thresholded at Z = 3.1 (p < 0.001, uncorrected).
Table 1 Talairach coordinates, maximum Z-value of the local maxima for the incongruent vs. neutral contrast across all subjects, Z-values were thresholded at Z = 3.1 (p < 0.001; uncorrected) and activations reported have a minimum size of 216 mm3 (6 voxels) Interference-specific activations Anatomical region
Left hemisphere
Superior frontal gyrus (medial portion) Superior frontal gyrus posterior Inferior frontal junction Inferior frontal sulcus anterior Inferior frontal sulcus Intraparietal sulcus Precuneus Cingulate sulcus Anterior insula Fusiform gyrus anterior Fusiform gyrus posterior Putamen, pars postero-lateral Caudate nucleus Cerebellum, lobus posterior Posterior cingulate cortex
Right hemisphere
Z-max
Tal. coord.
Z-max
5.22 4.41 6.39 4.39
−5 14 46 −23 2 52 −44 17 28 −44 32 10
4.93 4.82 5.72
1 17 49 28 2 46 40 8 34
6.43 4.21
−32 −55 46 −8 −70 52
5.56 6.24 4.47 4.62 5.04 4.79 4.03
43 23 28 31 −46 43 10 −67 49 10 23 34 40 14 4 37 −64 −5 31 −85 −2
−35 23 7 −44 −67 −5 −29 −82 1 −17 −22 4 −11 −1 19 −11 −76 −11 −8 −55 22
5.78 5.50 5.22 3.53 3.42 3.99 −4.08
10 −73 −17 4 −52 28
3.42 −3.90
73602 mm3
Total activated volume
Tal. coord.
36801 mm3
Negative Z-values indicate that the neutral condition was more pronounced.
Table 2 Talairach coordinates, maximum Z-value of the local maxima for the age-related changes, Z-values were thresholded at Z = 2.58 (p < 0.005; uncorrected) and activations reported have a minimum size of 216 mm3 (6 voxels) Age-related changes Anatomical region
Superior frontal gyrus (medial section) Inferior frontal junction Inferior frontal gyrus Anterior lingual gyrus Putamen, pars postero-lateral
Left hemisphere Volume
Z-max
Tal. coord.
702 1188 3105 432 324
3.72 3.29 4.05 3.01 3.45
−8 23 49 −44 8 37 −47 23 10 −17 −67 7 −26 −16 −2
Total activated volume
Volume
Z-max
Tal. coord.
1242
3.69
46 11 40
1512
4.19
16 −52 4
5751 mm3
Total activated volume RT-related changes Inferior frontal gyrus (post) Fusiform gyrus posterior
Right hemisphere
1701
3.32 1701 mm3
2754 mm3
−32 −79 −5
621 405
3.73 3.02 1026 mm3
52 17 22 34 −76 −2
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Fig. 5. Age- and RT-related changes: the figures show the age-related (top) and RT-related (bottom) activations of the second-level analysis for age and RT. The two sagittal slices in the top row show main activations in the left (x = −44) and right (x = 40) frontolateral cortex for age-related changes. The axial and sagittal slice in the bottom row show the activation changes in relation to RT. Averaged Z-maps are mapped on to the reference brain used for non-linear normalization, Z-values are thresholded at Z = 2.58 (p < 0.005, uncorrected).
frontal junction area (IFJ), along the left inferior frontal gyrus and the anterior part of the right lingual gyrus (LG). The IFJ is located in the mid-dorsolateral prefrontal cortex around the junction of the inferior precentral sulcus and the inferior frontal sulcus (for an overview see [5,10]). The center of activation in the IFG was located in the triangular part of the IFG, reaching into the opercular part of the IFG and extended into the frontal operculum. Smaller agerelated changes were detected in the medial section of the superior frontal gyrus (preSMA) and the posterio-lateral part of the left putamen. The activated volume in relation to age was twice as large in the left then in the right hemisphere (see Table 2; left 5751 mm3 versus right 2754 mm3 ). The preSMA, the left and right IFJ and the putamen showed activations related to the interference contrast, but these contrasts were greater for the middle-aged subjects. On the contrary, the IFG and the LG showed no interference contrast specific activations, but these regions were additionally activated in the middle-aged group. This speaks in favor of a stronger involvement of verbal components used by middle-aged subjects. Further, RT related changes were found in the FG (bilaterally) and the right IFG (see Table 2). The IFG also showed interference related activations and the FG showed age-related changes of activity. It appears that slower
subjects depend more on a bilateral activation of the IFG. 3.3. Timecourse analysis To investigate the hemodynamic response and its changes related to aging, timecourses were extracted and analyzed for age-specific effects. Four parameters (amplitude, slope, dispersion and time-to-max) were calculated for each subject and both conditions as reported in the method section. The averaged timecourses for the regions showing age-related changes are shown in Fig. 6. What becomes obvious from these timecourses is that the middle-aged subjects have a larger hemodynamic response then the young adults. For the main regions reported in Table 2, the retrieved parameters were averaged for the two groups and conditions and tested for significance. The results of the statistical tests are shown in Table 3. The IFJ, the left IFG, the LG and the Putamen showed significant larger amplitude for the middle-aged subjects compared to young subjects. The time-to-max did not shift in any of the investigated regions in relation to the factor age. The dispersion increased only in the left IFG and the left IFJ in relation to age. As the time-to-max is not significantly shifted, it is not that the time-on-task is longer
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Fig. 6. Averaged timecourses: for the main regions of interest showing age-related the percent signal change was averaged across conditions and age groups.
for the middle-aged subjects, but the initial neural activity appears to be greater. It has been shown that the hemodynamic response is proportional to the average neural activity [4]. It appears that middle-aged subjects need more neural Table 3 Results of the two-factorial ANOVA (age-groups and conditions) for the four hemodynamic parameters amplitude, slope, dispersion and time-to-max Amplitude
Slope
Dispersion
Time-to-max
pSMA
Age Cond Int
0.069 0.092 n.s.
0.009 n.s. n.s.
n.s. n.s. n.s.
n.s. n.s. n.s.
IFJ left
Age Cond Int
0.0001 0.0001 0.014
0.0001 n.s. n.s.
0.066 0.039 n.s.
n.s. n.s 0.07
IFJ right
Age Cond Int
0.025 0.001 n.s.
0.002 n.s. n.s.
n.s. 0.02 n.s.
n.s. 0.004 n.s.
IFG left
Age Cond Int
0.049 0.0007 0.09
n.s. n.s. n.s.
0.037 0.07 n.s.
n.s. n.s. n.s.
LG left
Age Cond Int
0.06 n.s. n.s.
n.s. 0.1 n.s.
n.s. n.s. n.s.
n.s. n.s. n.s.
LG right
Age Cond Int
0.01 n.s. n.s.
n.s. n.s. n.s.
n.s. n.s. n.s.
n.s. 0.07 n.s.
Putamen
Age Cond Int
0.002 n.s. n.s.
0.09 n.s. n.s.
n.s. n.s. n.s.
n.s. n.s. 0.04
These parameters were extracted from the averaged timecourses. n.s. signifies a p-value > 0.1.
processing in order to achieve the same behavioral output, and by this the amplitude of the hemodynamic response is higher with increasing age. As expected, there were also significant effects on the amplitude in relation to the factor condition for regions showing an interference effect (pSMA, IFJ, IFG).
4. Discussion Three main conclusions can be drawn from the present study. (i) The middle-aged subjects were generally slowed, but did not produce a more pronounced interference effect. (ii) The same neural network was activated by young and middle-aged subjects; but with increasing age, additional, predominately left-sided, areas were recruited. (iii) Middleaged adults showed a greater magnitude of the hemodynamic response in most task-related areas compared to the younger adults. 4.1. Behavioral results The behavioral results show that middle-aged subjects are generally slowed in processing information, but no age dependent interference deficit could be observed. This finding is supported by the unspecific hypothesis of general slowing, which claims that a broad range of age effects on perceptual, cognitive and memory tasks are a consequence of an agerelated decline in processing speed [40,51,49]. No evidence is provided for a qualitative different kind of processing that declines with age. These behavioral findings speak against
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the specific inhibition deficit hypothesis, which claims that with increasing age, inhibitory processes are reduced, leading to increased Stroop interference effects [24,52]. 4.2. Age-related activation changes In relation to age, several regions showed greater activations with increasing age. PreSMA and the left IFJ, which showed interference-specific activations, revealed agerelated increases in activation. Both areas, together with the bilateral IPS, are the principal activations related to the Stroop effect [55]. Our results suggest that in order to solve the task, the neural activity becomes greater for middle-aged subjects. This is consistent with the findings of Langenecker et al. [25] who found greater activations in the IFG with increasing age. In their study, this region is labeled as part of the IFG (BA 6/9; −40 0 32), but corresponds well with the IFJ (−53 14 33) in the present study. Further, with increasing age, additional regions become activated which were not modulated by the interference contrast. These regions were the triangular and opercular part of the IFG and the anterior portion of the LG. The activation in the IFG is clearly distinct from the activation in the IFJ (see Fig. 5). It corresponds with findings of Milham et al. [31] who found age-related increases in activity in the IFG. The additional activation in this fronto-temporal network has been related to syntactical and phonological processing [3,15]. It appears plausible that with increasing age, compensatory verbal strategies become involved. Hence, for middle-aged subjects, the main interferencespecific regions become more activated, speaking in favor of a greater neural effort to solve the task. Additionally, regions not specifically related to interference become activated, namely regions related to semantic processes, verbal strategies and object/color identification. This corresponds to the compensatory-recruitment hypothesis which claims that additional brain regions might be brought on-line to enable optimal performance [37,18]. These additional regions and processes do not compensate for all age-related declines, and do not allow for an equal performance as for the young subjects. Reaction times are slightly slowed, but the task can be performed. 4.3. Hemodynamic response Surprisingly, middle-aged subjects showed a greater magnitude of the BOLD signal in the investigated ROIs. The time-to-max, however, remained unchanged with increasing age. As the time to peak is not significantly shifted, it is not due to time-on-task, but the underlying average neural activity seems to be greater with increasing age. This higher neural activity might be necessary in order to achieve a behavioral result similar to younger adults. Differences in neuroimaging signal response between young and middle-aged adults can be interpreted only if the underlying neural coupling is still intact [11,12]. The middle-
aged participants were generally healthy. In the present study, the shape of the hemodynamic response remains the same, as in the study by Nielson et al. [34]. It could be that neural coupling and the shape of the hemodynamic response is not affected in healthy aging for middle-aged subjects in regions involved in the Stroop task. But one has to consider, that the lack of age-related differences in some aspects of the hemodynamic response might be due to the younger ages of participants in this study. Whereas this study tested healthy subjects mainly under the age of 60, other studies that found age-related effects had average ages of the subjects greater then 60 or 65. Reductions in the hemodynamic response and changes in the shape might only occur with elder and old subjects or might be related to pathological, not-healthy aging processes.
5. Conclusion The present study shows that middle-aged adults were generally slowed but no disproportionate interference effect occurred. Further, middle-aged subjects showed greater activations in several task-related regions, mainly in the inferior frontal junction area and the presupplementary motor area. With increasing age, regions in the inferior frontal gyrus and the lingual gyrus were additionally recruited, indicating a stronger dependence on compensatory strategies. Further, middle-aged subjects had generally a greater amplitude in the hemodynamic response, resulting in greater percent signal changes.
Acknowledgments The authors would like to thank Anke Mempel, Mandy Naumann, Simone Wipper and Annett Wiedemann for their help with running the fMRI experiment, Anja Faustmann for her help with the data analysis and Heike Schmidt-Duderstedt for the assistance with the graphics.
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