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Working memory is the limited capacity storage system involved in the maintenance and manipulation of information over short periods
of time. Individual capacity of working memory is associated with the integrity of white matter in the frontoparietal regions. It is unknown
to what extent the integrity of white matter underlying the working memory system is plastic. Using voxel-based analysis (VBA) of
fractional anisotropy (FA) measures of fiber tracts, we investigated the effect of working memory training on structural connectivity in an
interventional study. The amount of working memory training correlated with increased FA in the white matter regions adjacent to the
intraparietal sulcus and the anterior part of the body of the corpus callosum after training. These results showed training-induced
plasticity in regions that are thought to be critical in working memory. As changes in myelination lead to FA changes in diffusion tensor
imaging, a possible mechanism for the observed FA change is increased myelination after training. Observed structural changes may
underlie previously reported improvement of working memory capacity, improvement of other cognitive functions, and altered func-
tional activity following working memory training.
of white matter connectivity changes. DTI is used to measure the consisted of numbers, 1 to 4, presented in a random sequence in one of
magnitude and direction of water diffusion (i.e., anisotropy) in four places on a line. The participants were asked to memorize the loca-
brain tissue. FA is a measure of the degree of anisotropy and is tion and identity of the stimuli and their temporal order. The subjects
thought to be modulated by the degree of myelination, axonal then had to push the buttons, 1, 2, 3, or 4, with their left hand, to indicate
the identity of the stimuli N stimuli ago and push the buttons, 5, 6, 7, or
membrane thickness and diameter, and/or the amount of parallel
8, with their right hands to indicate the location of the stimuli N stimuli
organization of the axons (Basser and Pierpaoli, 1996; Beaulieu, ago (the locations of buttons 5, 6, 7, and 8 corresponded to the locations
2002). Thus, FA is interpreted as an indicator of white matter path- of the stimuli; button 5 corresponded to the leftmost stimulus and button
way strength, or integrity. We reasoned that the structural connec- 8 corresponded to the right-most stimulus). As was the case with the
tivity that underlies the working memory network (Klingberg, 2006) “operation” N-back task, one block of the task consisted of 5 ⫻ N stimuli.
would be affected by the training. In all of the three tasks, the level of difficulty was varied by changing the
level of the tasks, based on the participants’ performance.
When the participants answered the problems correctly, the level of
Materials and Methods the task increased by one, and when the participants failed to answer the
Participants problems correctly three times in a row, the level of the task decreased by
Eleven healthy, right-handed individuals (eight men, three women) par- one. In the first visuospatial working memory task, the level of difficulty
ticipated. The mean age was 21.7 years (SD, 1.44). All subjects were was varied by changing the number of presented stimuli. When partici-
students at Sendai University. All subjects had normal vision, and none pants answered the problem correctly (indicated the correct location of
had any history of neurological or psychiatric illness. Handedness was all the stimuli in the presented order), it was regarded as a correct answer.
evaluated using the Edinburgh handedness inventory (Oldfield, 1971). In the “operation” N-back task, the level of difficulty was varied by
Written informed consent was obtained from each subject. This study changing the level of N. Blocks were regarded as completed correctly
was approved by the Ethics Committee of Tohoku University. One par- when the participants made errors in ⬍20% of the trials. In the “dual”
ticipant who failed to perform two of our three training tasks was omitted N-back task, the level of difficulty was also varied by changing the level of
from further analysis. N. Blocks were regarded as completed correctly when the participants
made errors in ⬍25% of the trials for both location and identity identi-
Procedure fication. Each task of each session ended when subjects accumulated a
The working memory training programs were Borland C⫹⫹ computer
predetermined number of correct trials.
programs developed in-house and consisted of three working memory
tasks. Participants undertook 2 months of training. Training on each day
lasted ⬃25 min, but the total time depended on the level and time be- Image acquisition
All MRI data acquisition was conducted with a 3-T Philips Intera Achieva
tween trials. The working memory training program was provided to
scanner. Diffusion-weighted data were acquired using a spin-echo EPI
each of the participants and was used by the subjects on their personal
sequence (TR ⫽ 10,293 ms, TE ⫽ 55 ms, FOV ⫽ 22.4 cm, 2 ⫻ 2 ⫻ 2 mm 3
computers. They were recommended to do the working memory train-
voxels, 60 slices, SENSE reduction factor ⫽ 2, number of acquisitions ⫽
ing every day. When this was impossible for any reason (e.g., when they
1). The diffusion weighting was isotropically distributed along 32 direc-
had computer trouble), they were allowed to miss the working memory
tions (b value ⫽ 1000 s/mm2). Additionally, a single image with no
training. Subjects were also allowed to do the working memory training
diffusion weighting (b value ⫽ 0 s/mm2) (b value ⫽ 0 image) was ac-
more than once a day. Responses to each trial were logged in a file on the
quired. The total scan time was 7 min, 17 s. Other than 32 b ⫽ 1000
computer, and every 5 d, subjects were asked to submit the logs by mail so
images and one b value ⫽ 0 image, there are acquisitions for phase
that compliance could be verified. Participants were MRI scanned im-
correction and for signal stabilization and these are not used as recon-
mediately before and after the 2 month period, and all participants took
structed images.
psychological tests immediately before and after the 2 month period. The
Then, from the collected images, fractional anisotropy values were
experimenter gave feedback about the working memory training to the
calculated. In this study, we chose to set the number of acquisitions to
subjects as necessary.
one and instead of increasing the number of acquisitions, the diffusion
Training tasks weighting was isotropically distributed along as many as 32 directions.
Three working memory tasks were presented during each training ses-
sion: (1) A visuospatial working memory task in which circles were pre- Behavioral analysis
sented one at a time at a rate of 1/s in a three-by-three grid-like interface. Behavioral data were analyzed using the statistical software, SPSS 16.0.
Participants had to remember the location and order of the stimuli. After Because the usefulness of working memory training on improving work-
the presentation of stimuli, participants indicated the location and order ing memory tasks was our primary interest, in the behavioral analysis,
of the presented stimuli by clicking on a computer screen with a mouse. differences between the highest performances (highest level of the task
(2) “Operation” N-back task. Generally in the N-back task, participants that participants answered correctly) in the trained working memory
were asked to memorize a series of stimuli and their temporal order, tasks in the first three trained sessions and those in the last three trained
update the list of recent items, and select the responses that corresponded sessions were tested using one-tailed paired t tests, with a threshold of p ⬍
to the previously observed stimuli, according to the N-back rule (N stim- 0.05. After that, to show that any test–retest changes as a group were
uli ago). In our study, all the N-back tasks were designed to require associated with working memory training, simple regression analysis
individuals to push one of several buttons that corresponded to the stim- with a threshold of p ⬍ 0.05 was used to test whether there was a positive
uli that were shown N stimuli ago, continuously during the task period, correlation between the amount of improvement in performance (levels)
unlike other N-back types, which typically require individuals to push in the trained working memory tasks and the total amount of training
one of two buttons to judge whether the current stimuli and the stimuli that participants completed. The total amount of training was calculated
that were shown N stimuli ago were the same (Jaeggi et al., 2008). In this as follows: {(number of completed sessions of the visuospatial working
“operation” N-back task, the stimuli consisted of pairs of numbers, 1 to 4, memory task) ⫹ (number of completed sessions of the “operation”
shown in a random sequence on the screen (e.g., “1 ⫹ 4”). Participants N-back task) ⫹ (number of completed sessions of the “dual” N-back
were asked to memorize the sum of the two numbers presented (ranging task)}. Also, for the analysis of the performance of working memory
from 2 to 8). The subjects had to push the button on the keyboard that tasks, the performance of trained working memory tasks for each partic-
corresponded to N stimuli ago. The level of the task ( N) changed based ipant in the first and last three sessions was calculated as follows: {(high-
on participants’ performance, as described below, and the length of the est level of the visuospatial working memory task achieved in the first or
task changed based on the level of the task. One block of the task con- last three completed sessions) ⫹ (highest level of the “operation” N-back
sisted of 5 ⫻ N stimuli (for example, when N ⫽ 3, the number of the task achieved in the first or last three completed sessions) ⫹ 2 ⫻ (highest
stimuli was 15). (3) “Dual” N-back task. In this task, the number stimuli level of the “dual” N-back task achieved in the first or last three com-
Takeuchi et al. • Cognitive Training Impacts Structural Connectivity J. Neurosci., March 3, 2010 • 30(9):3297–3303 • 3299
pleted sessions) (the performance of the dual N-back task was multiplied
by two because when the level of the dual N-back task increased by one,
the number of stimuli to be remembered increased by two).
Table 1. Performance and amount of training for the three training tasks (mean ⴞ SD)
Highest level achieved Highest level achieved
in the first three in the last three Number of completed
sessions sessions training sessionsa
Visuospatial WM task 8.00 ⫾ 0.89 8.90 ⫾ 0.94 40.5 ⫾ 12.4
Operation N-back 3.20 ⫾ 0.75 4.30 ⫾ 1.10 39.1 ⫾ 12.7
Dual N-back 2.50 ⫾ 0.50 3.80 ⫾ 0.60 37.6 ⫾ 12.8
a
Note unless there was some reason for subjects to forgo completion of a task, the number of training sessions for the
three tasks would have been the same because subjects were required to do all the tasks. In addition, since subjects
were required to do the three training tasks in the same order, the number of training sessions in the first training
task (the visuospatial WM task) was the highest.
We suggest that increased myelination, caused by neural ac- from finding significant training effects on FA in other regions
tivity in fiber tracts during working memory training, is one pos- that are important to working memory, such as the right pre-
sible mechanism underlying the observed FA increases after frontal cortex. Also, because of our within-subject registration
working memory training. In the mouse, induction of myelina- between the pretraining and posttraining images, the post-
tion by neural activity has been demonstrated both in vivo and in training images undergo one interpolation operation more
vitro (Demerens et al., 1996), and the myelination process was than the pretraining images. This may be a potential pitfall in
affected by and could be manipulated from the outside within a finding differences between pretraining and posttraining data,
week (Koenig et al., 1995), as well as being affected by environ- although individual differences and their correlation with
mental influences (Juraska and Kopcik, 1988). It has been well amount of training cannot be explained by this problem. Finally,
established that myelination continues even into adulthood although the correlation between FA change and amount of training
(Yakovlev and Lecours, 1967; Benes et al., 1994; Nuñez et al., are impressive in and of themselves, it is still possible, (though un-
2000). Furthermore, preliminary research has suggested that my- likely), that FA could have changed over the time period for other
elination remains sensitive to experience, even in adulthood reasons.
(Markham and Greenough, 2004). Additionally, human studies In summary, the present results show the effects of working
using DTI showed practice-induced white matter plasticity, even memory training on white matter structures that are important
in adulthood (Bengtsson et al., 2005). Our results fit with the idea in working memory. White matter brain structure underlies cog-
that skill learning, and experiences, which clearly continue nitive abilities (Olesen et al., 2003), as well as several neurological
throughout life, are accompanied by structural changes, includ- and psychiatric disorders and normal aging (Moseley, 2002;
ing myelination (Koester, 1985). Kanaan et al., 2005; Chua et al., 2008). Thus, the idea that a brain
The increase in FA following training may be associated with structure can be changed through short-term cognitive training
the enhanced effectiveness of communication between neural may provide the basis for new insights into neural plasticity, and
circuits, which, in turn, leads to enhanced performance of WM may have clinical applications (Klingberg et al., 2002).
tasks. This is for the following reasons. An action potential
spreads faster along myelinated axons than unmyelinated ones References
(Bloom et al., 1988). In addition, the velocity of conduction of the Ashburner J, Friston KJ (2001) Why voxel-based morphometry should be
action potential spread increases with increased myelin thickness used. Neuroimage 14:1238 –1243.
in myelinated neuron fibers (Waxman, 1980). Faster conduction Baddeley A (2003) Working memory: looking back and looking forward.
Nat Rev Neurosci 4:829 – 839.
velocity can facilitate information flow not only by speeding it
Barbas H, Pandya DN (1984) Topography of commissural fibers of the pre-
up but also by allowing for precise temporal coding of high- frontal cortex in the rhesus monkey. Exp Brain Res 55:187–191.
frequency bursts of neuronal activity (McDonald and Sears, Barnea-Goraly N, Menon V, Eckert M, Tamm L, Bammer R, Karchemskiy A,
1970; Swadlow, 1985; Shrager, 1993). Furthermore, integrity in Dant CC, Reiss AL (2005) White matter development during childhood
the timing of sequential events in neuronal circuits could lead to and adolescence: a cross-sectional diffusion tensor imaging study. Cereb
more effective cognitive performance (Peters, 2002). Cortex 15:1848 –1854.
Basser PJ, Pierpaoli C (1996) Microstructural and physiological features of
To show that FA changes in the clusters that showed signifi-
tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B
cant FA increase after training were correlated with amount of 111:209 –219.
working memory training, we performed two correlation analy- Beaulieu C (2002) The basis of anisotropic water diffusion in the nervous
ses: one with FA change at each voxel (VBA) and the other with system-a technical review. NMR Biomed 15:435– 455.
mean FA change in the significant clusters that showed significant Benes FM, Turtle M, Khan Y, Farol P (1994) Myelination of a key relay zone
FA increase after training. The reason we performed a voxel- in the hippocampal formation occurs in the human brain during child-
based correlation analysis in addition to the correlation analysis hood, adolescence, and adulthood. Arch Gen Psychiatry 51:477– 484.
Bengtsson SL, Nagy Z, Skare S, Forsman L, Forssberg H, Ullén F (2005)
with mean FA changes in the clusters, was because averaging the Extensive piano practicing has regionally specific effects on white matter
strength of the signals in clusters with significant FA increase after development. Nat Neurosci 8:1148 –1150.
training, whose voxels can include noise or other effects, is not the Bloom FE, Lazerson A, Hofstadter L (1988) Brain, mind, and behavior. New
best way to look at the effects of training in the region of a signif- York: Freeman.
icant cluster. Cluster level inference does not statistically guaran- Bookstein FL (2001) “Voxel-based morphometry” should not be used with
tee that every single voxel in the significant cluster shows the imperfectly registered images. Neuroimage 14:1454 –1462.
Chua TC, Wen W, Slavin MJ, Sachdev PS (2008) Diffusion tensor imaging
effect of the contrast (Friston et al., 1996). Rather, the significant
in mild cognitive impairment and Alzheimer’s disease: a review. Curr
cluster in the cluster level analysis can include voxels that showed Opin Neurol 21:83–92.
a statistical tendency because of the noise or, in our study’s case, Collignon A, Maes F, Delaere D, Vandermeulen D, Suetens P, Marchal G
that showed a statistical tendency because of other effects (such as (1995) Automated multi-modality image registration based on informa-
time-lapse change). tion theory. In: The proceedings of information processing in medical
There are a few limitations to this study. One is that the sub- imaging (Bizais Y, Barillot C, DiPaola R, eds). Dordrecht, The Nether-
lands: Kluwer Academic.
jects’ characteristics might affect the results of morphological
Crottaz-Herbette S, Anagnoson RT, Menon V (2004) Modality effects in
data, because different subject characteristics (e.g., age) affect verbal working memory: differential prefrontal and parietal responses to
differential time-lapse changes in brain structure (Shaw et al., auditory and visual stimuli. Neuroimage 21:340 –351.
2006). Other limitations are the limited number of participants Demerens C, Stankoff B, Logak M, Anglade P, Allinquant B, Couraud F, Zalc
and number of b value ⫽ 0 images in our protocol. In our study, B, Lubetzki C (1996) Induction of myelination in the central nervous
because of our MRI scanner’s limitation, only a single b value ⫽ 0 system by electrical activity. Proc Natl Acad Sci U S A 93:9887–9892.
image (compared with 32 b value ⫽ 1000 images) has been ac- Draganski B, Gaser C, Kempermann G, Kuhn HG, Winkler J, Büchel C, May
A (2006) Temporal and spatial dynamics of brain structure changes
quired, even though previous studies (Jones et al., 1999, 2002) during extensive learning. J Neurosci 26:6314 – 6317.
recommended that 10% of total images acquired be with lower Friston KJ, Holmes A, Poline JB, Price CJ, Frith CD (1996) Detecting acti-
diffusion weighting for precision in estimates of diffusivity. The vations in PET and fMRI: levels of inference and power. Neuroimage
low statistical power caused by these factors might prevent us 4:223–235.
Takeuchi et al. • Cognitive Training Impacts Structural Connectivity J. Neurosci., March 3, 2010 • 30(9):3297–3303 • 3303
Gaser C (2006) VBM Toolbox. Retrieved December 1, 2009 from McDonald WI, Sears TA (1970) The effects of experimental demyelination
http://dbm.neuro.uni-jena.de/vbm/. on conduction in the central nervous system. Brain 93:583–598.
Genovese CR, Lazar NA, Nichols T (2002) Thresholding of statistical maps Moseley M (2002) Diffusion tensor imaging and aging-a review. NMR in
in functional neuroimaging using the false discovery rate. Neuroimage Biomedicine 15:553–560.
15:870 – 878. Nuñez JL, Nelson J, Pych JC, Kim JHY, Juraska JM (2000) Myelination in
Goldman-Rakic PS (1988) Topography of cognition: parallel distributed the splenium of the corpus callosum in adult male and female rats. Brain
networks in primate association cortex. Annu Rev Neurosci 11:137–156. Res Dev Brain Res 120:87–90.
Goldman-Rakic PS (1994) Working memory dysfunction in schizophrenia. Oldfield RC (1971) The assessment and analysis of handedness: the Edin-
J Neuropsychiatry Clin Neurosci 6:348 –357. burgh inventory. Neuropsychologia 9:97–113.
Good CD, Johnsrude I, Ashburner J, Henson RNA, Friston KJ, Frackowiak Olesen PJ, Nagy Z, Westerberg H, Klingberg T (2003) Combined analysis of
RSJ (2001) Cerebral asymmetry and the effects of sex and handedness DTI and fMRI data reveals a joint maturation of white and grey matter in
on brain structure: a voxel-based morphometric analysis of 465 normal a fronto-parietal network. Brain Res Cogn Brain Res 18:48 –57.
adult human brains. Neuroimage 14:685–700. Olesen PJ, Westerberg H, Klingberg T (2004) Increased prefrontal and pa-
Hayasaka S, Nichols TE (2003) Validating cluster size inference: random rietal activity after training of working memory. Nat Neurosci 7:75–79.
field and permutation methods. Neuroimage 20:2343–2356. Perrig WJ, Hollenstein M, Oelhafen S (2009) Can we improve fluid intelli-
Hsu YY, Huang CM, Kuan WC, Chen HM, Wai YY, Wan YL, Liu HL (2007) gence with training on working memory in persons with intellectual dis-
Spatial normalization of fMRI results using study-based EPI and T1- abilities? J Cogn Educ Psychol 8:148 –164.
weighted brain templates. Proc Intl Soc Magn Reson Med 15:1860. Peters A (2002) The effects of normal aging on myelin and nerve fibers: a
Jaeggi SM, Buschkuehl M, Jonides J, Perrig WJ (2008) Improving fluid in- review. J Neurocytol 31:581–593.
telligence with training on working memory. Proc Natl Acad Sci U S A Pfefferbaum A, Sullivan EV (2003) Increased brain white matter diffusivity
105:6829 – 6833. in normal adult aging: relationship to anisotropy and partial voluming.
Jäncke L, Koeneke S, Hoppe A, Rominger C, Hänggi J (2009) The architec- Magn Reson Med 49:953–961.
ture of the golfer’s brain. PLoS ONE 4:e4785. Poline JB, Worsley KJ, Evans AC, Friston KJ (1997) Combining spatial ex-
Jones DK, Horsfield MA, Simmons A (1999) Optimal strategies for measur-
tent and peak intensity to test for activations in functional imaging. Neu-
ing diffusion in anisotropic systems by magnetic resonance imaging.
roimage 5:83–96.
Magn Reson Med 42:515–525.
Salat DH, Tuch DS, Greve DN, van der Kouwe AJW, Hevelone ND, Zaleta
Jones DK, Williams SCR, Gasston D, Horsfield MA, Simmons A, Howard R
AK, Rosen BR, Fischl B, Corkin S, Rosas HD, Dale AM (2005) Age-
(2002) Isotropic resolution diffusion tensor imaging with whole brain
related alterations in white matter microstructure measured by diffusion
acquisition in a clinically acceptable time. Hum Brain Mapp 15:216 –230.
tensor imaging. Neurobiol Aging 26:1215–1227.
Jones DK, Symms MR, Cercignani M, Howard RJ (2005) The effect of filter
Selemon LD, Goldman-Rakic PS (1988) Common cortical and subcortical
size on VBM analyses of DT-MRI data. Neuroimage 26:546 –554.
targets of the dorsolateral prefrontal and posterior parietal cortices in the
Juraska JM, Kopcik JR (1988) Sex and environmental influences on the size
and ultrastructure of the rat corpus callosum. Brain Res 450:1– 8. rhesus monkey: evidence for a distributed neural network subserving
Kanaan RAA, Kim JS, Kaufmann WE, Pearlson GD, Barker GJ, McGuire PK spatially guided behavior. J Neurosci 8:4049 – 4068.
(2005) Diffusion tensor imaging in schizophrenia. Biological Psychiatry Shaw P, Greenstein D, Lerch J, Clasen L, Lenroot R, Gogtay N, Evans A,
58:921–929. Rapoport J, Giedd J (2006) Intellectual ability and cortical development
Kawashima R, Okita K, Yamazaki R, Tajima N, Yoshida H, Taira M, Iwata K, in children and adolescents. Nature 440:676 – 679.
Sasaki T, Maeyama K, Usui N, Sugimoto K (2005) Reading aloud and Shen S, Szameitat AJ, Sterr A (2007) VBM lesion detection depends on the
arithmetic calculation improve frontal function of people with dementia. normalization template: a study using simulated atrophy. Magn Reson
J Gerontol A Biol Sci Med Sci 60:380 –384. Imaging 25:1385–1396.
Klingberg T (2006) Development of a superior frontal-intraparietal net- Shrager P (1993) Axonal coding of action potentials in demyelinated nerve
work for visuo-spatial working memory. Neuropsychologia 44:2171– fibers. Brain Res 619:278 –290.
2177. Swadlow HA (1985) Physiological properties of individual cerebral axons
Klingberg T, Forssberg H, Westerberg H (2002) Increased brain activity in studied in vivo for as long as one year. J Neurophysiol 54:1346 –1362.
frontal and parietal cortex underlies the development of visuospatial Uchida S, Kawashima R (2008) Reading and solving arithmetic problems
working memory capacity during childhood. J Cogn Neurosci 14:1–10. improves cognitive functions of normal aged people: a randomized con-
Koenig HL, Schumacher M, Ferzaz B, Thi AN, Ressouches A, Guennoun R, trolled study. Age 30:21–29.
Jung-Testas I, Robel P, Akwa Y, Baulieu EE (1995) Progesterone synthe- Wager TD, Smith EE (2003) Neuroimaging studies of working memory: a
sis and myelin formation by Schwann cells. Science 268:1500 –1503. meta-analysis. Cogn Affect Behav Neurosci 3:255–274.
Koester J (1985) Functional consequences of passive membrane properties Waxman SG (1980) Determinants of conduction velocity in myelinated
of the neuron. In: Principles of neural science (Kandell ER, Schwartz JH, nerve fibers. Muscle Nerve 3:141–150.
eds), pp 66 –74. Amsterdam: Elsevier. Wingfield A, Stine EAL, Lahar CJ, Aberdeen JS (1988) Does the capacity of
Le Bihan D (2003) Looking into the functional architecture of the brain with working memory change with age? Exp Aging Res 14:103–107.
diffusion MRI. Nat Rev Neurosci 4:469 – 480. Yakovlev PI, Lecours AR (1967) The myelogenetic cycles of regional matu-
Markham JA, Greenough WT (2004) Experience-driven brain plasticity: ration of the brain. In: Regional development of the brain in early life
beyond the synapse. Neuron Glia Biol 1:351–363. (Minkowski A, ed), pp 3–70. Philadelphia: Davis.