Professional Documents
Culture Documents
Neuro Task-Dependent Effects
Neuro Task-Dependent Effects
Neuro Task-Dependent Effects
Brain Stimulation
journal homepage: www.brainstimjrnl.com
Original Articles
Laboratory for Cognition and Neural Stimulation, University of Pennsylvania, Philadelphia, PA, USA
Center for Cognitive Neuroscience, University of Pennsylvania, Philadelphia, PA, USA
c
Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 August 2014
Accepted 29 October 2014
Available online 25 November 2014
Background: Prior investigations employing transcranial direct current stimulation (tDCS) have shown
that stimulation can elicit subsequent improvement on tests of various cognitive abilities, including
working memory. While stimulation parameters such as intensity and duration are known to determine
the effects of tDCS, the degree to which stimulation effects are inuenced by the nature of cognitive
activities during stimulation remains unclear.
Objective/hypothesis: To determine whether manipulating the working memory load of a task performed
during stimulation would modulate tDCS-induced enhancement of performance on a different, related
measure after stimulation.
Methods: In two separate but closely related sham-controlled experiments, two groups of healthy
subjects underwent anodal tDCS (2 mA) of the left dorsolateral prefrontal cortex (DLPFC) for 20 min. In
Experiment 1, subjects (n 11) trained on a letter 3Back task during stimulation. In Experiment 2
subjects (n 11) trained on a letter 1Back task, which resembled the 3Back task but featured a lower
working memory load. In both experiments, before and after stimulation, subjects completed an
adjusting Paced Auditory Serial Addition Task (A-PASAT). Both the experimenter and subjects were blind
to stimulation conditions in both experiments.
Results: Subjects were both faster and more accurate on the A-PASAT task after receiving real tDCS paired
with 3Back training (Experiment1) compared to sham3Back, real1Back, and sham1Back conditions.
Conclusions: The cognitive demands of a task performed during tDCS can inuence the effects of tDCS on
post-stimulation performance. This nding has direct relevance to the use of tDCS as an investigative tool
in cognitive neuroscience and as a therapy.
2015 Elsevier Inc. All rights reserved.
Keywords:
tDCS
Working memory
Cognitive enhancement
Cognitive remediation
Introduction
While a growing body of experiments have shown that transcranial direct current stimulation (tDCS) can be employed to
modulate a variety of complex cognitive abilities [1e4], the
methods employed in this large and growing body of work remain
heterogenous. This variability reects, in part, incomplete understanding of how different properties of tDCS such as current intensity [5], duration of stimulation, electrode placement, and
* Corresponding author. Goddard Laboratories, Room 518, University of Pennsylvania, 3710 Hamilton Walk, Philadelphia, PA 19104, USA. Tel.: 1 215 573 7090;
fax: 1 215 898 1982.
E-mail address: Roy.Hamilton@uphs.upenn.edu (R. Hamilton).
http://dx.doi.org/10.1016/j.brs.2014.10.018
1935-861X/ 2015 Elsevier Inc. All rights reserved.
254
Counterbalanced
Anodal tDCS
Sham
Visit 1
Visit 2
> 48 hours
A-PASAT 3 Back
Visit 1
Visit 2
Experiment 2
1 Back
A-PASAT
A-PASAT 1 Back
Counterbalanced
Subjects
Eleven right-handed young adults (3 females) ages 18e25 years
(21.8 2.7 years) with no history of neurological or psychiatric
disorders were enrolled in Experiment 1. Subjects completed an
average of 15.6 years of education (SD 1.5). None were taking
prescribed anti-depressants or other psychoactive medications, and
none had contraindications to receiving tDCS. This study was
approved by the Institutional Review Board of the University of
Pennsylvania. All subjects provided informed consent.
A-PASAT
> 48 hours
A-PASAT
Experiment 1
Stimulation parameters
Experiment 1
A-PASAT
nBack
Time
a
o
1 Back target
3 Back target
a
Figure 2. Training task: Letter nBack performed during stimulation; 3Back was carried
out in Experiment 1 and 1Back was carried out in Experiment 2.
occurred 3 trials prior (Fig. 2). If the letter did not match, subjects
were instructed to press 1 while the letter was still on the screen.
A response was required for each stimulus that appeared on the
screen. For the 20-min stimulation period, the task consisted of 43%
targets (328 trials) and was divided into four 191 trial (4.25 min)
blocks, separated by 1-min breaks. During breaks, current was still
delivered and subjects cumulative accuracy up to that point was
displayed on the screen. To encourage adequate subject effort, those
who achieved a 75% or higher cumulative accuracy received additional compensation ($10). To reduce the inuence of practice
effects, 2 different versions of the 3Back were generated. The order
in which subjects performed different versions of the 3back was
counterbalanced.
Experiment 2
255
(in Experiment 1) or the 1Back (in Experiment 2) during stimulation, subjects practiced the task for 22 trials (7 targets), lasting
about 2-min, to ensure that they understood and followed the instructions appropriately. During practice, an accuracy of 65% was
required for the 3Back and 90% accuracy was required for the 1Back,
before subjects could advance to the stimulation sessions. Similarly,
during subjects rst visits, they practiced on the A-PASAT for 200
trials to familiarize them with the task. However, an accuracy
threshold was not implemented during practice for this task. In
Experiment 1, subjects completed practice trials, followed by a full
version of the A-PASAT. Subjects then received 20-min of stimulation (real or sham) and concurrent training with the 3Back task,
followed by completion of a second full version of the A-PASAT. For
the subsequent visit, subjects completed another full version of the
A-PASAT, followed by the stimulation (sham or real) that they did
not receive during their rst visit, again paired with the 3Back task,
and followed by another administration of the A-PASAT. Experiment 2 shared the same sequence of events, except that subjects
received training on the 1Back task concurrently with tDCS instead
of the 3Back (Fig. 1).
Results
SPSS v. 20 and R statistical packages were employed to analyze
and display the behavioral data.
To examine the main hypothesis that anodal stimulation paired
with an engaging working memory training task (3Back) would
facilitate subsequent working memory performance more than a
less demanding training task (1Back), we ran a 2 2 mixed design
ANOVA with change in the overall A-PASAT accuracy (across all ISIs)
as the dependent variable. The results of Experiment 1 and 2 were
combined for this analysis. Stimulation condition (real anodal,
sham) was included as the within-subject factor and the training
Subjects
Twelve right-handed young adults (5 female) ages of 18e25
(19.8 1.5 years) with no history of neurological or psychiatric
disorders were enrolled in Experiment 2; one subject had to be
excluded because of technical errors. Included subjects completed
an average of 14.1 years (1.0) years of education. The exclusion
criteria were identical to those used in Experiment 1.
Training task e letter 1Back
Subjects completed the 1Back task during stimulation in
Experiment 2 (Fig. 1). Equipment and software for displaying
stimuli were the same as in Experiment 1. The task consisted of 10
lower-case letters [a, b, j, z, k, t, o, p, x, r] presented in pseudorandom order over 764 trials (20-min). As in Experiment 1, stimuli
ashed on the screen for 1300 ms, followed by a 50 ms blank
screen. Subjects were instructed to identify whether a letter had
occurred twice in a row and press 2 while the second letter was
still on the screen (Fig. 2); otherwise, they were instructed to press
1. To maintain consistency with the 3Back task in Experiment 1,
the task was broken into 4, 4.25 min blocks separated by 3, 1-min
breaks. During breaks, subjects were provided with their cumulative accuracy. In line with 3Back training task, 2 different versions of
the 1Back were generated to reduce practice effects. The order in
which subjects performed different versions of the 1back was
counterbalanced.
Procedures for Experiments 1 and 2
During the rst visit, all subjects completed practice sessions
with the 3Back in Experiment 1, the 1Back in Experiment 2 and the
A-PASAT in both Experiment 1 and 2. Prior to performing the 3Back
256
Figure 4. Experiment 1: (A) Change in A-PASAT accuracy (%) per ISI group after training with 3Back task during stimulation. Based on subjects performance at baseline, the ISI
groups consisting of ISI range 2400e1100 ms was characterized as Hard conditions, and those consisting of 1080e220 ms as Easy conditions. (B) Grouping Hard and Easy ISI
conditions into Hard and Easy difculty groups. (C) A-PASAT trial frequencies across all ISI groups. Vertical lines represent standard errors, * reects statistical signicance at
P < 0.05), ** reects statistical signicance at P < 0.01, and y reects trend toward signicance (P < 0.1).
sham tDCS was 74.3 (11.8%); paired t-test revealed that the performance did not differ between real anodal and sham tDCS conditions (P > 0.05).
As expected, baseline accuracy diminished as the difculty of
A-PASAT increased (with the shortening of the ISIs) across the ISI
groups. Specically, baseline accuracy for ISI groups ranging from
1080 to 220 ms was below 75%; we characterized these ISI groups
as Hard conditions (average accuracy: 49.1 32%; range:
71.7e21.8%). ISI groups comprising 2400e1100 ms, for which the
average baseline accuracy was 75% or above, were characterized as
Easy conditions (average accuracy: 91.5 12%; range:
98.7e85.4%). We next evaluated differences in A-PASAT accuracies
across different ISI groups between the real anodal and sham
stimulation conditions. A repeated measures ANOVA with ISI
groups (2400e2200, ., 420e220) and stimulation (real, sham) as
xed factors revealed signicant main effects (P < 0.05) as well as
interaction between these variables (F9,90 2.28, P 0.024).
Posthoc paired t-tests revealed that in 3 out of 4 Hard ISI conditions,
differences in accuracy were greater in the real stimulation condition compared to the sham condition (P < 0.05; Fig. 4A); for a single
257
paired t-test revealed that the difference between real anodal and
sham tDCS conditions was not signicant (P > 0.05).
Accuracy diminished as the difculty level of A-PASAT increased
(with the shortening of the ISIs) across the ISI groups. The classication of Hard and Easy ISI conditions based on the average
baseline accuracy was similar to Experiment 1. The average accuracy at baseline for Hard ISI conditions was 39.7 30.1% (range:
67.3e5.4%), and that for the Easy conditions was 91.7 11.8%
(range: 96.4e88.9%).
A repeated measures ANOVA with ISI groups (2400e2200, .,
420e220) and stimulation (real, sham) revealed that none of the
main effects were signicant, and also the interaction between ISI
groups and stimulation was not signicant (all P > 0.05; Fig. 5A).
Although this interaction was not signicant, we compared the
performance across stimulation conditions in the Hard difculty
group, which revealed a trend toward somewhat better performance after real stimulation compared to the sham (d 5.8%;
t 1.32, P 0.097; Fig. 5B).
Discussion
We provide compelling evidence that, in addition to other
well-established stimulation parameters, the cognitive enhancement capacity of tDCS may also depend on the nature of the task
that is performed during stimulation. When administered concurrently with anodal tDCS of the left DLPFC, the letter 3Backda
task that robustly engages networks involved in working
memorydincreased prociency on the A-PASAT, a separate task
that relies on working memory. By contrast, when the subjects were
trained on the 1Backda task that is less engaging than the 3Back
with respect to working memorydno improvement on the
A-PASAT was observed. Insofar as the only difference between
the two experimental conditions was the working memory load of
the task performed during stimulation, we argue that the positive
effects of tDCS were dependent on the cognitive demands of the
task administered concurrently with stimulation.
Functional neuroimaging studies demonstrate that activation of
working memory-related brain regions, including the left DLPFC, is
highly correlated with the difculty of the nBack task (as indicated
by the size of n) [16,21]. We suggest that in this study endogenous
Figure 5. Experiment 2: (A) Change in A-PASAT accuracy (%) per ISI group after training with 1Back task during stimulation. Based on subjects performance at baseline, the ISI
groups consisting of ISI range 2400e1100 ms was characterized as Hard conditions, and those consisting of 1080e220 ms as Easy conditions. (B) Grouping Hard and Easy ISI
conditions into Hard and Easy difculty groups. Vertical lines represent standard errors, and y reects trend toward signicance (P < 0.1).
258
cognition; additional studies that further dene the role of taskdependency are clearly merited.
Acknowledgments
We would like to thank the University Scholars program at the
University of Pennsylvania e Center for Undergraduate Research for
funding this research. We would also like to thank Gabriella Garcia
and Olufunsho Faseyitan for their contribution in the implementation of the project.
References
[1] Fregni F, Boggio PS, Nitsche M, et al. Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory. Exp Brain Res
2005;166(1):23e30.
[2] Sparing R, Dafotakis M, Meister IG, Thirugnanasambandam N, Fink GR.
Enhancing language performance with non-invasive brain stimulation e a
transcranial direct current stimulation study in healthy humans. Neuropsychologia 2008;46(1):261e8.
[3] Moos K, Vossel S, Weidner R, Sparing R, Fink GR. Modulation of top-down
control of visual attention by cathodal tDCS over right IPS. J Neurosci
2012;32(46):16360e8.
[4] Marshall L, Molle M, Hallschmid M, Born J. Transcranial direct current
stimulation during sleep improves declarative memory. J Neurosci
2004;24(44):9985e92.
[5] Iyer MB, Mattu U, Grafman J, Lomarev M, Sato S, Wassermann EM. Safety and
cognitive effect of frontal DC brain polarization in healthy individuals.
Neurology 2005;64(5):872e5.
[6] Batsikadze G, Moliadze V, Paulus W, Kuo MF, Nitsche MA. Partially nonlinear stimulation intensity-dependent effects of direct current stimulation
on
motor
cortex
excitability
in
humans.
J
Physiol
2013;591(7):1987e2000.
[7] Boggio PS, Ferrucci R, Rigonatti SP, et al. Effects of transcranial direct current
stimulation on working memory in patients with Parkinsons disease. J Neurol
Sci 2006;249(1):31e8.
[8] Dockery CA, Hueckel-Weng R, Birbaumer N, Plewnia C. Enhancement of
planning ability by transcranial direct current stimulation. J Neurosci
2009;29(22):7271e7.
[9] Andrews SC, Hoy KE, Enticott PG, Daskalakis ZJ, Fitzgerald PB. Improving
working memory: the effect of combining cognitive activity and anodal
transcranial direct current stimulation to the left dorsolateral prefrontal cortex. Brain Stimul 2011;4(2):84e9.
[10] Segrave RA, Arnold S, Hoy K, Fitzgerald PB. Concurrent cognitive control
training augments the antidepressant efcacy of tDCS: a pilot study. Brain
Stimul 2014;7(2):325e31.
[11] Ohn SH, Park CI, Yoo WK, et al. Time-dependent effect of transcranial direct
current stimulation on the enhancement of working memory. Neuroreport
2008;19(1):43e7.
[12] Kincses T, Antal A, Nitsche M, Bartfai O, Paulus W. Facilitation of probabilistic
classication learning by transcranial direct current stimulation of the prefrontal cortex in the human. Neuropsychologia 2003;42:113e7.
[13] Bikson M, Rahman A. Origins of specicity during tDCS: anatomical, activityselective, and input-bias mechanisms. Front Hum Neurosci 2013:7.
[14] DEsposito M, Aguirre GK, Zarahn E, Ballard D, Shin RK, Lease J. Functional MRI
studies of spatial and nonspatial working memory. Cogn Brain Res
1998;7(1):1e13.
[15] Mottaghy FM, Krause BJ, Kemna LJ, et al. Modulation of the neuronal circuitry
subserving working memory in healthy human subjects by repetitive transcranial magnetic stimulation. Neurosci Lett 2000;280(3):167e70.
[16] Nagel IE, Preuschhof C, Li SC, et al. Load modulation of BOLD response and
connectivity predicts working memory performance in younger and older
adults. J Cogn Neurosci 2011;23(8):2030e45.
[17] Filmer HL, Mattingley JB, Dux PE. Improved multitasking following prefrontal
tDCS. Cortex 2013;49(10):2845e52.
[18] Karim AA, Schneider M, Lotze M, Veit R, Sauseng P, Braun C, et al. The truth
about lying: inhibition of the anterior prefrontal cortex improves deceptive
behavior. Cereb Cortex 2010;20(1):205e13.
[19] Weiss M, Lavidor M. When less is more: evidence for a facilitative
cathodal tDCS effect in attentional abilities. J Cogn Neurosci
2012;24(9):1826e33.
[20] Tombaugh TN. A comprehensive review of the paced auditory serial addition
test (PASAT). Arch Clin Neuropsychol 2006;21(1):53e76.
[21] Heinzel S, Lorenz RC, Brockhaus WR, et al. Working memory load-dependent
brain response predicts behavioral training gains in older adults. J Neurosci
2014;34(4):1224e33.
[22] Nitsche MA, Paulus W. Excitability changes induced in the human motor
cortex by weak transcranial direct current stimulation. J Physiol
2000;527(3):633e9.
[28]
[29]
[30]
[31]
259