Abstract
Working memory (WM) training paired with transcranial direct current stimulation (tDCS) can improve executive function in older adults. The unclear mechanism of tDCS likely depends on tDCS intensity, and task relevant genetic factors (e.g., for WM: COMT val158met, DAT, BDNF val66met). Higher tDCS intensity does not always lead to greater cognitive gains, and genetic polymorphisms may modulate tDCS-linked WM improvements. To evaluate these factors, 137 healthy older adults provided DNA samples and received Visual and Spatial WM training paired with tDCS (sham, 1, 1.5, 2 mA). After one session of tDCS, significant group differences in WM performance were predicted by COMT val158met status. One month after training, there was a significant interaction of tDCS intensity, COMT genotype, and WM task. Specifically, val/val homozygotes benefited most from 1.5 mA tDCS on Visual WM and from 1 mA tDCS on Spatial WM. For met/met homozygotes, 2 mA resulted in significantly poorer performance compared to 1.5 mA on Spatial WM. While this pattern was observed with relatively small sample sizes, these data indicate that variations in COMT val158met may predict the nature of WM improvement after initial and longitudinal tDCS. This contributes to our understanding of the underlying mechanism by which tDCS affects behaviour.
Similar content being viewed by others
Introduction
Working memory (WM) is essential for most cognitive tasks, yet is capacity limited, declines with age, and resists improvement. The importance of WM has prompted an industry devoted to enhancing WM, despite mixed evidence of efficacy1,2. One promising approach involves pairing WM training with non-invasive brain stimulation, including transcranial direct current stimulation (tDCS)3. Several longitudinal WM training + tDCS studies consistently show improvement in trained tasks4,5,6 and some even report transfer to untrained WM tasks7,8,9,10,11,12. Unfortunately, there is no comprehensive understanding of the mechanism underlying tDCS effects on behaviour. This gap in knowledge limits the translational potential of tDCS. What is known is that tDCS alters synaptic plasticity across many neurotransmitters and neuromodulators (reviewed in:13,14,15,16). At a network level, tDCS strengthens functional connectivity6,17,18,19,20,21,22,23,24,25,26,27,28,29,30 and enhances neural synchrony31. Importantly, factors such as educational attainment32, WM capacity33, and motivation34 also significantly influence responses to the same WM-tDCS protocol. Because such factors predict different responses to a single tDCS protocol, averaging across heterogeneous participants obscures tDCS effects. This likely contributes to inconsistent findings and may explain recent meta-analyses challenging the usefulness of tDCS35,36,37,38,39.
Additionally, the mechanism of tDCS likely differs as a function of task demands, stimulation intensity, electrode placement, and number of sessions. With regard to tDCS intensity, non-linear effects of tDCS intensity have been demonstrated, such that increased tDCS intensity does not necessarily equate to increased effectiveness40,41. Additionally, the success of varying tDCS intensities is influenced by the population targeted. For example, researchers studying healthy younger adults have reported that lower tDCS intensity (e.g. 1 mA) elicits greater WM gains than higher intensity31 whereas other researchers have found that higher intensity (e.g. 2 mA) is necessary to elicit WM gains in clinical populations42. In our previous work, we demonstrated that older adults are more similar to clinical populations in their requirement of higher tDCS intensity (e.g. 2 mA) for significant cognitive improvement12, but we would not necessarily expect linear improvements with increasingly higher intensities, as the effect of tDCS intensity on WM gains is likely influenced by other factors, especially in aging. At the cellular and network levels, WM training necessarily involves frontoparietal networks43,44 interacting with striatal regions45,46,47,48 and relying on dopamine (DA) signalling49. This establishes the rationale for extending work showing that tDCS modulates DA signalling in prefrontal regions via the D1 receptor50 and in the striatum, primarily via the D2 receptor51. Furthermore, tDCS modulates secretion of brain derived neurotropic factor (BDNF)52, a protein which supports memory and learning53,54 and perhaps WM53,55. Identifying how tDCS-linked WM improvement is influenced by genetic variability within genes that are known to have functional effects on cognitive tasks will enhance our understanding of individual differences following tDCS interventions and reveal aspects of the underlying neural mechanism.
Two common single nucleotide polymorphisms significantly modulate DA signalling in WM relevant networks with previous work describing interactions between genotype and tDCS on non-WM tasks (reviewed in56,57,58,59). The first and most studied polymorphism with regard to WM codes for catechol-o-methyl transferase (COMT), the enzyme primarily responsible for DA metabolism in prefrontal cortex (reviewed in:60,61,62). A common single point mutation (val158met) modulates the rate of DA metabolism at the synapse: val/val is rapid, whereas each additional met allele slows enzymatic activity60,63,64. This mutation predicts performance on WM and other executive function tasks65,66,67,68,69,70 in a task-dependent manner: val/val participants show greater cognitive flexibility benefiting task switching, whereas met/met homozygotes show enhanced cognitive stability, benefiting maintenance71. Age enhances these COMT effects72,73,74,75, such that val + older adults have worse spatial updating76, fluid intelligence, processing speed, and episodic memory compared to met + adults75. Furthermore, val + participants have lower baseline WM performance across various tasks but improve more than met/met individuals77. Possessing a met allele has been associated with a higher stress response, which in turn leads to reduced WM performance under acute stress78. However, one recent study found no WM impairment in met/met carriers, nor did early life stressful and traumatic events correlate with WM performance79. Several studies applying 1 mA tDCS to the left dorsolateral prefrontal cortex (PFC) and examining COMT genotype show that met/met carriers exhibit poorer cognitive flexibility following a single session of anodal tDCS80, whereas val/val carriers exhibited poorer response inhibition following cathodal tDCS81. These findings provide some support for the perspective that genotype does interact with the cognitive effects of tDCS.
A second common polymorphism relevant to WM and WM performance in older adulthood is the number of tandem repeats in a portion of the dopamine transporter (DAT) gene82. DAT facilitates dopamine (DA) clearing from the synapse for repackaging into new vesicles and is present in all DA networks throughout the brain83. More repeats are associated with higher DAT concentrations, less extracellular DA, and reduced striatal signalling84. Variations in DAT regulate pre- and postsynaptic DA concentration85, particularly in the striatum86,87,88,89, and frontostriatal interactions predict WM training gains48,90,91,92,93,94,95.
A third polymorphism determining tDCS response is brain derived neurotropic factor (BDNF val66met). Here, there is less accord regarding the effects on WM; BDNF is closely associated with episodic memory96, and a lack of BDNF is associated with age-related cognitive decline97. Older val/val adults are more susceptible to distractors98, and while met + participants performed better at WM tasks99, they were worse on tasks of processing speed, delayed recall, and general intelligence100. The most relevant recent finding is that anodal tDCS appears to increase BDNF in older adults (reviewed in:52) and may differentially facilitate benefits across genotypes.
Collectively, emerging findings suggest that common polymorphisms may influence tDCS effects. Understanding these contributions may elucidate an underlying mechanism of tDCS-linked benefits and may facilitate a priori identification of participants who are likely to benefit from tDCS. By combining data from two published WM training + tDCS studies we gained greater statistical power to evaluate whether these three polymorphisms predicted WM training gains9,12. Furthermore, these studies parametrically varied tDCS intensity (sham, 1.0 mA, 1.5 mA, or 2.0 mA), enabling us to investigate the dose-dependency of effects and test whether more is better in these WM tasks.
Results
For all results, Mixed-Method ANOVAs were completed comparing within (WM tasks) and between (tDCS intensity, genotypes) subject factors. All post-hoc pairwise analyses were conducted using Bonferroni corrections for multiple comparisons.
Day 1 Performance
To determine if genotype (COMT val158met, DAT, or BDNF val66met) predicted initial tDCS effects on the WM training tasks, Day 1 performance values were subjected to separate Mixed-Method ANOVAs: 2 (Task Type: Visual WM, Spatial WM) × 4 (tDCS intensity: Sham, Active1, Active1.5, Active2) x genotype. In these separate analyses, genotype was either 2 levels (DAT: 9 + DAT, 10 + DAT) or 3 levels (BDNF: val/val, val/met, met/met; COMT: val/val, val/met, met/met). Because neither the BDNF nor the DAT had significant main effects (both F values < 1, p values > 0.05) nor any significant interactions at baseline or after training (all p values > 0.17), these analyses are not further discussed. For the breakdown of tDCS Group by COMT genotype, see Table 1.
Results from a Mixed Method ANOVA (within-subject factor: WM task; between-subject factors: tDCS intensity and COMT genotype) revealed a significant main effect of WM task, such that for all participants, accuracy was higher on the Visual WM task (Mean (M) = 0.53, (Standard Error of the Mean (SE) (0.01)) compared to the Spatial WM task (M = 0.46 (0.01)), F1,125 = 13.73, p < 0.001, \({\eta }_{p}^{2}=0.10\)). The main effect of tDCS intensity approached significance (F3,125 = 2.55, p = 0.059, \({\eta }_{p}^{2}=0.058\)). There was no significant main effect of COMT genotype (F2,125 = 2.18, p = 0.12). There was, however, a significant COMT genotype x WM Task interaction (F(2,125) = 6.62, p = 0.002, \({\eta }_{p}^{2}=0.10\)). Bonferroni-corrected pairwise analyses revealed that on the Visual WM task, the COMT val/val (M = 0.55 (0.04)) and val/met (M = 0.54 (0.02)) groups had slightly better accuracy than the met/met group (M = 0.51 (0.03)), although these performance differences were not significant, p values > 0.41. Significant differences were observed on the Spatial WM task. The val/val group (M = 0.36 (0.03)) had significantly poorer accuracy than the val/met group (M = 0.47 (0.02)), p = 0.001 and the met/met group (M = 0.51 (0.03)), p < 0.001; see Fig. 1. No significant differences existed between the val/met group and the met/met group, p = 0.18. No other interactions approached significance (all p’s > 0.18).
Follow-up Accuracy
To identify interactions between longitudinal tDCS and genotype, a second set of analyses examined the change in performance from Day 1 to follow-up one month after the end of training and tDCS. Again, because neither BDNF nor DAT showed significant main effects or interactions, these analyses are not discussed.
Results from a Mixed Method ANOVA (within-subject factor: WM task; between-subject factors: tDCS intensity and COMT genotype) found no significant main effects of tDCS intensity (F3,125 = 1.75, p = 0.16), or WM Task (F1,125 = 2.22, p = 0.14). There was a significant main effect of COMT genotype (F2,125 = 4.44, p = 0.01, \({\eta }_{p}^{2}=0.07\)). Across tasks, the COMT val/val group (M = 0.18 (0.02)) showed significantly greater improvement than the val/met group (M = 0.11, (0.01)), p = 0.004 and the met/met group (M = 0.09 (0.02)), p = 0.01). No differences existed between the val/met group and the met/met group, p = 0.38. There was also a significant COMT genotype x WM task interaction (F2,125 = 5.14, p = 0.007, \({\eta }_{p}^{2}=0.08\)). Pairwise comparisons revealed that, on the Visual WM task, the val/val group (M = 0.13 (0.03)) and val/met group (M = 0.13, (0.02)) had less improvement than the met/met group (M = 0.14, (0.02)), but these differences did not reach statistical significance, p values > 0.68. However, there were significant between group differences on the Spatial WM task. The val/val group (M = 0.21, (0.04)) showed significantly greater improvement than the val/met group (M = 0.09, (0.02)), p = 0.006 and the met/met group (M = 0.02 (0.03)), p < 0.001. No significant differences existed between the val/met group and met/met group, p = 0.11; see Fig. 2. Although group differences were not significant on the Visual WM task, participants tended to show greater improvement in areas where they had been weakest. Importantly, because the WM tasks were difficult, performance was not affected by ceiling effects (overall accuracy across participants on the Visual WM task was 68.8% (SD: 0.17) and 55.6% (SD: 0.17) on the Spatial WM task).
Of greatest relevance, there was a significant 3-way interaction of tDCS intensity x COMT genotype x WM Task (F6,125 = 2.39, p = 0.03, \({\eta }_{p}^{2}=0.10\)) highlighting dose-dependent tDCS effects. To understand this complicated interaction, we examined change in performance as a function of tDCS intensity for each COMT genotype.
On the Visual WM task, in the val/val group, the Active 1.5 tDCS group (M = 0.25 (0.02)) had significantly greater gains than the Active 2 tDCS group (M = 0.06 (0.04)), p = 0.01. No other significant differences existed within the homozygous val/val group between tDCS groups, p values > 0.07. Additionally, no significant differences existed within the val/met group between tDCS groups, p values > 0.27 nor within the met/met group, p values > 0.42. On the Spatial WM task, within the val/val group, the Active 1 tDCS group (M = 0.39 (0.12)) group had significantly greater gains than the Sham tDCS group (M = 0.08 (0.06), p = 0.04). No other significant differences existed within the val/val group between tDCS groups, p values > 0.18. No significant differences existed within the val/met group between tDCS groups, p values > 0.33. Within the met/met group, the Active 1.5 tDCS group (M = 0.09 (0.04)) had significantly greater improvement than the Active 2 tDCS group (M = −0.08 (0.07)), p = 0.03. No other significant differences existed within the met/met group between tDCS groups, p values > 0.12; see Fig. 3.
We also examined change in performance as a function of COMT genotype in each tDCS group. On the Visual WM task, no significant differences existed between COMT groups within the Sham tDCS group, p values > 0.30, within the Active 1 tDCS group, p values > 0.32, within the Active 1.5 tDCS group, p values > 0.16, or within the Active 2 tDCS group, p values > 0.10. On the Spatial WM task, no significant differences existed between the COMT groups within the Sham tDCS group, p values > 0.58 or within the Active 1.5 tDCS group, p values > 0.36. Significant differences did exist within the Active 1 tDCS group. The val/val group (M = 0.39, (0.09)) had significantly greater improvement than the val/met group (M = 0.07, (0.05)), p = 0.003 and met/met group (M = 0.05 (0.06)), p = 0.003; see Fig. 3B. No differences existed within the Active 1 group between the val/met and met/met group, p = 0.79. There were also group differences within the Active 2 tDCS group. The val/val group (M = 0.21 (0.09)) had significantly greater gains than the met/met group (M = −0.08, (0.12)), p = 0.05. No other significant differences existed within the Active 2 group between the COMT groups within the Active 2 tDCS group, p values > 0.23.
Discussion
Older adults are interested in stabilizing or improving their cognitive ability. Non-invasive neurostimulation, including tDCS, is a welcome contender to achieve this goal. However, there is an incomplete understanding of the mechanisms underlying tDCS effects and unknown factors that may predict immediate and lasting tDCS effects. Here, we reported new analyses using data from two longitudinal studies that paired WM training with anodal frontoparietal tDCS in healthy older adults. We hypothesized that genetic polymorphisms - COMT val66met, DAT, and BDNF val66met – might predict the initial or the long-term effects of tDCS on visual and spatial WM. The results demonstrated no discernible effect of DAT or BDNF val66met but indicated that COMT val66met may influence the effects of WM training and tDCS. Interestingly, COMT did not have a simple influence, where one variation was optimal. Instead, COMT predicted initial WM performance after a single session of anodal frontoparietal tDCS and appeared to predict the nature of training related gains. Generally, each COMT group improved on a WM task where they needed improvement, although gains were higher on the Spatial WM task – a more challenging task for these participants. Perhaps more surprisingly, these COMT effects appeared to depend on tDCS intensity. At follow-up, the val/val group benefited most from intermediate intensity (1.5 mA) tDCS on Visual WM tasks but benefited most from lower intensity tDCS (1 mA) on Spatial WM tasks. The met/met group responded differently; high intensity tDCS (2 mA) elicited significantly poorer performance on the Spatial WM task compared to intermediate intensity (1.5 mA). Because there is a relationship between the COMT status and the effects of longitudinal tDCS paired with WM training, we interpret the findings as supporting the involvement of prefrontal DA signalling in the underlying tDCS-linked neuroplastic mechanism. They also indicate that more distal effects on DA in striatal regions via DAT, or effects on BDNF are less likely to account for tDCS-linked WM benefits.
Previous findings propose that ideal prefrontal DA levels are intermediate and follow an inverted U-shaped function49. Some of these data follow that prediction. On the Visual WM task the COMT val/val participants showed their greatest gains after intermediate intensity tDCS; see Fig. 3. However, this did not occur in val/val group where low tDCS intensity (1 mA) prompted the greatest gains on the Spatial WM task. Thus, the U-shaped function is difficult to fit to each genotype to select the ideal tDCS intensity across WM tasks. Presumably other factors, genetic or paradigmatic, contribute to tDCS effect on complex cognitive tasks like WM. These factors increase dopaminergic levels in the PFC, which in turn likely interact to a greater extent with the effects of tDCS to this region. The current findings support further investigation to eventually develop a clear relationship between tDCS intensity and task relevant genotypes. Achieving this ambitious goal requires more scientific inquiry, including how the training task and cognitive domain influence results. Furthermore, these data highlight the need for greater demographic collection in tDCS studies, as not all participants respond similarly to the same protocol32,34,101.
Why and how tDCS impacts WM performance matters. Although the effect of tDCS is mostly predictable in motor behaviour paradigms (reviewed in:102), the effect on higher order cognitive processes is more convoluted. Executive function tasks, like WM, require many regions working together (e.g., frontoparietal network for WM). More information is essential for determining how to optimize tDCS-based interventions for individuals. There is likely a role of COMT genotype in predicting tDCS-linked WM gains, yet this role is difficult to describe simply. A conservative approach may be to apply an intermediate dose of tDCS (1.5 mA), but it remains possible that gains in one domain (e.g. Visual WM) come with losses in another (e.g. Spatial WM). These data suggest that uniform tDCS parameters, such as current intensity, are not appropriate. The existence of a do-it-yourself tDCS community, individuals who self-administer commercial products or homemade tDCS devices to benefit from these nootropic therapies may be disappointed, but a Supercharged Brain is unlikely. Only with more research can we elucidate the full range of gains and losses across individuals and accurately recommend a tailor-made tDCS intervention.
One challenge in exploring genetic contributions to cognition is the need for a larger number of participants to achieve adequate power. Despite combining data from two studies with large sample sizes, several cells had very low N. Although this limitation reduced the generalizability of the present findings, it nevertheless provided provocative support for future investigation. We acknowledge that with additional power, a contribution of DAT and BDNF might emerge. To address this, future studies should consider replicating these methods with larger N or conducting genotyping across multiple research groups of tDCS researchers to accumulate sufficient data while being cost-effective. A related limitation is associated with statistical analysis of uneven and small tDCS x COMT groups. Although the use of parametric statistics does not necessarily violate statistical assumptions, it is a conservative approach that makes detection of significant differences between small groups challenging, and there is not a universally agreed-upon non-parametric analogue. Given low power, when we corrected for multiple comparisons, we saw limited differences between the COMT polymorphisms as a function of tDCS intensity. A substantially increased sample size may reveal additional tDCS intensity and COMT genotype interactions that we had insufficient power to detect. As an alternative statistical approach, we examined our data by subjecting the follow-up − baseline normalized difference scores ((follow-up − baseline)/(follow-up + baseline)) to a univariate Analysis of Co-variance (ANCOVA) with baseline performance as the covariate. This alternative approach was generally consistent with the results we described – which improved our confidence in the findings - but it is not consistent with how we previously analysed. Overall, we acknowledge that the small tDCS x COMT group sizes within our study render our findings as an early step in understanding the mechanism behind tDCS-linked WM training benefits. Subsequently, we remain tentative about our conclusions. Our hypotheses were exploratory and challenging to test, especially given the substantial cost and time necessary for adequate statistical power. Nevertheless, these results provide important insight into one of factors that should be included in future study designs to either mitigate or explain inter-subject variability in tDCS-linked responsiveness.
A third limitation of this work is that we tested one population: healthy older adults. Because aging induces grey matter loss, degrades white matter integrity103,104,105, and influences the gene expression73,75,76,82,97,100, may mean the aging population is not representative. Again, replication in a more diverse age range would better clarify how age predicts outcomes. Finally, the two studies we combined included slightly varied tDCS protocols. The participants completed different durations of tDCS + WM training following slightly different tDCS protocols. Finally, one subgroup received tDCS to PPC only without frontal lobe stimulation. Although tDCS affects large cortical regions, it is a reasonable criticism that the mechanism we propose highlights prefrontal activity, when in this subgroup we did not target PFC. However, based on the results of that study9, we propose that stimulation of any node of the frontoparietal network, likely influences the entire network. Nevertheless, by pairing slightly different studies, we improved our statistical power to explore our hypotheses. We acknowledge that better consistency with the protocol duration would strengthen our methodology and interpretation of findings. Importantly, however, future work can build upon these preliminary findings to confirm and clarify the role of frontal and parietal regions in tDCS-linked WM improvement and continue to optimize tDCS protocols. We note that tDCS may enhance empirically designed brain training106, and exercise107 as a beneficial approach for countering other age-related concerns such as cortical disconnection108, or reduced connectivity109. TDCS may thus serve to facilitate neuroplastic changes in the brain. However, more work is needed to clarify how to maximize cognitive benefits in each participant.
A conservative message for those interested in tDCS is: tDCS is complicated. Merely placing electrodes on the head and supplying current may not elicit positive results. There are influences of task demands, individual differences (education, age, anatomy, genotype, level of fatigue, diet, others yet to be considered), and stimulation parameters (duration, intensity, location) that must be better researched and understood before tDCS effects can be reliably predicted ahead of use. The weight that each of these influences affects the tDCS-linked cognitive benefits is also still unknown; however, the present results shed light on one likely mechanism, participant genotype, which may be responsible for some of the previously reported inconsistent or null tDCS findings.
Conclusion
Here, we demonstrated the influences of tDCS intensity, COMT genotype, and task demands on tDCS-linked WM training gains. Specifically, our results suggest PFC tDCS amplitude disproportionally affects those with different COMT genotypes based on task demands. This trend may be one of many which influence the variable effects reported in the neurostimulation literature specific to cognitive tasks. Despite the small sample size for some of the genotype and amplitude cells, we observed the largest effect in those with the val/val COMT polymorphism, where 1.5 mA of tDCS improved performance on Visual WM tasks, whereas 1 mA had the greatest improvement on Spatial WM tasks. These U-shaped dose-response findings were most apparent in the COMT val/val genotype; however, the same pattern was observed in the opposite direction for the COMT met/met genotype. These findings point toward a future where an individual’s genotype may play a role in specifying an appropriate tDCS-linked cognitive intervention. For WM, these data demonstrate that tDCS to frontoparietal networks likely relies on titrating DA. More studies are needed to identify who is likely to benefit from any tDCS protocol on a per task domain basis. Continued research exploring these influences findings may allow researchers and clinicians to capitalize on translational use of tDCS in cognitive maintenance or enhancement via interventions tailored for individual needs and characteristics.
Methods
Participants
Data were collected from 146 participants from a 10-day9 and a 5-day12 tDCS + WM training study. The 10-day study included 72 neurotypical right-handed older adult participants (mean age: 64.27; SD: 5.15; 38 female); 57 of whom provided viable DNA samples9. The 5-day study included 90 neurotypical right-handed older adults (mean age: 69.03; SD: 8.63; 48 female), and 89 participants provided usable DNA samples12. To ensure that assumptions were met for our statistical analyses, nine outliers were removed based on floor (<10%: N = 7) or ceiling (>90%: N = 2) baseline performance. 137 participants are included in analyses. No significant differences were observed between tDCS, DAT, COMT or BDNF groups in age or years of education (p values > 0.05).
10-Day and 5-Day Study Differences
There were some differences between the two studies (for full details, see:9,12). The 10-day study involved training over 10 consecutive weekdays, whereas the 5-day study was completed over 5 consecutive weekdays (see Fig. 4). Participants completed the same WM training tasks and genotyping procedure, but tDCS protocols differed (see tDCS Administration). All experimental protocols were carried out in accordance with the Declaration of Helsinki and with the recommendations of the University of Nevada’s Institutional Review Board. The University of Nevada’s Institutional Review Board approved all study procedures. All subjects provided informed written consent and received $15/hour.
WM Training Tasks
Each 45-minute training session immediately followed tDCS. Participants performed a Spatial and Visual recall WM task (see:9,12 for further paradigm details; Fig. 4). In the Spatial WM task, 5 images (e.g. corn, flower, fence, carrot, chicken; 3° visual angle) were presented (200 ms) in 5 of 16 possible locations. After a delay (4000 ms), 12 images appeared. Participants selected the 1 location that was occupied during the initial presentation. This task is more accurately a ‘visuospatial’ task, which requires participants to track spatial locations with visual input. To differentiate it from the Visual WM task, we refer it to it as the Spatial WM task. In the Visual WM task, 5 items were presented (2000 ms) and after a delay (500 ms), 16 items appeared. Participants selected the 1 item that was repeated from the initial stimulus array. Both tasks were un-speeded. Participants completed 2 blocks of 25 trials per task; tasks were presented in a counterbalanced order. The primary outcome measures were accuracy on Day 1 (i.e. baseline) and a calculated change in performance through normalized difference scores ((Follow-up accuracy − Day 1 accuracy)/(Follow-up accuracy + Day 1 accuracy)). This calculation has precedence in other WM training studies9,110,111,112. Note that these are WM tasks probed by recall, making chance performance less than 50%.
Genotyping Procedure
DNA samples were genotyped in an off-site commercial laboratory (GenoTek Labs, United States) using standard procedures (http://www.dnagenotek.com/US/genomicservices/genofind.html ). Two single nucleotide polymorphisms, COMT val158met (rs4680: val/val, val/met, met/met) and BDNF val66met (rs6265: val/val, val/met, met/met), and DAT variable number tandem repeat (VNTR), DAT1 (SLC6A: 9/9 or 9/10 Repeats (9 + DAT), 10/10 or 10/11 Repeats (10 + DAT)) were analysed. The DAT groupings were completed by grouping 9/9 and 9/10 together and 10/10 and 10/11 to form a 9 + DAT and 10 + DAT groups, as few participants were 9 allele homozygous (4 participants) and only 1 participant was 10/11. This is consistent with other analyses in the DAT literature84.The observed genotype frequencies were found to be consistent with the Hardy-Weinberg equilibrium (COMT: χ2 = 3.34; p > .05; val/val = 25, val/met = 74, met/met = 38; BDNF: χ2 = 1.79; p > .05; val/val = 84, val/met = 46, met/met = 7; DAT: χ2 = 2.65; p > .05; 9DAT = 67, 10DAT = 70). Participants were arrayed among the tDCS groups as follows: Sham (N = 40), Active1 (N = 28), Active1.5 (N = 41), Active2 (N = 28).
TDCS Administration
The neuroConn tDCS device provided stimulation (Eldith MagSteim, GmbH, Ilmenau, Germany). Current was delivered through two 5 × 7 cm electrodes encased in saline-soaked sponges; the reference electrode was placed on the contralateral cheek33,113,114,115,116,117,118. Participants were blind to their tDCS condition. In the 10-day study, participants received 10 minutes of 1.5 mA (Active 1.5) anodal tDCS to a) the right PFC (F4), b) right posterior parietal cortex (PPC: P4), or c) stimulation altered between PFC and PPC sites119 while completing practice trials of the WM training tasks. This created four groups of 18 participants in each of the four conditions. As there were no between group behavioural differences (p = 0.74), data were collapsed across stimulation site to form the ‘Active 1.5’ group. In the 5-day study, participants received sham or 15 minutes of anodal tDCS to the right PFC (F4) while completing practice trials of the WM training tasks. Thirty participants received 1 mA (Active 1), thirty participants received 2 mA (Active 2), and thirty participants received only sham tDCS. For both studies, the tDCS group sizes represent all included participants and exclude the participants who did not provide DNA samples or those who were excluded for floor or ceiling effects.
Data Availability
The data reported in this study are included in the Supplementary Information files.
References
Constantinidis, C. & Klingberg, T. The neuroscience of working memory capacity and training. Nature reviews. Neuroscience 17, 438–449, https://doi.org/10.1038/nrn.2016.43 (2016).
Morrison, A. B. & Chein, J. M. Does working memory training work? The promise and challenges of enhancing cognition by training working memory. Psychon Bull Rev 18, 46–60, https://doi.org/10.3758/s13423-010-0034-0 (2011).
Nitsche, M. A. & Paulus, W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. The Journal of physiology 527(Pt 3), 633–639 (2000).
Elmasry, J., Loo, C. & Martin, D. A systematic review of transcranial electrical stimulation combined with cognitive training. Restor Neurol Neurosci 33, 263–278, https://doi.org/10.3233/RNN-140473 (2015).
Martin, D. M., Liu, R., Alonzo, A., Green, M. & Loo, C. K. Use of transcranial direct current stimulation (tDCS) to enhance cognitive training: effect of timing of stimulation. Exp Brain Res 232, 3345–3351, https://doi.org/10.1007/s00221-014-4022-x (2014).
Park, S. H., Seo, J. H., Kim, Y. H. & Ko, M. H. Long-term effects of transcranial direct current stimulation combined with computer-assisted cognitive training in healthy older adults. Neuroreport 25, 122–126, https://doi.org/10.1097/WNR.0000000000000080 (2014).
Au, J. et al. Enhancing Working Memory Training with Transcranial Direct Current Stimulation. J Cogn Neurosci, 1–14, doi:https://doi.org/10.1162/jocn_a_00979 (2016).
Gill, J., Shah-Basak, P. P. & Hamilton, R. It’s the thought that counts: examining the task-dependent effects of transcranial direct current stimulation on executive function. Brain Stimul 8, 253–259, https://doi.org/10.1016/j.brs.2014.10.018 (2015).
Jones, K. T., Stephens, J. A., Alam, M., Bikson, M. & Berryhill, M. E. Longitudinal neurostimulation in older adults improves working memory. Plos One 10, e0121904, https://doi.org/10.1371/journal.pone.0121904 (2015).
Martin, D. M. et al. Can transcranial direct current stimulation enhance outcomes from cognitive training? A randomized controlled trial in healthy participants. International Journal of Neuropsychopharmacology 16, 1927–1936, https://doi.org/10.1017/S1461145713000539 (2013).
Richmond, L. L., Wolk, D., Chein, J. & Olson, I. R. Transcranial Direct Current Stimulation Enhances Verbal Working Memory Training Performance over Time and Near Transfer Outcomes. Journal of Cognitive Neuroscience 26, 2443–2454, https://doi.org/10.1162/jocn_a_00657 (2014).
Stephens, J. A. & Berryhill, M. E. Older Adults Improve on Everyday Tasks after Working Memory Training and Neurostimulation. Brain Stimul, doi:https://doi.org/10.1016/j.brs.2016.04.001 (2016).
Bikson, M. et al. Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. Brain Stimul 9, 641–661, https://doi.org/10.1016/j.brs.2016.06.004 (2016).
Medeiros, L. F. et al. Neurobiological effects of transcranial direct current stimulation: a review. Frontiers in psychiatry 3, 110, https://doi.org/10.3389/fpsyt.2012.00110 (2012).
Stagg, C. J. & Nitsche, M. A. Physiological basis of transcranial direct current stimulation. The Neuroscientist: a review journal bringing neurobiology, neurology and psychiatry 17, 37–53, https://doi.org/10.1177/1073858410386614 (2011).
Woods, A. J. et al. A technical guide to tDCS, and related non-invasive brain stimulation tools. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 127, 1031–1048, https://doi.org/10.1016/j.clinph.2015.11.012 (2016).
Amadi, U., Ilie, A., Johansen-Berg, H. & Stagg, C. J. Polarity-specific effects of motor transcranial direct current stimulation on fMRI resting state networks. NeuroImage 88C, 155–161, https://doi.org/10.1016/j.neuroimage.2013.11.037 (2013).
Bachtiar, V., Near, J., Johansen-Berg, H. & Stagg, C. J. Modulation of GABA and resting state functional connectivity by transcranial direct current stimulation. Elife 4, e08789, https://doi.org/10.7554/eLife.08789 (2015).
Hunter, M. A. et al. Baseline effects of transcranial direct current stimulation on glutamatergic neurotransmission and large-scale network connectivity. Brain Res 1594, 92–107, https://doi.org/10.1016/j.brainres.2014.09.066 (2015).
Krishnamurthy, V., Gopinath, K., Brown, G. S. & Hampstead, B. M. Resting-state fMRI reveals enhanced functional connectivity in spatial navigation networks after transcranial direct current stimulation. Neurosci Lett 604, 80–85, https://doi.org/10.1016/j.neulet.2015.07.042 (2015).
Kunze, T., Hunold, A., Haueisen, J., Jirsa, V. & Spiegler, A. Transcranial direct current stimulation changes resting state functional connectivity: A large-scale brain network modeling study. NeuroImage, doi:https://doi.org/10.1016/j.neuroimage.2016.02.015 (2016).
Lindenberg, R., Sieg, M. M., Meinzer, M., Nachtigall, L. & Floel, A. Neural correlates of unihemispheric and bihemispheric motor cortex stimulation in healthy young adults. NeuroImage, doi:https://doi.org/10.1016/j.neuroimage.2016.01.057 (2016).
Meinzer, M. et al. Electrical brain stimulation improves cognitive performance by modulating functional connectivity and task-specific activation. The Journal of neuroscience: the official journal of the Society for Neuroscience 32, 1859–1866, https://doi.org/10.1523/JNEUROSCI.4812-11.2012 (2012).
Meinzer, M., Lindenberg, R., Antonenko, D., Flaisch, T. & Floel, A. Anodal transcranial direct current stimulation temporarily reverses age-associated cognitive decline and functional brain activity changes. The Journal of neuroscience: the official journal of the Society for Neuroscience 33, 12470–12478, https://doi.org/10.1523/JNEUROSCI.5743-12.2013 (2013).
Pena-Gomez, C. et al. Modulation of large-scale brain networks by transcranial direct current stimulation evidenced by resting-state functional MRI. Brain Stimul 5, 252–263, https://doi.org/10.1016/j.brs.2011.08.006 (2012).
Polania, R., Nitsche, M. A. & Paulus, W. Modulating functional connectivity patterns and topological functional organization of the human brain with transcranial direct current stimulation. Human brain mapping 32, 1236–1249, https://doi.org/10.1002/hbm.21104 (2011).
Polania, R., Paulus, W., Antal, A. & Nitsche, M. A. Introducing graph theory to track for neuroplastic alterations in the resting human brain: a transcranial direct current stimulation study. NeuroImage 54, 2287–2296, https://doi.org/10.1016/j.neuroimage.2010.09.085 (2011).
Polania, R., Paulus, W. & Nitsche, M. A. Reorganizing the intrinsic functional architecture of the human primary motor cortex during rest with non-invasive cortical stimulation. Plos One 7, e30971, https://doi.org/10.1371/journal.pone.0030971 (2012).
Polania, R., Paulus, W. & Nitsche, M. A. Modulating cortico-striatal and thalamo-cortical functional connectivity with transcranial direct current stimulation. Human brain mapping 33, 2499–2508, https://doi.org/10.1002/hbm.21380 (2012).
Wang, J. X. & Voss, J. L. Long-lasting enhancements of memory and hippocampal-cortical functional connectivity following multiple-day targeted noninvasive stimulation. Hippocampus 25, 877–883, https://doi.org/10.1002/hipo.22416 (2015).
Hoy, K. E. et al. Testing the limits: Investigating the effect of tDCS dose on working memory enhancement in healthy controls. Neuropsychologia 51, 1777–1784, https://doi.org/10.1016/j.neuropsychologia.2013.05.018 (2013).
Berryhill, M. E. & Jones, K. T. tDCS selectively improves working memory in older adults with more education. Neurosci Lett 521, 148–151, https://doi.org/10.1016/j.neulet.2012.05.074 (2012).
Jones, K. T. & Berryhill, M. E. Parietal contributions to visual working memory depend on task difficulty. Front Psychiatry 3, 81, https://doi.org/10.3389/fpsyt.2012.00081 (2012).
Jones, K. T., Gozenman, F. & Berryhill, M. E. The strategy and motivational influences on the beneficial effect of neurostimulation: A tDCS and fNIRS study. NeuroImage 105, 238–247, https://doi.org/10.1016/j.neuroimage.2014.11.012 (2015).
Mancuso, L. E., Ilieva, I. P., Hamilton, R. H. & Farah, M. J. Does Transcranial Direct Current Stimulation Improve Healthy Working Memory?: A Meta-analytic Review. J Cogn Neurosci, 1-27, doi:https://doi.org/10.1162/jocn_a_00956 (2016).
Horvath, J. C., Forte, J. D. & Carter, O. Evidence that transcranial direct current stimulation (tDCS) generates little-to-no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: A systematic review. Neuropsychologia 66, 213–236, https://doi.org/10.1016/j.neuropsychologia.2014.11.021 (2015).
Horvath, J. C., Forte, J. D. & Carter, O. Quantitative Review Finds No Evidence of Cognitive Effects in Healthy Populations From Single-session Transcranial Direct Current Stimulation (tDCS). Brain Stimul 8, 535–550, https://doi.org/10.1016/j.brs.2015.01.400 (2015).
Horvath, J. C., Carter, O. & Forte, J. D. Transcranial direct current stimulation: five important issues we aren’t discussing (but probably should be). Front Syst Neurosci 8, 2, https://doi.org/10.3389/fnsys.2014.00002 (2014).
Dedoncker, J., Brunoni, A. R., Baeken, C. & Vanderhasselt, M. A. A Systematic Review and Meta-Analysis of the Effects of Transcranial Direct Current Stimulation (tDCS) Over the Dorsolateral Prefrontal Cortex in Healthy and Neuropsychiatric Samples: Influence of Stimulation Parameters. Brain Stimul 9, 501–517, https://doi.org/10.1016/j.brs.2016.04.006 (2016).
Batsikadze, G., Moliadze, V., Paulus, W., Kuo, M. F. & Nitsche, M. A. Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans. The Journal of physiology 591, 1987–2000, https://doi.org/10.1113/jphysiol.2012.249730 (2013).
Benwell, C. S. Y., Learmonth, G., Miniussi, C., Harvey, M. & Thut, G. Non-linear effects of transcranial direct current stimulation as a function of individual baseline performance: Evidence from biparietal tDCS influence on lateralized attention bias. Cortex 69, 152–165, https://doi.org/10.1016/j.cortex.2015.05.007 (2015).
Boggio, P. S. et al. Effects of transcranial direct current stimulation on working memory in patients with Parkinson’s disease. J Neurol Sci 249, 31–38, https://doi.org/10.1016/j.jns.2006.05.062 (2006).
Klingberg, T. Development of a superior frontal-intraparietal network for visuo-spatial working memory. Neuropsychologia 44, 2171–2177, https://doi.org/10.1016/j.neuropsychologia.2005.11.019 (2006).
Klingberg, T. Training and plasticity of working memory. Trends in cognitive sciences 14, 317–324, https://doi.org/10.1016/j.tics.2010.05.002 (2010).
Backman, L. et al. Effects of Working-Memory Training on Striatal Dopamine Release. Science 333, 718–718, https://doi.org/10.1126/Science.1204978 (2011).
Cools, R. Dopaminergic control of the striatum for high-level cognition. Current opinion in neurobiology 21, 402–407, https://doi.org/10.1016/j.conb.2011.04.002 (2011).
Cools, R. The costs and benefits of brain dopamine for cognitive control. Wiley interdisciplinary reviews. Cognitive science 7, 317–329, https://doi.org/10.1002/wcs.1401 (2016).
Dahlin, E., Neely, A. S., Larsson, A., Backman, L. & Nyberg, L. Transfer of learning after updating training mediated by the striatum. Science 320, 1510–1512, https://doi.org/10.1126/science.1155466 (2008).
Cools, R. & D’Esposito, M. Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry 69, e113–125, https://doi.org/10.1016/j.biopsych.2011.03.028 (2011).
Fresnoza, S., Paulus, W., Nitsche, M. A. & Kuo, M. F. Nonlinear dose-dependent impact of D1 receptor activation on motor cortex plasticity in humans. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 2744–2753, https://doi.org/10.1523/JNEUROSCI.3655-13.2014 (2014).
Fresnoza, S. et al. Dosage-dependent effect of dopamine D2 receptor activation on motor cortex plasticity in humans. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 10701–10709, https://doi.org/10.1523/JNEUROSCI.0832-14.2014 (2014).
Kar, K. & Wright, J. Probing the mechanisms underlying the mitigation of cognitive aging with anodal transcranial direct current stimulation. J Neurophysiol 111, 1397–1399, https://doi.org/10.1152/jn.00736.2013 (2014).
Egan, M. F. et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257–269 (2003).
Hariri, A. R. et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. The Journal of neuroscience: the official journal of the Society for Neuroscience 23, 6690–6694 (2003).
Chen, C. C. et al. BDNF Val66Met Polymorphism on Functional MRI During n-Back Working Memory Tasks. Medicine 94, e1586, https://doi.org/10.1097/MD.0000000000001586 (2015).
Antal, A. et al. Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans. Brain Stimul 3, 230–237, https://doi.org/10.1016/j.brs.2009.12.003 (2010).
Brunoni, A. R. et al. Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: implications for the serotonergic system. Eur Neuropsychopharmacol 23, 1530–1540, https://doi.org/10.1016/j.euroneuro.2013.03.009 (2013).
Chhabra, H. et al. Transcranial direct current stimulation and neuroplasticity genes: implications for psychiatric disorders. Acta Neuropsychiatr 28, 1–10, https://doi.org/10.1017/neu.2015.20 (2016).
Fritsch, B. et al. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron 66, 198–204, https://doi.org/10.1016/j.neuron.2010.03.035 (2010).
Lachman, H. M. et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6, 243–250 (1996).
Lotta, T. et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34, 4202–4210 (1995).
Wishart, H. A. et al. COMT Val158Met Genotype and Individual Differences in Executive Function in Healthy Adults. J Int Neuropsychol Soc 17, 174–180, https://doi.org/10.1017/S1355617710001402 (2011).
Chen, J. et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75, 807–821, https://doi.org/10.1086/425589 (2004).
Karoum, F., Chrapusta, S. J. & Egan, M. F. 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem 63, 972–979 (1994).
Berryhill, M. E., Wiener, M., Stephens, J. A., Lohoff, F. W. & Coslett, H. B. COMT and ANKK1-Taq-Ia genetic polymorphisms influence visual working memory. Plos One 8, e55862, https://doi.org/10.1371/journal.pone.0055862 (2013).
Bruder, G. E. et al. Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. Biol Psychiatry 58, 901–907, https://doi.org/10.1016/j.biopsych.2005.05.010 (2005).
de Frias, C. M. et al. Influence of COMT gene polymorphism on fMRI-assessed sustained and transient activity during a working memory task. J Cogn Neurosci 22, 1614–1622, https://doi.org/10.1162/jocn.2009.21318 (2010).
Egan, M. F. et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98, 6917–6922, https://doi.org/10.1073/pnas.111134598 (2001).
Mier, D., Kirsch, P. & Meyer-Lindenberg, A. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry 15, 918–927, https://doi.org/10.1038/mp.2009.36 (2010).
Tan, H. Y. et al. Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function. Proc Natl Acad Sci USA 104, 12536–12541, https://doi.org/10.1073/pnas.0610125104 (2007).
Versace, M. & Zorzi, M. The role of dopamine in the maintenance of working memory in prefrontal cortex neurons: input-driven versus internally-driven networks. Int J Neural Syst 20, 249–265, https://doi.org/10.1142/S0129065710002401 (2010).
Harris, S. E. & Deary, I. J. The genetics of cognitive ability and cognitive ageing in healthy older people. Trends in cognitive sciences 15, 388–394, https://doi.org/10.1016/j.tics.2011.07.004 (2011).
Laukka, E. J. et al. Genetic effects on old-age cognitive functioning: a population-based study. Psychol Aging 28, 262–274, https://doi.org/10.1037/a0030829 (2013).
Nyberg, L. et al. Age-related and genetic modulation of frontal cortex efficiency. J Cogn Neurosci 26, 746–754, https://doi.org/10.1162/jocn_a_00521 (2014).
Raz, N., Rodrigue, K. M., Kennedy, K. M. & Land, S. Genetic and vascular modifiers of age-sensitive cognitive skills: effects of COMT, BDNF, ApoE, and hypertension. Neuropsychology 23, 105–116, https://doi.org/10.1037/a0013487 (2009).
Stormer, V. S., Passow, S., Biesenack, J. & Li, S. C. Dopaminergic and cholinergic modulations of visual-spatial attention and working memory: insights from molecular genetic research and implications for adult cognitive development. Dev Psychol 48, 875–889, https://doi.org/10.1037/a0026198 (2012).
Bellander, M. et al. Lower baseline performance but greater plasticity of working memory for carriers of the val allele of the COMT Val(1)(5)(8)Met polymorphism. Neuropsychology 29, 247–254, https://doi.org/10.1037/neu0000088 (2015).
Buckert, M., Kudielka, B. M., Reuter, M. & Fiebach, C. J. The COMT Val158Met polymorphism modulates working memory performance under acute stress. Psychoneuroendocrinology 37, 1810–1821, https://doi.org/10.1016/j.psyneuen.2012.03.014 (2012).
Klaus, K. et al. The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress. Brain Behav 7, e00695, https://doi.org/10.1002/brb3.695 (2017).
Plewnia, C. et al. Effects of transcranial direct current stimulation (tDCS) on executive functions: influence of COMT Val/Met polymorphism. Cortex; a journal devoted to the study of the nervous system and behavior 49, 1801–1807, https://doi.org/10.1016/j.cortex.2012.11.002 (2013).
Nieratschker, V., Kiefer, C., Giel, K., Kruger, R. & Plewnia, C. The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition. Brain stimulation 8, 283–288, https://doi.org/10.1016/j.brs.2014.11.009 (2015).
Erixon-Lindroth, N. et al. The role of the striatal dopamine transporter in cognitive aging. Psychiatry Res 138, 1–12, https://doi.org/10.1016/j.pscychresns.2004.09.005 (2005).
Ciliax, B. J. et al. Immunocytochemical localization of the dopamine transporter in human brain. The Journal of comparative neurology 409, 38–56 (1999).
Sambataro, F. et al. A variable number of tandem repeats in the 3′-untranslated region of the dopamine transporter modulates striatal function during working memory updating across the adult age span. The European journal of neuroscience 42, 1912–1918, https://doi.org/10.1111/ejn.12956 (2015).
Giros, B. et al. Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter. Mol Pharmacol 42, 383–390 (1992).
Cheon, K. A., Ryu, Y. H., Kim, J. W. & Cho, D. Y. The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate. European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 15, 95–101, https://doi.org/10.1016/j.euroneuro.2004.06.004 (2005).
Heinz, A. et al. Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 22, 133–139, https://doi.org/10.1016/S0893-133X(99)00099-8 (2000).
Jacobsen, L. K. et al. Prediction of dopamine transporter binding availability by genotype: a preliminary report. Am J Psychiatry 157, 1700–1703, https://doi.org/10.1176/appi.ajp.157.10.1700 (2000).
van de Giessen, E. et al. Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3. J Nucl Med 50, 45–52, https://doi.org/10.2967/jnumed.108.053652 (2009).
Backman, L. & Nyberg, L. Dopamine and training-related working-memory improvement. Neurosci Biobehav Rev 37, 2209–2219, https://doi.org/10.1016/j.neubiorev.2013.01.014 (2013).
Buschkuehl, M., Jaeggi, S. M. & Jonides, J. Neuronal effects following working memory training. Dev Cogn Neurosci 2(Suppl 1), S167–179, https://doi.org/10.1016/j.dcn.2011.10.001 (2012).
Darki, F. & Klingberg, T. The role of fronto-parietal and fronto-striatal networks in the development of working memory: a longitudinal study. Cereb Cortex 25, 1587–1595, https://doi.org/10.1093/cercor/bht352 (2015).
Kuhn, S. et al. The dynamics of change in striatal activity following updating training. Hum Brain Mapp 34, 1530–1541, https://doi.org/10.1002/hbm.22007 (2013).
Olesen, P. J., Westerberg, H. & Klingberg, T. Increased prefrontal and parietal activity after training of working memory. Nat Neurosci 7, 75–79, https://doi.org/10.1038/nn1165 (2004).
Yu, Y., FitzGerald, T. H. & Friston, K. J. Working memory and anticipatory set modulate midbrain and putamen activity. J Neurosci 33, 14040–14047, https://doi.org/10.1523/JNEUROSCI.1176-13.2013 (2013).
Lu, B. BDNF and activity-dependent synaptic modulation. Learning & memory 10, 86–98, https://doi.org/10.1101/lm.54603 (2003).
Li, G. et al. Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. Plos One 4, e5424, https://doi.org/10.1371/journal.pone.0005424 (2009).
Getzmann, S., Gajewski, P. D., Hengstler, J. G., Falkenstein, M. & Beste, C. BDNF Val66Met polymorphism and goal-directed behavior in healthy elderly - evidence from auditory distraction. NeuroImage 64, 290–298, https://doi.org/10.1016/j.neuroimage.2012.08.079 (2013).
Brooks, S. J. et al. BDNF Polymorphisms Are Linked to Poorer Working Memory Performance, Reduced Cerebellar and Hippocampal Volumes and Differences in Prefrontal Cortex in a Swedish Elderly Population. Plos One 9, doi:ARTN e82707 10.1371/journal.pone.0082707 (2014).
Miyajima, F. et al. Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav 7, 411–417, https://doi.org/10.1111/j.1601-183X.2007.00363.x (2008).
Berryhill, M. E., Peterson, D. J., Jones, K. T. & Stephens, J. A. Hits and misses: leveraging tDCS to advance cognitive research. Front Psychol 5, 800, https://doi.org/10.3389/fpsyg.2014.00800 (2014).
Jaberzadeh, S. & Zoghi, M. Non-invasive brain stimulation for enhancement of corticospinal excitability and motor performance. Basic Clin Neurosci 4, 257–265 (2013).
Pfefferbaum, A. et al. Age-related decline in brain white matter anisotropy measured with spatially corrected echo-planar diffusion tensor imaging. Magn Reson Med 44, 259–268 (2000).
Raz, N. et al. Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. Cerebral cortex 7, 268–282 (1997).
Verwer, R. W. et al. Post-mortem brain tissue cultures from elderly control subjects and patients with a neurodegenerative disease. Exp Gerontol 38, 167–172 (2003).
Hsu, W. Y., Ku, Y., Zanto, T. P. & Gazzaley, A. Effects of noninvasive brain stimulation on cognitive function in healthy aging and Alzheimer’s disease: a systematic review and meta-analysis. Neurobiol Aging 36, 2348–2359, https://doi.org/10.1016/j.neurobiolaging.2015.04.016 (2015).
Prehn, K. et al. Using resting-state fMRI to assess the effect of aerobic exercise on functional connectivity of the DLPFC in older overweight adults. Brain and Cognition (2017).
Liu, H. et al. Aging of cerebral white matter. Ageing Res Rev 34, 64–76, https://doi.org/10.1016/j.arr.2016.11.006 (2017).
Sala-Llonch, R., Bartres-Faz, D. & Junque, C. Reorganization of brain networks in aging: a review of functional connectivity studies. Front Psychol 6, 663, https://doi.org/10.3389/fpsyg.2015.00663 (2015).
Noack, H., Lovden, M., Schmiedek, F. & Lindenberger, U. Cognitive plasticity in adulthood and old age: gauging the generality of cognitive intervention effects. Restor Neurol Neurosci 27, 435–453, https://doi.org/10.3233/RNN-2009-0496 (2009).
Carretti, B., Borella, E., Fostinelli, S. & Zavagnin, M. Benefits of training working memory in amnestic mild cognitive impairment: specific and transfer effects. Int Psychogeriatr 25, 617–626, https://doi.org/10.1017/S1041610212002177 (2013).
Borella, E. et al. Benefits of training visuospatial working memory in young-old and old-old. Dev Psychol 50, 714–727, https://doi.org/10.1037/a0034293 (2014).
Berryhill, M. E. & Jones, K. T. tDCS selectively improves working memory in older adults with more education. Neurosci Lett 521, 148–151, https://doi.org/10.1016/j.neulet.2012.05.074 (2012).
Berryhill, M. E., Wencil, E. B., Branch Coslett, H. & Olson, I. R. A selective working memory impairment after transcranial direct current stimulation to the right parietal lobe. Neurosci Lett 479, 312–316, https://doi.org/10.1016/j.neulet.2010.05.087 (2010).
Elmer, S., Burkard, M., Renz, B., Meyer, M. & Jancke, L. Direct current induced short-term modulation of the left dorsolateral prefrontal cortex while learning auditory presented nouns. Behav Brain Funct 5, 29, https://doi.org/10.1186/1744-9081-5-29 (2009).
Hsu, T. Y. et al. Modulating inhibitory control with direct current stimulation of the superior medial frontal cortex. NeuroImage 56, 2249–2257, https://doi.org/10.1016/j.neuroimage.2011.03.059 (2011).
Tseng, P. et al. Unleashing potential: transcranial direct current stimulation over the right posterior parietal cortex improves change detection in low-performing individuals. The Journal of neuroscience: the official journal of the Society for Neuroscience 32, 10554–10561, https://doi.org/10.1523/JNEUROSCI.0362-12.2012 (2012).
Zaehle, T., Sandmann, P., Thorne, J. D., Jancke, L. & Herrmann, C. S. Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: combined behavioural and electrophysiological evidence. BMC Neurosci 12, 2, https://doi.org/10.1186/1471-2202-12-2 (2011).
Jasper, H. Report of the committee on methods of clinical examination in electroencephalography: 1957. Electroencephalography and clinical neurophysiology. 10, 370–375 (1958).
Acknowledgements
This work was supported by the National Eye Institute at the National Institutes of Health (Grant Number: R15EY022775) to M.E.B.; the National Institute of General Medical Sciences Institutional Development Award at the National Institutes of Health (Grant Number: 1P20GM103650) with Project 1 Leader M.E.B, NSF EPSCOR Track II funding (NSF 1632738) the Bilinski Foundation (Dissertation Fellowship) to J.A.S. The funding agencies had no role in study design, data collection, analysis or interpretation of these findings.
Author information
Authors and Affiliations
Contributions
J.A.S. and K.T.J. collected and analysed behavioural-tDCS and genotyping data. J.A.S., K.T.J., and M.E.B. contributed to writing and reviewing the manuscript.
Corresponding author
Ethics declarations
Competing Interests
The authors declare that they have no competing interests.
Additional information
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Stephens, J.A., Jones, K.T. & Berryhill, M.E. Task demands, tDCS intensity, and the COMT val158met polymorphism impact tDCS-linked working memory training gains. Sci Rep 7, 13463 (2017). https://doi.org/10.1038/s41598-017-14030-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-017-14030-7
This article is cited by
-
Neuromodulation to Enhance Creative Cognition: a Review of New and Emerging Approaches
Journal of Cognitive Enhancement (2023)
-
Protocols for cognitive enhancement. A user manual for Brain Health Services—part 5 of 6
Alzheimer's Research & Therapy (2021)
-
Increased leg muscle fatigability during 2 mA and 4 mA transcranial direct current stimulation over the left motor cortex
Experimental Brain Research (2020)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.