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Met Polymorphism Modulates Effects of tDCS on Response Inhibition
Accepted Manuscript The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition Vanessa Nieratschker , PhD, Christoph Kiefer , B.Sc., Katrin Giel , PhD, Rejko Krüger , MD, Christian Plewnia , MD PII:
S1935-861X(14)00384-2
DOI:
10.1016/j.brs.2014.11.009
Reference:
BRS 638
To appear in:
Brain Stimulation
Received Date: 16 September 2014 Revised Date:
11 November 2014
Accepted Date: 17 November 2014
Please cite this article as: Nieratschker V, Kiefer C, Giel K, Krüger R, Plewnia C, The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition, Brain Stimulation (2014), doi: 10.1016/ j.brs.2014.11.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition Vanessa Nieratschker, PhD1; Christoph Kiefer, B.Sc.1; Katrin Giel, PhD2; Rejko Krüger, MD3, 4; Christian Plewnia, MD1*
Department of Psychiatry and Psychotherapy, Calwerstrasse 14, 72076 Tübingen, Germany 2
University
of
Tübingen,
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Department of Psychosomatic Medicine and Psychotherapy, University of Tübingen, Osianderstrasse 5, 72076 Tübingen, Germany
3
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Clinical and Experimental Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg and Centre Hospitalier de Luxembourg, Campus Belval, 7, avenue des Hauts-Forneaux, L-4362 Eschsur-Alzette, Luxembourg
4
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, University of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany
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* Correspondence and proofs: Christian Plewnia, MD; Department of Psychiatry and Psychotherapy; Neurophysiology & Interventional Neuropsychiatry; University of Tübingen, Calwerstrasse 14, D-72076 Tübingen, Germany; Tel: +49 7071 2986121, Fax: +49 7071 295904, e-mail: [email protected]
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Running title: COMT polymorphism and tDCS effects on executive functions
e-mails: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
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ACCEPTED MANUSCRIPT Abstract Background: Transcranial direct current stimulation (tDCS) is increasingly discussed as a new option to support the cognitive rehabilitation in neuropsychiatric disorders. However, the therapeutic impact of tDCS is limited by high interindividual variability.
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Genetic factors most likely contribute to this variability by modulating the effects of tDCS.
Objectives: We aimed to investigate the influence of the COMT Val(108/158)Met
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polymorphism on cathodal tDCS effects on executive functioning.
Methods: Cathodal tDCS was applied to the left dorsolateral prefrontal cortex (dlPFC)
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during the performance of a parametric Go/No-Go test.
Results: We demonstrate an impairing effect of cathodal tDCS to the dlPFC on response inhibition. This effect was only found in individuals homozygous for the Valallele of the COMT Val(108/158)Met polymorphism. No effects of stimulation on
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executive functions in Met-allele carriers were detected.
Conclusion: Our data indicate that i) cathodal, excitability reducing tDCS, interferes with inhibitory cognitive control, ii) the left dlPFC is critically involved in the neuronal
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network underlying the control of response inhibition, and iii) the COMT Val(108/158)Met polymorphism modulates the impact of cathodal tDCS on inhibitory
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control. Together with our previous finding that anodal tDCS selectively impairs setshifting abilities in COMT Met/Met homozygous individuals, these results indicate that genetic factors modulate effects of tDCS on cognitive performance. Therefore, future tDCS research should account for genetic variability in the design and analysis of neurocognitive as well as therapeutic applications to reduce the variability of results and facilitate individualized neurostimulation approaches.
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ACCEPTED MANUSCRIPT Keywords: Genetics, catechol-O-methyltransferase, COMT, dopamine, response
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inhibition, brain stimulation
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ACCEPTED MANUSCRIPT Introduction
Executive functions such as the control of attention and memory, response selection, planning ability and task flexibility enable goal-directed behaviour. Impaired executive
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functions are often linked with characteristic symptoms of various psychiatric
disorders like schizophrenia [1], affective disorders [2] and addiction [3]. Recently, it has been demonstrated that non-invasive brain stimulation of the prefrontal cortex
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(PFC) can modulate executive functioning in healthy subjects and psychiatric patients [4; 5]. Especially the effects of transcranial direct current stimulation (tDCS) on
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various cognitive functions are well described [6]. This is an easy to use and well tolerated technique which transiently modulates cortical excitability by applying a weak current to a certain brain area [7]. Anodal tDCS enhances neuronal excitability and thus plasticity by depolarization of the neuronal resting membrane potential,
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whereas cathodal tDCS reduces neuronal activity by hyperpolarization of the affected neurons, leading to a reduction in excitability [8]. Linked with cognitive training paradigms, tDCS is increasingly discussed as a new
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option to support cognitive rehabilitation in neuropsychiatric disorders [4]. However, the observed effects still lack consistency, particularly regarding the specificity of
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polarity, the optimal stimulation parameters and the most effective training schedules and paradigms [9; 10]. Enhancing effects of anodal tDCS on executive functions, especially improvements of working-memory performance [11], attention control [12], and planning abilities [13] have been already shown. On the contrary, impairing effects of cathodal tDCS have been less clearly demonstrated [10], and moreover even improvements of performance during cathodal tDCS have been described [1416]. This inconsistency has been attributed to the complex interactions of inhibition and excitation in the cognitive domain [17], the relevance of various -4-
ACCEPTED MANUSCRIPT neurophysiological mechanisms in different tasks [15; 16] and throughout the course of training [14], as well as variations in the inter-individual responsiveness [18]. Several previous studies indicate that genetic factors most likely contribute to this variability [19; 20]. Given the perspectives of tDCS as a treatment for psychiatric
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disorders, determining potential genetic factors of inter-individual variability is an important prerequisite for further developments in this effort.
We recently demonstrated an influence of the functional Val(108/158)Met
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polymorphism in the catechol-O-methyltransferase (COMT) gene on the effect of anodal tDCS stimulation on executive functioning [21]. COMT is an important
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regulator of dopaminergic neurotransmission as it catalyzes the degradation of dopamine particularly in prefrontal regions of the brain [22; 23]. The COMT Val(108/158)Met substitution affects the thermostability of COMT which leads to a significant decrease in enzymatic activity. The two alleles are codominant, resulting in
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the lowest levels of dopamine in Val/Val homozygous individuals, intermediate levels of dopamine in heterozygous individuals and the highest levels of dopamine in Met/Met homozygous individuals [24]. Dopaminergic activity is essential for the
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neuronal underpinnings of cognitive functioning and a non-linear inverted-U relationship has been proposed between dopaminergic signalling and executive
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performance (Fig. 1) [25]. Interestingly, the effects of tDCS on executive function are also modulated by dopamine concentration in a non-linear manner [26; 27]. In our previous study, while there was no anodal stimulation main effect, we demonstrated lower set-shifting abilities in healthy individuals homozygous for the COMT Met-allele compared to Val-allele carriers under anodal tDCS stimulation [21]. This finding suggested that enhancement of neuronal excitability through anodal tDCS stimulation shifts dopaminergic activity in Met/Met homozygous individuals,
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ACCEPTED MANUSCRIPT displaying high baseline dopaminergic activity, to the far right of the inverted-U curve pushing these subjects below their optimal level of cognitive performance (Fig. 1 A). To further characterize the modulatory influence of COMT on tDCS effects, we designed the present study. We hypothesized that in contrast to anodal stimulation
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which affects Met/Met homozygous individuals, reduction of neuronal excitability through cathodal tDCS stimulation shifts dopaminergic activity in Val/Val
homozygous individuals, displaying low baseline dopamiergic activity, to the far left of
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the inverted-U curve pushing these subjects below their optimal level of cognitive performance. In contrast, in Met-allele carriers executive performance will not be
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significantly affected as the shift to lower dopaminergic activity levels due to cathodal stimulation will not reach the threshold where it affects executive performance (Fig. 1B).
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ACCEPTED MANUSCRIPT Material and Methods
Subjects
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Forty-one right-handed (mean handedness score = 86.0, SD = 13.7 according to the Edinburgh Handedness Inventory, [28]) healthy volunteers (all of them students; 9 males, 32 females; mean age = 24.0, standard deviation (SD) = 4.2)) participated in
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this study and gave written informed consent to the experimental procedure approved by the University of Tübingen local ethics committee. None of the subjects had a
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history of physical, mental, or neurological illness and none of the subjects had performed the parametric Go/No-Go (PGNG) task before.
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Parametric Go/No-Go (PGNG) task
A Parametric Go/No-Go (PGNG) task [29] was used to assess sustained attention, response inhibition, and set-shifting abilities; core aspects of executive functioning.
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The task was conducted as previously described [21]. In brief, participants were presented with a continuous stream of letters, each displayed for 500ms with no
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interstimulus interval. Three letters served as target letters (x, y, z), all other letters as distractor stimuli. The PGNG measures different aspects of executive functioning: On the first level, participants were asked for a “go” response to the target letters by pressing a button as fast as possible after the target letter was presented. This level measures sustained attention and establishes reaction tendency to the target letters. The second and third level additionally asked for a “no-go” response, where participants had to inhibit their reaction to the target letter depending on a specific context rule. Level 2 used two target letters and mainly measures response inhibition, -7-
ACCEPTED MANUSCRIPT whereas level 3 used three target letters and is primarily measuring set-shifting abilities. Each level was presented twice in the following order: 1-2-3-1-3-2. Speed and accuracy were assessed on each level. The percentage of correct “go” response (PCTT – percentage correct target trials) on level 1 was used as a measure of
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sustained attention. The percentage of correct “no-go” responses (PCIT- percent correct inhibitory trials) on level 2 was used as a measure of response inhibition, and the percentage of correct “go” responses (PCTT – percentage correct target trials) on
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level 3 was used as a measure of set-shifting ability.
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Experimental procedure
The study was designed as a double-blind, sham-controlled crossover trial. 1 mA of cathodal tDCS was applied for 20 min by a battery driven stimulator (NeuroConn
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GmbH, Illmenau, Germany) via a pair of saline (0,9%)-soaked sponge electrodes (35 cm2 surface area). To affect the left dorsolateral prefrontal cortex (dlPFC), the cathodal electrode was placed on the scalp at F3 according to the international 10-20
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system of electrode placement and the reference electrode (anode) was placed above the right orbit. The current was increased and decreased for 5 seconds at the
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beginning and end of stimulation. For the sham condition, the electrodes were placed at the same positions, but the current was only applied for 40 seconds. This produces the same tingling sensation as verum stimulation but does not have sustained effects on cortical activation. This approach warrants that subjects are not able to distinguish 1mA tDCS from sham stimulation [30]. Performance of the PGNG outlasted the simulation for about 8 minutes. The order of verum and sham stimulation was balanced across the participants and the second session followed 2 days after the
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ACCEPTED MANUSCRIPT first. Predefined codes assigned to either sham or verum stimulation were used to start the stimulator and thus allowed for a double-blind study design.
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Genotyping
Genomic DNA was extracted from ethylenediaminetetraacetic acid (EDTA) anticoagulated venous blood samples according to standard protocols. Of the 41
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individuals included in the study, 28 were genotyped for rs4680 on a StepOne
system (life technologies; Darmstadt; Germany) using TaqMan®SNP Genotyping
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Assay C__25746809_50 (life technologies; Darmstadt; Germany) and the standard protocol for allelic discrimination. Accuracy was assessed by duplicating 15% of the original sample, and reproducibility was 100%. The genotype frequencies did not deviate from Hardy–Weinberg equilibrium (HWE; p = 0.75). In order to increase the
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sample size, 13 previously genotyped individuals were additionally included. Genotyping for this group has been performed as described earlier [21].
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Statistical analysis
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All statistical calculations were performed with SPSS (IBM SPSS Statistics 22.0; Ehningen; Germany) using repeated-measures ANOVAs with the within-factor tDCS stimulationsham,verum and the between factor genotypeVal/Val,Met. Results were considered significant when p ≤ 0.05. As the effects of cathodal tDCS on three different aspects of executive functioning were investigated, nominally significant main effects were multiplied by 3 to Bonferroni correct for multiple comparisons. For significant interaction F-values, post hoc t-tests were performed.
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ACCEPTED MANUSCRIPT Results
Genotypes
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Genotype distribution was as follows: 16 COMT Val/Val homozygous individuals and 25 Met-allele carriers. Both genotype groups did not differ significantly with respect to age (Val/Val: 24.56 ± 3.65, Met-allele carriers: 23.63 ± 4.55, p = 0.5), gender ratio
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(Val/Val: 75.0% female, Met-allele carriers: 80.0% female; p = 0.72), and education
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(100% secondary school education).
Sustained attention
No difference between sham and verum [F(1,39) = 1.58 p = 0.22] and no main effect
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of genotypeVal/Val,Met (p = 0.29) was observed on PGNG level 1. No significant interaction between COMT genotypeVal/Val,Met and stimulationsham,verum was detected [F(1,39) = 0.31, p = 0.58] (Fig.2). No significant main effects or interaction was found
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with regard to reaction time [F(1,39) = 0.06, p = 0.81].
--- Fig. 2 about here ---
Response inhibition
On PGNG level 2 a significant interference of cathodal tDCS stimulation with response inhibition was observed in the overall group [F(1,39) = 7.52, p = 0.01, adjusted p = 0.03, partial η2 = 0.16] (Fig. 3a). No main effect of genotypeVal/Val,Met was observed (p = 0.78), but interaction analysis revealed a significant interaction - 10 -
ACCEPTED MANUSCRIPT between COMT genotypeVal/Val,Met and stimulationsham,verum [F(1,39) = 4.05, p = 0.05, partial η2 = 0.09)]. Within the Val/Val group, response inhibition was significantly impaired under cathodal stimulation as compared to sham stimulation (p = 0.01), whereas cathodal stimulation had no effect on Met-carriers (p = 0.56; Fig. 3b). No
0.12, p = 0.74].
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significant main effects or interaction on reaction time have been observed [F(1,39) =
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Set-shifting
Sham and verum stimulation did not lead to significantly different performances on set-shifting abilities as measured on PGNG level 3 [F(1,39) = 0.05, p = 0.83]. No main effect of genotypeVal/Val,Met (p = 0.38) and no significant interaction between
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COMT genotypeVal/Val,Met and stimulationsham,verum was observed [F(1,39) = 0.02, p = 0.89] (Fig. 4). Analysis of reaction time also did not yield significant main effects or
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interaction [F(1,39) = 0.1, p = 0.75].
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ACCEPTED MANUSCRIPT Discussion
The present study provides new evidence for individual genetic determinants crucially modulating the efficacy of non-invasive brain stimulation on response inhibition, a
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core aspect of executive function. To our knowledge, these are the first data showing that the COMT Val(108/158)Met polymorphism critically modulates the detrimental effect of cathodal tDCS on response inhibition.
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Currently, a major challenge in the growing field of brain stimulation research is the consistency of the observed effects. Although the behavioral relevance of techniques
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modulating cortical activity like repetitive transcranial magnetic stimulation (rTMS) and tDCS on cognitive functions is non-controversial [5] the broader use particularly in a clinical context is thwarted by low-effect sizes, high inter-individual variability [31] and a substantial number of non-responders to the intervention [18]. Nevertheless,
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linking non-invasive brain stimulation techniques with cognitive training is a promising new neurorehabilitative approach [4]. Therefore, individual predictors of efficacy of tDCS are warranted and would significantly enhance the knowledge about the
applicability.
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mechanisms of non-invasive brain stimulation, thereby improving its clinical
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To this aim, first pivotal studies have demonstrated the interaction of brain-stimulation effects and individual genetic predispositions on neuroplasticity and cognitive functioning [19-21; 32]. The results of the present study, however, verify a specific contribution of genetic factors to the modulatory effects of tDCS on behavioral measures. As suggested by our previous work demonstrating an interference of anodal tDCS with executive functioning specifically in Met/Met homozygotes [21], we proceeded with investigating the effect of cathodal tDCS and were able to confirm our hypothesis assuming a detrimental influence distinctively in Val/Val-homozygous - 12 -
ACCEPTED MANUSCRIPT individuals. Taken together, these data are particularly compatible with the theoretical model of an inverted-U relationship between prefrontal dopaminergic signalling and executive functioning (Fig. 1) [25]. Executive functions successfully targeted by tDCS critically involve prefrontal dopaminergic activity which is modulated by the functional
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COMT Val(108/158)Met polymorphism. The findings presented in the current study suggest that the lower dopaminergic activity in Val/Val homozygous individuals is critical for an inhibitory effect of cathodal tDCS on response inhibition. COMT does
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not only regulate dopamine levels; norepinephrine, epinephrine and other catecholcontaining compounds are also putative substrates of COMT. Therefore, we can not
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clearly state, that the effects we observed are based on alterations of dopaminergic neurotransmission. However, the influence of other catecholamines do not seem to play a major role in the prefrontal cortex as demonstrated by Tunbridge et al., who showed that the COMT-inhibitor tolocapone increases dopamine levels but not
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norepinephrine levels in the prefrontal cortex of the rat when catecholamine efflux is induced [33]. It is important to consider that we did not quantify dopaminergic signalling or dopamine levels in both of our studies and our conclusions are
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exclusively based on a theoretical model which needs to be confirmed and replicated in further studies by independent groups. An acute dopaminergic challenge could be
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included in further studies to examine if the observed effect of cathodal tDCS on response inhibition actually follows the inverted-U model of dopaminergic signalling. A further limitation of our study is that only one genetic variant was investigated and the contribution of other genetic variants, especially genes important for dopaminergic neurotransmission have not been considered. However, the COMT Val(108/158)Met polymorphism was chosen because of its clear influence on dopamine levels especially in the prefrontal regions of the brain where the dopamine
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ACCEPTED MANUSCRIPT transporter is less abundant [34] and because we aimed to validate and extend the findings from our previous anodal study [21]. Cathodal tDCS affects response inhibition, but had no influence on the other executive functions tested with the PGNG. Particularly, we did not observe effects of
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cathodal stimulation on set-shifting ability. This effect is in line with the notion of
COMT-genotype dependent differences in cognitive stability and flexibility [35]. In this conception, Val-allele dependent lower prefrontal dopamine is associated with less
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cognitive stability but higher flexibility. In turn, Met-allele dependent higher dopamine concentrations are linked with impaired flexibility but stronger stability. Consistently, a
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further reduction of dopaminergic signalling by cathodal tDCS reduces the already weaker stability in Val-homozygous individuals to a behaviorally relevant impairment of response inhibition with no effect on set-shifting ability as a measure of flexibility. Reciprocally, in our previous study [21], set-shifting ability was compromised by an
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anodal tDCS-induced further increase of dopaminergic signalling in Met-homozygous individuals. It is important to note that there is a lack of clarity in the literature about the task specificity of the effects of the COMT Val(108/158)Met polymorphism.
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Converging evidence from pharmacological, clinical, and imaging studies suggest that response inhibition is based on frontostriatal networks which are predominantly
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modulated by dopamine and noradrenaline [36-40]. However, we did not measure dopaminergic signalling or dopamine levels in the different genotype groups and the contribution of other genetic variants, especially genes important for dopaminergic neurotransmission have not been considered. With respect to a general influence of the COMT Val(108/158)Met polymorphism on the executive functions addressed with the PGNG, we did not find an effect in the sham condition. This is consistent with a recent study using the Go/No-Go task [41]. However, differential effects of genetic variation in COMT on the neural substrates of - 14 -
ACCEPTED MANUSCRIPT executive functioning have been reliably demonstrated [42]. Most relevant to our study is the finding that Val-allele homozygous show increased activation in cognitive paradigms most likely indicating decreased cortical efficiency. Based on these data, it is plausible that an interference with this presumably compensatory activity by
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cathodal tDCS can induce a loss of function at the behavioural level. Similarly, an interaction between pharmacological treatment and COMT Val(108/158)Met
polymorphism on cognitive improvements after cognitive remediation therapy was
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found to corroborate the close interaction between COMT activity and neuromodulatory interventions relating to cognition [43].
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Irrespective of the genetic influence on the effect, the significant impairment of response inhibition during cathodal tDCS supports the general concept that a reduction of neuronal excitability by cathodal tDCS, of the left dlPFC can provoke a disturbance of executive control [44; 45]. However, it has to be kept in mind that the
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interaction of stimulation and task performance is complex and a simple beneficial/detrimental dichotomy of anodal and cathodal tDCS could be misleading [5; 10]. Nevertheless, our findings clearly demonstrate an involvement of the left
inhibition [46].
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dlPFC and support the relevance of top-down control processes for response
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For inhibitory control, particularly tested with the Go/No-Go paradigm, previous imaging studies suggested a decisive contribution of ventro- and dorsolateral prefrontal as well as parietal activations [47]. However, data on laterality are variable with a recent study reporting predominantly right-sided activity associated with response inhibition [48]. Accordingly, brain stimulation studies also provided evidence for a bilateral frontoparietal network underlying the control of response inhibition [49]. Specifically, rTMS studies indicated an involvement of the right inferior and right superior prefrontal cortex [50; 51] and the pre-supplementary motor area (pre-SMA; - 15 -
ACCEPTED MANUSCRIPT [52]). Studies using tDCS provided similar results indicating a functional relevance of the right inferior frontal cortex [53], the right dlPFC [54]) and the pre-SMA [55]. Notably, available evidence does not allow for a clear discrimination between different task demands, particularly action cancellation in stop-signal tasks and action
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restraint in Go/No-Go tasks most likely involve different networks. However, our
findings of reduced inhibition after cathodal tDCS of the left dlPFC are in line with two other brain stimulation studies indicating the critical involvement of the left dlPFC in
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efficient response inhibition [56; 57].
In conclusion, our findings demonstrate that i) cathodal, excitability reducing tDCS,
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can interfere with inhibitory cognitive control, ii) the left dlPFC is critically involved in the neuronal network underlying the control of response inhibition, and iii) this effect is modulated by the COMT Val(108/158)Met polymorphism. Our study suggests that inclusion of genetic information in the design and analysis of brain stimulation studies
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will be valuable to expand our knowledge on the underlying mechanisms. Finally, this approach will offer new perspectives for an individualised and effective therapeutic
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use of brain stimulation techniques.
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ACCEPTED MANUSCRIPT Funding and Disclosure
Dr. Plewnia received a research grant from the Werner Reichardt Centre for Integrative Neuroscience (CIN, PP2011_11) and speaker’s honoraria from inomed
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Medizintechnik GmbH. The funding source had no role in study design, the collection, analysis and interpretation of data, the writing of the manuscript and the decision to
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submit the article for publication. The authors declare no conflict of interest.
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Acknowledgement
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We would like to thank Dr. Daniel Bucher for critical reading of the manuscript.
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ACCEPTED MANUSCRIPT References
[1] Eisenberg DP, Berman KF. Executive function, neural circuitry, and genetic mechanisms in schizophrenia. Neuropsychopharmacology 2010; 35: 258-277.
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[2] Roiser JP, Elliott R, Sahakian BJ. Cognitive mechanisms of treatment in depression. Neuropsychopharmacology 2012; 37: 117-136. [3] Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 2011; 12: 652-669.
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[4] Kuo MF, Paulus W, Nitsche MA. Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases. Neuroimage 2014; 85 Pt 3: 948-960.
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[5] Miniussi C, Harris JA, Ruzzoli M. Modelling non-invasive brain stimulation in cognitive neuroscience. Neurosci Biobehav Rev 2013; 37: 1702-1712. [6] Mondino M, Bennabi D, Poulet E, Galvao F, Brunelin J, Haffen E. Can transcranial direct current stimulation (tDCS) alleviate symptoms and improve cognition in psychiatric disorders? World J Biol Psychiatry 2014; 15: 261-275.
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[7] George MS, Aston-Jones G. Noninvasive techniques for probing neurocircuitry and treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Neuropsychopharmacology 2010; 35: 301-316. [8] Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 2000; 527 Pt 3: 633-639.
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[9] Nitsche MA, Paulus W. Transcranial direct current stimulation--update 2011. Restor Neurol Neurosci 2011; 29: 463-492.
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[10] Jacobson L, Koslowsky M, Lavidor M. tDCS polarity effects in motor and cognitive domains: a meta-analytical review. Exp Brain Res 2012; 216: 1-10. [11] Brunoni AR, Vanderhasselt MA. Working memory improvement with noninvasive brain stimulation of the dorsolateral prefrontal cortex: a systematic review and meta-analysis. Brain Cogn 2014; 86: 1-9. [12] Wolkenstein L, Plewnia C. Amelioration of cognitive control in depression by transcranial direct current stimulation. Biol Psychiatry 2013; 73: 646-651. [13] Dockery CA, Liebetanz D, Birbaumer N, Malinowska M, Wesierska MJ. Cumulative benefits of frontal transcranial direct current stimulation on visuospatial working memory training and skill learning in rats. Neurobiol Learn Mem 2011; 96: 452-460. [14] Dockery CA, Hueckel-Weng R, Birbaumer N, Plewnia C. Enhancement of planning ability by transcranial direct current stimulation. J Neurosci 2009; 29: 72717277. - 18 -
ACCEPTED MANUSCRIPT [15] Chrysikou EG, Hamilton RH, Coslett HB, Datta A, Bikson M, Thompson-Schill SL. Noninvasive transcranial direct current stimulation over the left prefrontal cortex facilitates cognitive flexibility in tool use. Cogn Neurosci 2013; 4: 81-89. [16] Zwissler B, Sperber C, Aigeldinger S, Schindler S, Kissler J, Plewnia C. Shaping memory accuracy by left prefrontal transcranial direct current stimulation. J Neurosci 2014; 34: 4022-4026.
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[17] Krause B, Marquez-Ruiz J, Kadosh RC. The effect of transcranial direct current stimulation: a role for cortical excitation/inhibition balance? Front Hum Neurosci 2013; 7: 602. [18] Wiethoff S, Hamada M, Rothwell JC. Variability in response to transcranial direct current stimulation of the motor cortex. Brain Stimul 2014; 7: 468-475.
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[19] Antal A, Chaieb L, Moliadze V, Monte-Silva K, Poreisz C, Thirugnanasambandam N, et al. Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans. Brain Stimul 2010; 3: 230-237.
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[20] Witte AV, Kurten J, Jansen S, Schirmacher A, Brand E, Sommer J, et al. Interaction of BDNF and COMT polymorphisms on paired-associative stimulationinduced cortical plasticity. J Neurosci 2012; 32: 4553-4561. [21] Plewnia C, Zwissler B, Langst I, Maurer B, Giel K, Kruger R. Effects of transcranial direct current stimulation (tDCS) on executive functions: influence of COMT Val/Met polymorphism. Cortex 2013; 49: 1801-1807.
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[22] Fallgatter AJ, Lesch KP. 22q11.2 deletion syndrome as a natural model for COMT haploinsufficiency-related dopaminergic dysfunction in ADHD. Int J Neuropsychopharmacol 2007; 10: 295-299.
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[23] Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, 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 2004; 75: 807-821.
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[24] Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6: 243-250. [25] Cools R, D'Esposito M. Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry 2011; 69: e113-125. [26] Fresnoza S, Paulus W, Nitsche MA, Kuo MF. Nonlinear dose-dependent impact of d1 receptor activation on motor cortex plasticity in humans. J Neurosci 2014; 34: 2744-2753. [27] Monte-Silva K, Liebetanz D, Grundey J, Paulus W, Nitsche MA. Dosagedependent non-linear effect of L-dopa on human motor cortex plasticity. J Physiol 2010; 588: 3415-3424.
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ACCEPTED MANUSCRIPT [28] Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971; 9: 97-113. [29] Langenecker SA, Zubieta JK, Young EA, Akil H, Nielson KA. A task to manipulate attentional load, set-shifting, and inhibitory control: convergent validity and test-retest reliability of the Parametric Go/No-Go Test. J Clin Exp Neuropsychol 2007; 29: 842-853.
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[30] Ambrus GG, Al-Moyed H, Chaieb L, Sarp L, Antal A, Paulus W. The fade-in-short stimulation--fade out approach to sham tDCS--reliable at 1 mA for naive and experienced subjects, but not investigators. Brain Stimul 2012; 5: 499-504.
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[31] Lopez-Alonso V, Cheeran B, Rio-Rodriguez D, Fernandez-Del-Olmo M. Interindividual variability in response to non-invasive brain stimulation paradigms. Brain Stimul 2014; 7: 372-380.
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[32] Cheeran B, Talelli P, Mori F, Koch G, Suppa A, Edwards M, et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Physiol 2008; 586: 5717-5725. [33] Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-omethyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 2004; 24: 53315335.
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[34] Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A. Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 2001; 432: 119-136. [35] Witte AV, Floel A. Effects of COMT polymorphisms on brain function and behavior in health and disease. Brain Res Bull 2012; 88: 418-428.
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[36] Nandam LS, Hester R, Wagner J, Dean AJ, Messer C, Honeysett A, et al. Dopamine D(2) receptor modulation of human response inhibition and error awareness. J Cogn Neurosci 2013; 25: 649-656.
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[37] Morein-Zamir S, Robbins TW. Fronto-striatal circuits in response-inhibition: Relevance to addiction. Brain Res 2014. [38] Vriend C, Gerrits NJ, Berendse HW, Veltman DJ, van den Heuvel OA, van der Werf YD. Failure of stop and go in de novo Parkinson's disease-a functional magnetic resonance imaging study. Neurobiol Aging 2014. [39] Albrecht DS, Kareken DA, Christian BT, Dzemidzic M, Yoder KK. Cortical dopamine release during a behavioral response inhibition task. Synapse 2014; 68: 266-274. [40] Cummins TD, Hawi Z, Hocking J, Strudwick M, Hester R, Garavan H, et al. Dopamine transporter genotype predicts behavioural and neural measures of response inhibition. Mol Psychiatry 2012; 17: 1086-1092. [41] Gurvich CT, Rossell SL. Genetic variations in dopamine and inhibitory control: lack of influence on action restraint. Behav Brain Res 2014; 267: 12-16. - 20 -
ACCEPTED MANUSCRIPT [42] Mier D, Kirsch P, Meyer-Lindenberg A. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry 2009. [43] Bosia M, Zanoletti A, Spangaro M, Buonocore M, Bechi M, Cocchi F, et al. Factors affecting cognitive remediation response in schizophrenia: the role of COMT gene and antipsychotic treatment. Psychiatry Res 2014; 217: 9-14.
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[44] Javadi AH, Walsh V. Transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex modulates declarative memory. Brain Stimul 2012; 5: 231-241. [45] Zaehle T, Sandmann P, Thorne JD, Jancke L, Herrmann CS. Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: combined behavioural and electrophysiological evidence. BMC Neurosci 2011; 12: 2.
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[46] Chikazoe J. Localizing performance of go/no-go tasks to prefrontal cortical subregions. Curr Opin Psychiatry 2010; 23: 267-272.
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[47] Rubia K, Russell T, Overmeyer S, Brammer MJ, Bullmore ET, Sharma T, et al. Mapping motor inhibition: conjunctive brain activations across different versions of go/no-go and stop tasks. Neuroimage 2001; 13: 250-261. [48] Steele VR, Aharoni E, Munro GE, Calhoun VD, Nyalakanti P, Stevens MC, et al. A large scale (N=102) functional neuroimaging study of response inhibition in a Go/NoGo task. Behav Brain Res 2013; 256: 529-536.
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[49] Juan CH, Muggleton NG. Brain stimulation and inhibitory control. Brain Stimul 2012; 5: 63-69. [50] Chambers CD, Bellgrove MA, Stokes MG, Henderson TR, Garavan H, Robertson IH, et al. Executive "brake failure" following deactivation of human frontal lobe. J Cogn Neurosci 2006; 18: 444-455.
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[51] Dambacher F, Sack AT, Lobbestael J, Arntz A, Brugmann S, Schuhmann T. The Role of Right Prefrontal and Medial Cortex in Response Inhibition: Interfering with Action Restraint and Action Cancellation Using Transcranial Magnetic Brain Stimulation. J Cogn Neurosci 2014. [52] Chen CY, Muggleton NG, Tzeng OJ, Hung DL, Juan CH. Control of prepotent responses by the superior medial frontal cortex. Neuroimage 2009; 44: 537-545. [53] Jacobson L, Javitt DC, Lavidor M. Activation of inhibition: diminishing impulsive behavior by direct current stimulation over the inferior frontal gyrus. J Cogn Neurosci 2011; 23: 3380-3387. [54] Beeli G, Casutt G, Baumgartner T, Jancke L. Modulating presence and impulsiveness by external stimulation of the brain. Behav Brain Funct 2008; 4: 33. [55] Hsu TY, Tseng LY, Yu JX, Kuo WJ, Hung DL, Tzeng OJ, et al. Modulating inhibitory control with direct current stimulation of the superior medial frontal cortex. Neuroimage 2011; 56: 2249-2257.
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ACCEPTED MANUSCRIPT [56] Hwang JH, Kim SH, Park CS, Bang SA, Kim SE. Acute high-frequency rTMS of the left dorsolateral prefrontal cortex and attentional control in healthy young men. Brain Res 2010; 1329: 152-158.
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[57] Li D, Zuo C, Guan Y, Zhao Y, Shen J, Zan S, et al. FDG-PET study of the bilateral subthalamic nucleus stimulation effects on the regional cerebral metabolism in advanced Parkinson disease. Acta Neurochir Suppl 2006; 99: 51-54.
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ACCEPTED MANUSCRIPT Figure legends
Fig. 1: Model of the nonlinear association between prefrontal dopaminergic signalling and cognitive performance dependent on COMT Val(108/158)Met genotype and tDCS.
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A) In Met-homozygous individuals who display the highest levels of dopaminergic signalling, executive functioning is impaired by anodal tDCS as the enhancement of neuronal activity pushes performance to the right side of an inverted-U shape curve beyond the optimal level. This model is supported by our previous results [21].
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B) In contrast, cathodal tDCS impairs executive functioning in Val-homozygous
individuals,who display the lowest levels of dopaminergic signalling, by a reduction of
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neuronal activity below the level of optimal performance.
Baseline position of the two genotypes is based on our results which do not indicate baseline differences in executive functioning between the two groups.
Fig. 2: No effect of stimulation or stimulation-by-genotype interaction on
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sustained attention.
Differences in accuracy between sham and cathodal (verum) stimulation are shown for the two genotype groups (COMT Val/Val homozygous individuals and Met-
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carriers). Error bars represent standard error of the mean.
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Fig. 3: Stimulation main effect and stimulation-by-genotype interaction effect on response inhibition. Differences of correctly inhibited trials between sham and cathodal (verum) stimulation is shown for the overall group (Fig. 3a), as well as for the two genotype groups (COMT Val/Val homozygous individuals and Met-carriers; Fig. 3b). ** p ≤ 0.01, error bars represent standard error of the mean.
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ACCEPTED MANUSCRIPT Fig. 4: No effect of stimulation or stimulation-by-genotype interaction on setshifting ability. Differences of accuracy between sham and cathodal (verum) stimulation are shown
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carriers). Error bars represent standard error of the mean.
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for the two genotype groups (COMT Val/Val homozygous individuals and Met-
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Highlights
Cathodal, inhibitory tDCS to the left prefrontal cortex impairs response
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inhibition •
This effect was found in COMT Val-Val homozygous but not in Met-allele
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The COMT polymorphism predicts the influence of tDCS on response
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Genetic information appears effective to individualize brain stimulation effects
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S1935-861X(14)00384-2
DOI:
10.1016/j.brs.2014.11.009
Reference:
BRS 638
To appear in:
Brain Stimulation
Received Date: 16 September 2014 Revised Date:
11 November 2014
Accepted Date: 17 November 2014
Please cite this article as: Nieratschker V, Kiefer C, Giel K, Krüger R, Plewnia C, The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition, Brain Stimulation (2014), doi: 10.1016/ j.brs.2014.11.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition Vanessa Nieratschker, PhD1; Christoph Kiefer, B.Sc.1; Katrin Giel, PhD2; Rejko Krüger, MD3, 4; Christian Plewnia, MD1*
Department of Psychiatry and Psychotherapy, Calwerstrasse 14, 72076 Tübingen, Germany 2
University
of
Tübingen,
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1
Department of Psychosomatic Medicine and Psychotherapy, University of Tübingen, Osianderstrasse 5, 72076 Tübingen, Germany
3
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Clinical and Experimental Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg and Centre Hospitalier de Luxembourg, Campus Belval, 7, avenue des Hauts-Forneaux, L-4362 Eschsur-Alzette, Luxembourg
4
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, University of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany
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* Correspondence and proofs: Christian Plewnia, MD; Department of Psychiatry and Psychotherapy; Neurophysiology & Interventional Neuropsychiatry; University of Tübingen, Calwerstrasse 14, D-72076 Tübingen, Germany; Tel: +49 7071 2986121, Fax: +49 7071 295904, e-mail: [email protected]
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Running title: COMT polymorphism and tDCS effects on executive functions
e-mails: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
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ACCEPTED MANUSCRIPT Abstract Background: Transcranial direct current stimulation (tDCS) is increasingly discussed as a new option to support the cognitive rehabilitation in neuropsychiatric disorders. However, the therapeutic impact of tDCS is limited by high interindividual variability.
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Genetic factors most likely contribute to this variability by modulating the effects of tDCS.
Objectives: We aimed to investigate the influence of the COMT Val(108/158)Met
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polymorphism on cathodal tDCS effects on executive functioning.
Methods: Cathodal tDCS was applied to the left dorsolateral prefrontal cortex (dlPFC)
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during the performance of a parametric Go/No-Go test.
Results: We demonstrate an impairing effect of cathodal tDCS to the dlPFC on response inhibition. This effect was only found in individuals homozygous for the Valallele of the COMT Val(108/158)Met polymorphism. No effects of stimulation on
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executive functions in Met-allele carriers were detected.
Conclusion: Our data indicate that i) cathodal, excitability reducing tDCS, interferes with inhibitory cognitive control, ii) the left dlPFC is critically involved in the neuronal
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network underlying the control of response inhibition, and iii) the COMT Val(108/158)Met polymorphism modulates the impact of cathodal tDCS on inhibitory
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control. Together with our previous finding that anodal tDCS selectively impairs setshifting abilities in COMT Met/Met homozygous individuals, these results indicate that genetic factors modulate effects of tDCS on cognitive performance. Therefore, future tDCS research should account for genetic variability in the design and analysis of neurocognitive as well as therapeutic applications to reduce the variability of results and facilitate individualized neurostimulation approaches.
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ACCEPTED MANUSCRIPT Keywords: Genetics, catechol-O-methyltransferase, COMT, dopamine, response
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inhibition, brain stimulation
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ACCEPTED MANUSCRIPT Introduction
Executive functions such as the control of attention and memory, response selection, planning ability and task flexibility enable goal-directed behaviour. Impaired executive
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functions are often linked with characteristic symptoms of various psychiatric
disorders like schizophrenia [1], affective disorders [2] and addiction [3]. Recently, it has been demonstrated that non-invasive brain stimulation of the prefrontal cortex
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(PFC) can modulate executive functioning in healthy subjects and psychiatric patients [4; 5]. Especially the effects of transcranial direct current stimulation (tDCS) on
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various cognitive functions are well described [6]. This is an easy to use and well tolerated technique which transiently modulates cortical excitability by applying a weak current to a certain brain area [7]. Anodal tDCS enhances neuronal excitability and thus plasticity by depolarization of the neuronal resting membrane potential,
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whereas cathodal tDCS reduces neuronal activity by hyperpolarization of the affected neurons, leading to a reduction in excitability [8]. Linked with cognitive training paradigms, tDCS is increasingly discussed as a new
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option to support cognitive rehabilitation in neuropsychiatric disorders [4]. However, the observed effects still lack consistency, particularly regarding the specificity of
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polarity, the optimal stimulation parameters and the most effective training schedules and paradigms [9; 10]. Enhancing effects of anodal tDCS on executive functions, especially improvements of working-memory performance [11], attention control [12], and planning abilities [13] have been already shown. On the contrary, impairing effects of cathodal tDCS have been less clearly demonstrated [10], and moreover even improvements of performance during cathodal tDCS have been described [1416]. This inconsistency has been attributed to the complex interactions of inhibition and excitation in the cognitive domain [17], the relevance of various -4-
ACCEPTED MANUSCRIPT neurophysiological mechanisms in different tasks [15; 16] and throughout the course of training [14], as well as variations in the inter-individual responsiveness [18]. Several previous studies indicate that genetic factors most likely contribute to this variability [19; 20]. Given the perspectives of tDCS as a treatment for psychiatric
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disorders, determining potential genetic factors of inter-individual variability is an important prerequisite for further developments in this effort.
We recently demonstrated an influence of the functional Val(108/158)Met
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polymorphism in the catechol-O-methyltransferase (COMT) gene on the effect of anodal tDCS stimulation on executive functioning [21]. COMT is an important
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regulator of dopaminergic neurotransmission as it catalyzes the degradation of dopamine particularly in prefrontal regions of the brain [22; 23]. The COMT Val(108/158)Met substitution affects the thermostability of COMT which leads to a significant decrease in enzymatic activity. The two alleles are codominant, resulting in
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the lowest levels of dopamine in Val/Val homozygous individuals, intermediate levels of dopamine in heterozygous individuals and the highest levels of dopamine in Met/Met homozygous individuals [24]. Dopaminergic activity is essential for the
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neuronal underpinnings of cognitive functioning and a non-linear inverted-U relationship has been proposed between dopaminergic signalling and executive
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performance (Fig. 1) [25]. Interestingly, the effects of tDCS on executive function are also modulated by dopamine concentration in a non-linear manner [26; 27]. In our previous study, while there was no anodal stimulation main effect, we demonstrated lower set-shifting abilities in healthy individuals homozygous for the COMT Met-allele compared to Val-allele carriers under anodal tDCS stimulation [21]. This finding suggested that enhancement of neuronal excitability through anodal tDCS stimulation shifts dopaminergic activity in Met/Met homozygous individuals,
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ACCEPTED MANUSCRIPT displaying high baseline dopaminergic activity, to the far right of the inverted-U curve pushing these subjects below their optimal level of cognitive performance (Fig. 1 A). To further characterize the modulatory influence of COMT on tDCS effects, we designed the present study. We hypothesized that in contrast to anodal stimulation
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which affects Met/Met homozygous individuals, reduction of neuronal excitability through cathodal tDCS stimulation shifts dopaminergic activity in Val/Val
homozygous individuals, displaying low baseline dopamiergic activity, to the far left of
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the inverted-U curve pushing these subjects below their optimal level of cognitive performance. In contrast, in Met-allele carriers executive performance will not be
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significantly affected as the shift to lower dopaminergic activity levels due to cathodal stimulation will not reach the threshold where it affects executive performance (Fig. 1B).
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ACCEPTED MANUSCRIPT Material and Methods
Subjects
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Forty-one right-handed (mean handedness score = 86.0, SD = 13.7 according to the Edinburgh Handedness Inventory, [28]) healthy volunteers (all of them students; 9 males, 32 females; mean age = 24.0, standard deviation (SD) = 4.2)) participated in
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this study and gave written informed consent to the experimental procedure approved by the University of Tübingen local ethics committee. None of the subjects had a
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history of physical, mental, or neurological illness and none of the subjects had performed the parametric Go/No-Go (PGNG) task before.
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Parametric Go/No-Go (PGNG) task
A Parametric Go/No-Go (PGNG) task [29] was used to assess sustained attention, response inhibition, and set-shifting abilities; core aspects of executive functioning.
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The task was conducted as previously described [21]. In brief, participants were presented with a continuous stream of letters, each displayed for 500ms with no
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interstimulus interval. Three letters served as target letters (x, y, z), all other letters as distractor stimuli. The PGNG measures different aspects of executive functioning: On the first level, participants were asked for a “go” response to the target letters by pressing a button as fast as possible after the target letter was presented. This level measures sustained attention and establishes reaction tendency to the target letters. The second and third level additionally asked for a “no-go” response, where participants had to inhibit their reaction to the target letter depending on a specific context rule. Level 2 used two target letters and mainly measures response inhibition, -7-
ACCEPTED MANUSCRIPT whereas level 3 used three target letters and is primarily measuring set-shifting abilities. Each level was presented twice in the following order: 1-2-3-1-3-2. Speed and accuracy were assessed on each level. The percentage of correct “go” response (PCTT – percentage correct target trials) on level 1 was used as a measure of
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sustained attention. The percentage of correct “no-go” responses (PCIT- percent correct inhibitory trials) on level 2 was used as a measure of response inhibition, and the percentage of correct “go” responses (PCTT – percentage correct target trials) on
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level 3 was used as a measure of set-shifting ability.
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Experimental procedure
The study was designed as a double-blind, sham-controlled crossover trial. 1 mA of cathodal tDCS was applied for 20 min by a battery driven stimulator (NeuroConn
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GmbH, Illmenau, Germany) via a pair of saline (0,9%)-soaked sponge electrodes (35 cm2 surface area). To affect the left dorsolateral prefrontal cortex (dlPFC), the cathodal electrode was placed on the scalp at F3 according to the international 10-20
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system of electrode placement and the reference electrode (anode) was placed above the right orbit. The current was increased and decreased for 5 seconds at the
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beginning and end of stimulation. For the sham condition, the electrodes were placed at the same positions, but the current was only applied for 40 seconds. This produces the same tingling sensation as verum stimulation but does not have sustained effects on cortical activation. This approach warrants that subjects are not able to distinguish 1mA tDCS from sham stimulation [30]. Performance of the PGNG outlasted the simulation for about 8 minutes. The order of verum and sham stimulation was balanced across the participants and the second session followed 2 days after the
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ACCEPTED MANUSCRIPT first. Predefined codes assigned to either sham or verum stimulation were used to start the stimulator and thus allowed for a double-blind study design.
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Genotyping
Genomic DNA was extracted from ethylenediaminetetraacetic acid (EDTA) anticoagulated venous blood samples according to standard protocols. Of the 41
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individuals included in the study, 28 were genotyped for rs4680 on a StepOne
system (life technologies; Darmstadt; Germany) using TaqMan®SNP Genotyping
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Assay C__25746809_50 (life technologies; Darmstadt; Germany) and the standard protocol for allelic discrimination. Accuracy was assessed by duplicating 15% of the original sample, and reproducibility was 100%. The genotype frequencies did not deviate from Hardy–Weinberg equilibrium (HWE; p = 0.75). In order to increase the
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sample size, 13 previously genotyped individuals were additionally included. Genotyping for this group has been performed as described earlier [21].
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Statistical analysis
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All statistical calculations were performed with SPSS (IBM SPSS Statistics 22.0; Ehningen; Germany) using repeated-measures ANOVAs with the within-factor tDCS stimulationsham,verum and the between factor genotypeVal/Val,Met. Results were considered significant when p ≤ 0.05. As the effects of cathodal tDCS on three different aspects of executive functioning were investigated, nominally significant main effects were multiplied by 3 to Bonferroni correct for multiple comparisons. For significant interaction F-values, post hoc t-tests were performed.
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ACCEPTED MANUSCRIPT Results
Genotypes
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Genotype distribution was as follows: 16 COMT Val/Val homozygous individuals and 25 Met-allele carriers. Both genotype groups did not differ significantly with respect to age (Val/Val: 24.56 ± 3.65, Met-allele carriers: 23.63 ± 4.55, p = 0.5), gender ratio
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(Val/Val: 75.0% female, Met-allele carriers: 80.0% female; p = 0.72), and education
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(100% secondary school education).
Sustained attention
No difference between sham and verum [F(1,39) = 1.58 p = 0.22] and no main effect
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of genotypeVal/Val,Met (p = 0.29) was observed on PGNG level 1. No significant interaction between COMT genotypeVal/Val,Met and stimulationsham,verum was detected [F(1,39) = 0.31, p = 0.58] (Fig.2). No significant main effects or interaction was found
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with regard to reaction time [F(1,39) = 0.06, p = 0.81].
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Response inhibition
On PGNG level 2 a significant interference of cathodal tDCS stimulation with response inhibition was observed in the overall group [F(1,39) = 7.52, p = 0.01, adjusted p = 0.03, partial η2 = 0.16] (Fig. 3a). No main effect of genotypeVal/Val,Met was observed (p = 0.78), but interaction analysis revealed a significant interaction - 10 -
ACCEPTED MANUSCRIPT between COMT genotypeVal/Val,Met and stimulationsham,verum [F(1,39) = 4.05, p = 0.05, partial η2 = 0.09)]. Within the Val/Val group, response inhibition was significantly impaired under cathodal stimulation as compared to sham stimulation (p = 0.01), whereas cathodal stimulation had no effect on Met-carriers (p = 0.56; Fig. 3b). No
0.12, p = 0.74].
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significant main effects or interaction on reaction time have been observed [F(1,39) =
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Set-shifting
Sham and verum stimulation did not lead to significantly different performances on set-shifting abilities as measured on PGNG level 3 [F(1,39) = 0.05, p = 0.83]. No main effect of genotypeVal/Val,Met (p = 0.38) and no significant interaction between
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COMT genotypeVal/Val,Met and stimulationsham,verum was observed [F(1,39) = 0.02, p = 0.89] (Fig. 4). Analysis of reaction time also did not yield significant main effects or
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interaction [F(1,39) = 0.1, p = 0.75].
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ACCEPTED MANUSCRIPT Discussion
The present study provides new evidence for individual genetic determinants crucially modulating the efficacy of non-invasive brain stimulation on response inhibition, a
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core aspect of executive function. To our knowledge, these are the first data showing that the COMT Val(108/158)Met polymorphism critically modulates the detrimental effect of cathodal tDCS on response inhibition.
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Currently, a major challenge in the growing field of brain stimulation research is the consistency of the observed effects. Although the behavioral relevance of techniques
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modulating cortical activity like repetitive transcranial magnetic stimulation (rTMS) and tDCS on cognitive functions is non-controversial [5] the broader use particularly in a clinical context is thwarted by low-effect sizes, high inter-individual variability [31] and a substantial number of non-responders to the intervention [18]. Nevertheless,
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linking non-invasive brain stimulation techniques with cognitive training is a promising new neurorehabilitative approach [4]. Therefore, individual predictors of efficacy of tDCS are warranted and would significantly enhance the knowledge about the
applicability.
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mechanisms of non-invasive brain stimulation, thereby improving its clinical
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To this aim, first pivotal studies have demonstrated the interaction of brain-stimulation effects and individual genetic predispositions on neuroplasticity and cognitive functioning [19-21; 32]. The results of the present study, however, verify a specific contribution of genetic factors to the modulatory effects of tDCS on behavioral measures. As suggested by our previous work demonstrating an interference of anodal tDCS with executive functioning specifically in Met/Met homozygotes [21], we proceeded with investigating the effect of cathodal tDCS and were able to confirm our hypothesis assuming a detrimental influence distinctively in Val/Val-homozygous - 12 -
ACCEPTED MANUSCRIPT individuals. Taken together, these data are particularly compatible with the theoretical model of an inverted-U relationship between prefrontal dopaminergic signalling and executive functioning (Fig. 1) [25]. Executive functions successfully targeted by tDCS critically involve prefrontal dopaminergic activity which is modulated by the functional
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COMT Val(108/158)Met polymorphism. The findings presented in the current study suggest that the lower dopaminergic activity in Val/Val homozygous individuals is critical for an inhibitory effect of cathodal tDCS on response inhibition. COMT does
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not only regulate dopamine levels; norepinephrine, epinephrine and other catecholcontaining compounds are also putative substrates of COMT. Therefore, we can not
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clearly state, that the effects we observed are based on alterations of dopaminergic neurotransmission. However, the influence of other catecholamines do not seem to play a major role in the prefrontal cortex as demonstrated by Tunbridge et al., who showed that the COMT-inhibitor tolocapone increases dopamine levels but not
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norepinephrine levels in the prefrontal cortex of the rat when catecholamine efflux is induced [33]. It is important to consider that we did not quantify dopaminergic signalling or dopamine levels in both of our studies and our conclusions are
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exclusively based on a theoretical model which needs to be confirmed and replicated in further studies by independent groups. An acute dopaminergic challenge could be
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included in further studies to examine if the observed effect of cathodal tDCS on response inhibition actually follows the inverted-U model of dopaminergic signalling. A further limitation of our study is that only one genetic variant was investigated and the contribution of other genetic variants, especially genes important for dopaminergic neurotransmission have not been considered. However, the COMT Val(108/158)Met polymorphism was chosen because of its clear influence on dopamine levels especially in the prefrontal regions of the brain where the dopamine
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ACCEPTED MANUSCRIPT transporter is less abundant [34] and because we aimed to validate and extend the findings from our previous anodal study [21]. Cathodal tDCS affects response inhibition, but had no influence on the other executive functions tested with the PGNG. Particularly, we did not observe effects of
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cathodal stimulation on set-shifting ability. This effect is in line with the notion of
COMT-genotype dependent differences in cognitive stability and flexibility [35]. In this conception, Val-allele dependent lower prefrontal dopamine is associated with less
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cognitive stability but higher flexibility. In turn, Met-allele dependent higher dopamine concentrations are linked with impaired flexibility but stronger stability. Consistently, a
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further reduction of dopaminergic signalling by cathodal tDCS reduces the already weaker stability in Val-homozygous individuals to a behaviorally relevant impairment of response inhibition with no effect on set-shifting ability as a measure of flexibility. Reciprocally, in our previous study [21], set-shifting ability was compromised by an
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anodal tDCS-induced further increase of dopaminergic signalling in Met-homozygous individuals. It is important to note that there is a lack of clarity in the literature about the task specificity of the effects of the COMT Val(108/158)Met polymorphism.
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Converging evidence from pharmacological, clinical, and imaging studies suggest that response inhibition is based on frontostriatal networks which are predominantly
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modulated by dopamine and noradrenaline [36-40]. However, we did not measure dopaminergic signalling or dopamine levels in the different genotype groups and the contribution of other genetic variants, especially genes important for dopaminergic neurotransmission have not been considered. With respect to a general influence of the COMT Val(108/158)Met polymorphism on the executive functions addressed with the PGNG, we did not find an effect in the sham condition. This is consistent with a recent study using the Go/No-Go task [41]. However, differential effects of genetic variation in COMT on the neural substrates of - 14 -
ACCEPTED MANUSCRIPT executive functioning have been reliably demonstrated [42]. Most relevant to our study is the finding that Val-allele homozygous show increased activation in cognitive paradigms most likely indicating decreased cortical efficiency. Based on these data, it is plausible that an interference with this presumably compensatory activity by
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cathodal tDCS can induce a loss of function at the behavioural level. Similarly, an interaction between pharmacological treatment and COMT Val(108/158)Met
polymorphism on cognitive improvements after cognitive remediation therapy was
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found to corroborate the close interaction between COMT activity and neuromodulatory interventions relating to cognition [43].
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Irrespective of the genetic influence on the effect, the significant impairment of response inhibition during cathodal tDCS supports the general concept that a reduction of neuronal excitability by cathodal tDCS, of the left dlPFC can provoke a disturbance of executive control [44; 45]. However, it has to be kept in mind that the
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interaction of stimulation and task performance is complex and a simple beneficial/detrimental dichotomy of anodal and cathodal tDCS could be misleading [5; 10]. Nevertheless, our findings clearly demonstrate an involvement of the left
inhibition [46].
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dlPFC and support the relevance of top-down control processes for response
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For inhibitory control, particularly tested with the Go/No-Go paradigm, previous imaging studies suggested a decisive contribution of ventro- and dorsolateral prefrontal as well as parietal activations [47]. However, data on laterality are variable with a recent study reporting predominantly right-sided activity associated with response inhibition [48]. Accordingly, brain stimulation studies also provided evidence for a bilateral frontoparietal network underlying the control of response inhibition [49]. Specifically, rTMS studies indicated an involvement of the right inferior and right superior prefrontal cortex [50; 51] and the pre-supplementary motor area (pre-SMA; - 15 -
ACCEPTED MANUSCRIPT [52]). Studies using tDCS provided similar results indicating a functional relevance of the right inferior frontal cortex [53], the right dlPFC [54]) and the pre-SMA [55]. Notably, available evidence does not allow for a clear discrimination between different task demands, particularly action cancellation in stop-signal tasks and action
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restraint in Go/No-Go tasks most likely involve different networks. However, our
findings of reduced inhibition after cathodal tDCS of the left dlPFC are in line with two other brain stimulation studies indicating the critical involvement of the left dlPFC in
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efficient response inhibition [56; 57].
In conclusion, our findings demonstrate that i) cathodal, excitability reducing tDCS,
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can interfere with inhibitory cognitive control, ii) the left dlPFC is critically involved in the neuronal network underlying the control of response inhibition, and iii) this effect is modulated by the COMT Val(108/158)Met polymorphism. Our study suggests that inclusion of genetic information in the design and analysis of brain stimulation studies
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will be valuable to expand our knowledge on the underlying mechanisms. Finally, this approach will offer new perspectives for an individualised and effective therapeutic
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use of brain stimulation techniques.
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ACCEPTED MANUSCRIPT Funding and Disclosure
Dr. Plewnia received a research grant from the Werner Reichardt Centre for Integrative Neuroscience (CIN, PP2011_11) and speaker’s honoraria from inomed
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Medizintechnik GmbH. The funding source had no role in study design, the collection, analysis and interpretation of data, the writing of the manuscript and the decision to
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submit the article for publication. The authors declare no conflict of interest.
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Acknowledgement
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We would like to thank Dr. Daniel Bucher for critical reading of the manuscript.
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ACCEPTED MANUSCRIPT References
[1] Eisenberg DP, Berman KF. Executive function, neural circuitry, and genetic mechanisms in schizophrenia. Neuropsychopharmacology 2010; 35: 258-277.
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[2] Roiser JP, Elliott R, Sahakian BJ. Cognitive mechanisms of treatment in depression. Neuropsychopharmacology 2012; 37: 117-136. [3] Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 2011; 12: 652-669.
SC
[4] Kuo MF, Paulus W, Nitsche MA. Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases. Neuroimage 2014; 85 Pt 3: 948-960.
M AN U
[5] Miniussi C, Harris JA, Ruzzoli M. Modelling non-invasive brain stimulation in cognitive neuroscience. Neurosci Biobehav Rev 2013; 37: 1702-1712. [6] Mondino M, Bennabi D, Poulet E, Galvao F, Brunelin J, Haffen E. Can transcranial direct current stimulation (tDCS) alleviate symptoms and improve cognition in psychiatric disorders? World J Biol Psychiatry 2014; 15: 261-275.
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[7] George MS, Aston-Jones G. Noninvasive techniques for probing neurocircuitry and treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Neuropsychopharmacology 2010; 35: 301-316. [8] Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 2000; 527 Pt 3: 633-639.
EP
[9] Nitsche MA, Paulus W. Transcranial direct current stimulation--update 2011. Restor Neurol Neurosci 2011; 29: 463-492.
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[10] Jacobson L, Koslowsky M, Lavidor M. tDCS polarity effects in motor and cognitive domains: a meta-analytical review. Exp Brain Res 2012; 216: 1-10. [11] Brunoni AR, Vanderhasselt MA. Working memory improvement with noninvasive brain stimulation of the dorsolateral prefrontal cortex: a systematic review and meta-analysis. Brain Cogn 2014; 86: 1-9. [12] Wolkenstein L, Plewnia C. Amelioration of cognitive control in depression by transcranial direct current stimulation. Biol Psychiatry 2013; 73: 646-651. [13] Dockery CA, Liebetanz D, Birbaumer N, Malinowska M, Wesierska MJ. Cumulative benefits of frontal transcranial direct current stimulation on visuospatial working memory training and skill learning in rats. Neurobiol Learn Mem 2011; 96: 452-460. [14] Dockery CA, Hueckel-Weng R, Birbaumer N, Plewnia C. Enhancement of planning ability by transcranial direct current stimulation. J Neurosci 2009; 29: 72717277. - 18 -
ACCEPTED MANUSCRIPT [15] Chrysikou EG, Hamilton RH, Coslett HB, Datta A, Bikson M, Thompson-Schill SL. Noninvasive transcranial direct current stimulation over the left prefrontal cortex facilitates cognitive flexibility in tool use. Cogn Neurosci 2013; 4: 81-89. [16] Zwissler B, Sperber C, Aigeldinger S, Schindler S, Kissler J, Plewnia C. Shaping memory accuracy by left prefrontal transcranial direct current stimulation. J Neurosci 2014; 34: 4022-4026.
RI PT
[17] Krause B, Marquez-Ruiz J, Kadosh RC. The effect of transcranial direct current stimulation: a role for cortical excitation/inhibition balance? Front Hum Neurosci 2013; 7: 602. [18] Wiethoff S, Hamada M, Rothwell JC. Variability in response to transcranial direct current stimulation of the motor cortex. Brain Stimul 2014; 7: 468-475.
SC
[19] Antal A, Chaieb L, Moliadze V, Monte-Silva K, Poreisz C, Thirugnanasambandam N, et al. Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans. Brain Stimul 2010; 3: 230-237.
M AN U
[20] Witte AV, Kurten J, Jansen S, Schirmacher A, Brand E, Sommer J, et al. Interaction of BDNF and COMT polymorphisms on paired-associative stimulationinduced cortical plasticity. J Neurosci 2012; 32: 4553-4561. [21] Plewnia C, Zwissler B, Langst I, Maurer B, Giel K, Kruger R. Effects of transcranial direct current stimulation (tDCS) on executive functions: influence of COMT Val/Met polymorphism. Cortex 2013; 49: 1801-1807.
TE D
[22] Fallgatter AJ, Lesch KP. 22q11.2 deletion syndrome as a natural model for COMT haploinsufficiency-related dopaminergic dysfunction in ADHD. Int J Neuropsychopharmacol 2007; 10: 295-299.
EP
[23] Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, 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 2004; 75: 807-821.
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[24] Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6: 243-250. [25] Cools R, D'Esposito M. Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry 2011; 69: e113-125. [26] Fresnoza S, Paulus W, Nitsche MA, Kuo MF. Nonlinear dose-dependent impact of d1 receptor activation on motor cortex plasticity in humans. J Neurosci 2014; 34: 2744-2753. [27] Monte-Silva K, Liebetanz D, Grundey J, Paulus W, Nitsche MA. Dosagedependent non-linear effect of L-dopa on human motor cortex plasticity. J Physiol 2010; 588: 3415-3424.
- 19 -
ACCEPTED MANUSCRIPT [28] Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971; 9: 97-113. [29] Langenecker SA, Zubieta JK, Young EA, Akil H, Nielson KA. A task to manipulate attentional load, set-shifting, and inhibitory control: convergent validity and test-retest reliability of the Parametric Go/No-Go Test. J Clin Exp Neuropsychol 2007; 29: 842-853.
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[30] Ambrus GG, Al-Moyed H, Chaieb L, Sarp L, Antal A, Paulus W. The fade-in-short stimulation--fade out approach to sham tDCS--reliable at 1 mA for naive and experienced subjects, but not investigators. Brain Stimul 2012; 5: 499-504.
SC
[31] Lopez-Alonso V, Cheeran B, Rio-Rodriguez D, Fernandez-Del-Olmo M. Interindividual variability in response to non-invasive brain stimulation paradigms. Brain Stimul 2014; 7: 372-380.
M AN U
[32] Cheeran B, Talelli P, Mori F, Koch G, Suppa A, Edwards M, et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Physiol 2008; 586: 5717-5725. [33] Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-omethyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 2004; 24: 53315335.
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[34] Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A. Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 2001; 432: 119-136. [35] Witte AV, Floel A. Effects of COMT polymorphisms on brain function and behavior in health and disease. Brain Res Bull 2012; 88: 418-428.
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[36] Nandam LS, Hester R, Wagner J, Dean AJ, Messer C, Honeysett A, et al. Dopamine D(2) receptor modulation of human response inhibition and error awareness. J Cogn Neurosci 2013; 25: 649-656.
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[37] Morein-Zamir S, Robbins TW. Fronto-striatal circuits in response-inhibition: Relevance to addiction. Brain Res 2014. [38] Vriend C, Gerrits NJ, Berendse HW, Veltman DJ, van den Heuvel OA, van der Werf YD. Failure of stop and go in de novo Parkinson's disease-a functional magnetic resonance imaging study. Neurobiol Aging 2014. [39] Albrecht DS, Kareken DA, Christian BT, Dzemidzic M, Yoder KK. Cortical dopamine release during a behavioral response inhibition task. Synapse 2014; 68: 266-274. [40] Cummins TD, Hawi Z, Hocking J, Strudwick M, Hester R, Garavan H, et al. Dopamine transporter genotype predicts behavioural and neural measures of response inhibition. Mol Psychiatry 2012; 17: 1086-1092. [41] Gurvich CT, Rossell SL. Genetic variations in dopamine and inhibitory control: lack of influence on action restraint. Behav Brain Res 2014; 267: 12-16. - 20 -
ACCEPTED MANUSCRIPT [42] Mier D, Kirsch P, Meyer-Lindenberg A. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry 2009. [43] Bosia M, Zanoletti A, Spangaro M, Buonocore M, Bechi M, Cocchi F, et al. Factors affecting cognitive remediation response in schizophrenia: the role of COMT gene and antipsychotic treatment. Psychiatry Res 2014; 217: 9-14.
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[44] Javadi AH, Walsh V. Transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex modulates declarative memory. Brain Stimul 2012; 5: 231-241. [45] Zaehle T, Sandmann P, Thorne JD, Jancke L, Herrmann CS. Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: combined behavioural and electrophysiological evidence. BMC Neurosci 2011; 12: 2.
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[46] Chikazoe J. Localizing performance of go/no-go tasks to prefrontal cortical subregions. Curr Opin Psychiatry 2010; 23: 267-272.
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[47] Rubia K, Russell T, Overmeyer S, Brammer MJ, Bullmore ET, Sharma T, et al. Mapping motor inhibition: conjunctive brain activations across different versions of go/no-go and stop tasks. Neuroimage 2001; 13: 250-261. [48] Steele VR, Aharoni E, Munro GE, Calhoun VD, Nyalakanti P, Stevens MC, et al. A large scale (N=102) functional neuroimaging study of response inhibition in a Go/NoGo task. Behav Brain Res 2013; 256: 529-536.
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[49] Juan CH, Muggleton NG. Brain stimulation and inhibitory control. Brain Stimul 2012; 5: 63-69. [50] Chambers CD, Bellgrove MA, Stokes MG, Henderson TR, Garavan H, Robertson IH, et al. Executive "brake failure" following deactivation of human frontal lobe. J Cogn Neurosci 2006; 18: 444-455.
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EP
[51] Dambacher F, Sack AT, Lobbestael J, Arntz A, Brugmann S, Schuhmann T. The Role of Right Prefrontal and Medial Cortex in Response Inhibition: Interfering with Action Restraint and Action Cancellation Using Transcranial Magnetic Brain Stimulation. J Cogn Neurosci 2014. [52] Chen CY, Muggleton NG, Tzeng OJ, Hung DL, Juan CH. Control of prepotent responses by the superior medial frontal cortex. Neuroimage 2009; 44: 537-545. [53] Jacobson L, Javitt DC, Lavidor M. Activation of inhibition: diminishing impulsive behavior by direct current stimulation over the inferior frontal gyrus. J Cogn Neurosci 2011; 23: 3380-3387. [54] Beeli G, Casutt G, Baumgartner T, Jancke L. Modulating presence and impulsiveness by external stimulation of the brain. Behav Brain Funct 2008; 4: 33. [55] Hsu TY, Tseng LY, Yu JX, Kuo WJ, Hung DL, Tzeng OJ, et al. Modulating inhibitory control with direct current stimulation of the superior medial frontal cortex. Neuroimage 2011; 56: 2249-2257.
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ACCEPTED MANUSCRIPT [56] Hwang JH, Kim SH, Park CS, Bang SA, Kim SE. Acute high-frequency rTMS of the left dorsolateral prefrontal cortex and attentional control in healthy young men. Brain Res 2010; 1329: 152-158.
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M AN U
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[57] Li D, Zuo C, Guan Y, Zhao Y, Shen J, Zan S, et al. FDG-PET study of the bilateral subthalamic nucleus stimulation effects on the regional cerebral metabolism in advanced Parkinson disease. Acta Neurochir Suppl 2006; 99: 51-54.
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ACCEPTED MANUSCRIPT Figure legends
Fig. 1: Model of the nonlinear association between prefrontal dopaminergic signalling and cognitive performance dependent on COMT Val(108/158)Met genotype and tDCS.
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A) In Met-homozygous individuals who display the highest levels of dopaminergic signalling, executive functioning is impaired by anodal tDCS as the enhancement of neuronal activity pushes performance to the right side of an inverted-U shape curve beyond the optimal level. This model is supported by our previous results [21].
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B) In contrast, cathodal tDCS impairs executive functioning in Val-homozygous
individuals,who display the lowest levels of dopaminergic signalling, by a reduction of
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neuronal activity below the level of optimal performance.
Baseline position of the two genotypes is based on our results which do not indicate baseline differences in executive functioning between the two groups.
Fig. 2: No effect of stimulation or stimulation-by-genotype interaction on
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sustained attention.
Differences in accuracy between sham and cathodal (verum) stimulation are shown for the two genotype groups (COMT Val/Val homozygous individuals and Met-
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carriers). Error bars represent standard error of the mean.
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Fig. 3: Stimulation main effect and stimulation-by-genotype interaction effect on response inhibition. Differences of correctly inhibited trials between sham and cathodal (verum) stimulation is shown for the overall group (Fig. 3a), as well as for the two genotype groups (COMT Val/Val homozygous individuals and Met-carriers; Fig. 3b). ** p ≤ 0.01, error bars represent standard error of the mean.
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ACCEPTED MANUSCRIPT Fig. 4: No effect of stimulation or stimulation-by-genotype interaction on setshifting ability. Differences of accuracy between sham and cathodal (verum) stimulation are shown
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carriers). Error bars represent standard error of the mean.
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for the two genotype groups (COMT Val/Val homozygous individuals and Met-
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Highlights
Cathodal, inhibitory tDCS to the left prefrontal cortex impairs response
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•
inhibition •
This effect was found in COMT Val-Val homozygous but not in Met-allele
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carriers
The COMT polymorphism predicts the influence of tDCS on response
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Genetic information appears effective to individualize brain stimulation effects
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•
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inhibition