No evidence for any effect of multiple sessions of frontal transcranial direct stimulation on mood in healthy older adults

Journal Pre-proof No evidence for any effect of multiple sessions of frontal transcranial direct stimulation on mood in healthy older adults Malin Freidle, Jonna Nilsson, Alexander V. Lebedev, Martin Lövdén PII:

S0028-3932(19)30368-9

DOI:

https://doi.org/10.1016/j.neuropsychologia.2019.107325

Reference:

NSY 107325

To appear in:

Neuropsychologia

Received Date: 23 May 2019 Revised Date:

6 December 2019

Accepted Date: 20 December 2019

Please cite this article as: Freidle, M., Nilsson, J., Lebedev, A.V., Lövdén, M., No evidence for any effect of multiple sessions of frontal transcranial direct stimulation on mood in healthy older adults, Neuropsychologia (2020), doi: https://doi.org/10.1016/j.neuropsychologia.2019.107325. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Published by Elsevier Ltd.

Author contributions

M. Lövdén developed the study concept. M.Lövdén, J. Nilsson and A. V. Lebedev designed the study. M.Freidle analysed the data and drafted the manuscript under the supervision of M. Lövdén. All other authors provided critical revisions and approved the final version of the manuscript for submission.

EFFECT OF MULTIPLE TDCS ON MOOD 1

No evidence for any effect of multiple sessions of frontal transcranial direct stimulation on

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mood in healthy older adults

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Malin Freidle a, Jonna Nilsson a, Alexander V. Lebedev a, b, and Martin Lövdén a

5 6 7 8

a

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Karolinska Institutet and Stockholm University, Stockholm, Sweden.

Aging Research Center, Department of Neurobiology, Care Sciences and Society,

b

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

12

*

Correspondence should be addressed to Malin Freidle, [email protected],

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Tomtebodavägen 18 A, 171 65 Stockholm, Sweden.

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14 15

EFFECT OF MULTIPLE TDCS ON MOOD 16

Abstract

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The dorsolateral prefrontal cortex (DLPFC) is part of a network important for

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emotional regulation and the possibility of modulating activity in this region with transcranial

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direct current stimulation (TDCS) to change mood has gained great interest, particularly for

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application in clinical populations. Whilst results in major depressive disorder have been

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promising, less is known about the effects of TDCS on mood in non-clinical populations. We

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hypothesized that multiple sessions of anodal TDCS applied over the left DLPFC would

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enhance mood, primarily as measured by the Profile of Mood States questionnaire, in healthy

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older adults. In addition, in an exploratory analysis, we examined the potentially moderating

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role of working memory training. Working memory, just like emotional regulation, taxes the

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DLPFC, which suggests that engaging in a working memory task whilst receiving TDCS may

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have a different effect on activity in this region and consequently mood. A total of 123

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participants between 65 and 75 years of age were randomly assigned to receive either 20

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sessions of TDCS, with or without working memory training, or 20 sessions sham

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stimulation, with or without working memory training. We found no support for enhancement

33

of mood due to TDCS in healthy older adults, with or without cognitive training and conclude

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that the TDCS protocol used is unlikely to improve mood in non-depressed older individuals.

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Keywords: TDCS, mood, DLPFC, healthy, aged

EFFECT OF MULTIPLE TDCS ON MOOD 39 40

1. Introduction Emotions and the states of prolonged and pervasive emotions that are often described as

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mood are complexly intertwined with the foundations of a human life, including interactions

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with others, sleep and decision-making. (Kahn, Sheppes, & Sadeh, 2013; Tversky &

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Kahneman, 1981; Vittengl & Holt, 1998). Emotions and mood are not solely determined by

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external stimuli but also by emotional reactivity i.e., an individual’s disposition towards

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experiencing emotions in response to stimuli (Boyes, Carmody, Clarke, & Hasking, 2017),

46

and emotional regulation. An integrative definition of emotional regulation encompasses the

47

abilities to modulate emotional arousal and to be aware, understand and accept emotions, as

48

well as being able to act as desired regardless of the present emotional state (Gratz &

49

Roemer, 2004). A meta-analysis of RCT studies that aimed to improve emotional regulation

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by behavioural techniques showed small to moderate effect sizes on well-being, with fairly

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robust long-term effects. A majority of the studies used healthy samples and so the results

52

indicate that a more effective emotional regulation can affect mood in healthy individuals

53

(Bolier, et al., 2013).

54

As for the neural correlates of emotional regulation, we know that the dorsolateral

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prefrontal cortex (DLPFC) has a central role (Buhle, et al., 2014; Kohn, et al., 2014; Ochsner,

56

Silvers, & Buhle, 2012). Findings point to more right-pronounced activity in the DLPFC

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during negative stimuli processing (Beraha, et al., 2012) and more left-pronounced activity

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during positive stimuli processing (Herrington, et al., 2010). There has been a great interest in

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modulating mood by changing the pattern of neural activity in the DLPFC. A potential way to

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do this is to use Transcranial Direct Current Stimulation (TDCS), a non-invasive technique

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with few and mild side effects (Poreisz, Boros, Antal, & Paulus, 2007; Priori, Hallett, &

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Rothwell, 2009). Using TDCS, a weak electrical current is passed through the brain by one

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anode and one cathode placed on the scalp. Based on findings in the motor cortex, it has been

EFFECT OF MULTIPLE TDCS ON MOOD 64

suggested that anodal stimulation leads to a hyperpolarisation of the underlying region; that

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is, an increase of the likelihood of neuronal firing, and that cathodal stimulation leads to

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hypopolarisation (Nitsche & Paulus, 2000).

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The majority of previous studies that used TDCS in healthy individuals with the aim of

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affecting mood, used a single stimulation session (Mondino, Thiffault, & Fecteau, 2015).

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However, a recent systematic review (Remue, Baeken, & De Raedt, 2016) concluded that a

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single session of prefrontally applied TDCS, or the similar method Transcranial magnetic

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stimulation (TMS), does not affect mood in healthy individuals. Out of the three published

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studies that have used multiple TDCS (3-4 stimulations) in healthy individuals, two reported

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a positive effect on mood (Austin, et al., 2016; Newstead, et al., 2018) while the third not

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(Motohashi, Yamaguchi, Fujii, & Kitahara, 2013). All three studies placed the anode over the

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left DLPFC but differed in the placement of the cathode, placing it over the right DLPFC

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(Austin, et al., 2016), the orbital area (Motohashi, et al., 2013), or the right cerebellum

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(Newstead, et al., 2018). These studies all had a small number of participants (n = 12-42).

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Thus, due to the diverse outcomes, the diverse placements of the cathode as well as the small

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samples, the mood effects of repeated sessions of frontal TDCS in healthy adults remains

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unclear.

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The DLPFC has also consistently been found to be important in depression. (Fitzgerald,

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Laird, Maller, & Daskalakis, 2008; Hamilton, et al., 2012; Jaworska, Yang, Knott, &

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Macqueen, 2015; Sacher, et al., 2012). Meta-analyses have suggested that depressed

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individuals have decreased activity in the DLPFC at rest, relative to healthy individuals, as

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well as a lack of activation in the DLPFC when presented with negative stimuli (Fitzgerald, et

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al., 2008; Hamilton, et al., 2012). Some findings indicate that the hypoactivation concerns the

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left DLPFC specifically with the right DLPFC actually being hyperactive (Grimm, et al.,

EFFECT OF MULTIPLE TDCS ON MOOD 88

2008). The abnormal pattern of activation in the DLPFC in depression has been shown to lead

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to a failure in attenuating the impact of negative stimuli (Hamilton, et al., 2012).

90

To date, ten randomised controlled trials (RCTs) have evaluated the effect of TDCS in

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depression and the two most recent meta-analyses demonstrated effect sizes of around 0.3 on

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depressive symptoms, supporting its potential as an effective treatment in depression

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(Brunoni, et al., 2015; Meron, Hedger, Garner, & Baldwin, 2015). All the ten RCTs placed

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the anode over the left DLPFC (i.e., aiming to increase the activity in the left DLPFC), whilst

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the position of the cathode varied between the orbital area and the right DLPFC. Importantly,

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all ten studies used multiple (5-15) TDCS sessions.

97

The present study is based on the sample from the REBOOT trial that investigated

98

effects of TDCS on working memory training for healthy older adults (Nilsson, Lebedev,

99

Rydstrom, and Lovden (2017). In this study, participants were not only assigned TDCS or

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sham stimulation but also simultaneous working memory training or control cognitive

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training. The anodal TDCS was placed over the left DLPFC i.e., a central area in emotional

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regulation (as well as working memory) and the number of sessions was large (20) as well as

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the sample size (n = 123). In the present investigation, we will therefore use the same sample

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for investigating the effects of TDCS in mood, in healthy older adults. Whilst TDCS did not

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improve the cognitive outcomes of working memory training, we also took the opportunity

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to explore the possibility that working memory training, as a modulator of the effects of

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TDCS, could affect mood indirectly by its modulation of DLPFC activity (D'Esposito, Postle,

108

& Rypma, 2000). The combination TDCS and cognitive training has been investigated for

109

depressive symptoms in two smaller studies (n = 27-37), but not for healthy individuals. The

110

reported effects on depressive symptoms were divergent as can be expected from small

111

samples (Brunoni, et al., 2014; Segrave, Arnold, Hoy, & Fitzgerald, 2014).

EFFECT OF MULTIPLE TDCS ON MOOD 112

Empirical findings indicate that compared to younger adults, older adults attend to

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negative stimuli to a lesser degree, remember positive stimuli to a higher degree than

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negative stimuli, and experience less negative affect in general (Charles, Mather, &

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Carstensen, 2003; Mather & Carstensen, 2003; Reynolds & Gatz, 2001). In terms of brain

116

activity, a frequently reported pattern is that older adults show less activity in the amygdala

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and other temporo-limbic areas in response to emotional stimuli, but more prefrontal activity,

118

relative to younger adults (Gunning-Dixon, et al., 2003; Roalf, Pruis, Stevens, & Janowsky,

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2011). This changed activity pattern has been suggested to explain the often found increased

120

emotional well-being in older adults, possibly through increased emotional regulation

121

(Nashiro, Sakaki, & Mather, 2012). However, it should also be pointed out that a large

122

subgroup of older adults suffers from depression, characterized by lower well-being and loss

123

in daily function (Beekman, et al., 2002; Djernes, 2006).

124

Life expectancy keeps raising in developed countries and, despite higher prevalence of

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diseases, this is accompanied by an increase in life-years with good self-rated health and

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possibly life-years without disability (Christensen, Doblhammer, Rau, & Vaupel, 2009;

127

Crimmins & Beltran-Sanchez, 2011). This makes understanding the brain in self-rated

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healthy individuals a compelling topic. The present investigation is the first study that aims to

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stimulate the brain through TDCS to examine mood effects in healthy, older adults. By this

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we hope to extend the knowledge of the aged, healthy emotional system that emerged from

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passive observations of brain activity (Gunning-Dixon, et al., 2003; Roalf, et al., 2011).

132

Importantly, understanding the aged healthy emotional system may also serve as a foundation

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for understanding depression and its associated changes in brain function in old age.

134

We administered 20 anodal TDCS sessions (five a week for four weeks) over the left

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DLPFC in older healthy individuals. We hypothesized a positive effect on mood through an

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increased activity in the left DLPFC. The hypothesis follows from the findings of a

EFFECT OF MULTIPLE TDCS ON MOOD 137

hypoactive (left) DLPFC in depression, the empirical studies reporting a mood effect of

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anodal TDCS over the DLPFC in healthy individuals and to some extent also from the

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association between elevated frontal activity in older adults and well-being (i.e., the

140

possibility that the increased well-being in older adults is caused by enhanced frontal

141

activity).

142

A positive effect on mood would have several implications. Firstly, it would suggest

143

that the DLPFC continues to be an area important in emotional regulation in old age despite

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the reorganization of brain activity in the aged emotional system. Secondly, it would

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strengthen the implications from studies of behavioural techniques that emotional regulation

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and mood can be enhanced in individuals within a normal mood range, including in older

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individuals. And thirdly, it would also further support that multiple TDCS can indeed affect

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brain activity in frontal areas. This is important since general concerns about the effects of

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TDCS have recently been brought up (Horvath, Carter, & Forte, 2015).

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As such, the primary aim of the present study was to deepen our understanding of

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emotional regulation and its neural correlates in healthy older individuals. The administration

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of 20 stimulation sessions in healthy adults is unprecedented and the sample size is by far the

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largest in the context of TDCS in healthy individuals (Remue, et al., 2016). Our primary

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mood outcome measure, the Total Mood Disturbance score as derived from the Profile of

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Mood Scale (POMS), was administered once before the intervention period and thereafter at

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the beginning of every fifth stimulation session i.e., once a week. The secondary mood

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outcome measure, answer to the question “How are you feeling today?” on a 10-point Likert

158

scale, was administered at the beginning of every stimulation session, as well as five times

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before and after the intervention period. We predicted larger improvements in mood for the

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primary and secondary measure for participants receiving TDCS, relative to participants

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receiving a sham stimulation, over the course of the intervention period.

EFFECT OF MULTIPLE TDCS ON MOOD 162 163

2. Materials and methods

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2.1. Participants

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We advertised the study in local newspapers and recruited 142 healthy adults aged 65

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to 75 that met full eligibility criteria (primarily: no somatic or psychiatric illness, and no

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sensory impairment) and gave written informed consent for participation. See the Supplement

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for full inclusion criteria and Table 1 for demographic data of the four experimental groups.

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One hundred and twenty-three participants completed the study. Approval was granted by the

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regional ethics review board of Stockholm (2014/2188-31/1), and the study was conducted in

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accordance with the Declaration of Helsinki. A sample size of 120 was targeted to achieve

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90% power to study a standardised mean difference of 0.3 on the main outcome of the trial

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(i.e., working memory), as based on a repeated-measures ANOVA (α=.05). See the primary

174

publication for details (Nilsson, et al., 2017).

175 176

Table 1. Demographic data for the four experimental groups Variable

TDCS + WM task (n = 32)

TDCS + control task (n = 30)

Sham TDCS + WM task (n = 33)

Sham TDCS + control task (n = 28)

Age (years)

M = 69.31, SD = 2.73

M = 69.87, SD = 2.91

M = 69.64, SD = 2.97

M = 69.82, SD = 2.62

Sex

16 females, 16 males

17 females, 13 males

22 females, 11 males

16 females, 12 males

Education (years)

M = 15.05, SD = 3.19

M = 14.29, SD = 2.29

M = 14.68, SD = 2.86

M = 15.84, SD = 4.09

Reasoning ability (score)

M = 7.06, SD = 2.72

M = 6.97, SD = 3.02

M = 6.88, SD = 2.36

M = 6.93, SD = 2.26

POMS Tot. Mood Dist.

M = 2.19, SD = 21.26

M = - 0.74, SD = 11.08

M = 1.53, SD = 16.81

M = 2.07, SD = 15.62

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Note. Tot. Mood. Dist. = Total Mood Disturbance, “Reasoning ability” refers to pre-test performance on

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Raven’s Advanced Progressive Matrices (odd items of Set II).

179 180

2.2. Design and procedure

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A mixed factorial design was used with the factors cognitive training (working memory

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training vs. control training) and stimulation (TDCS vs. sham). Stratified randomisation using

EFFECT OF MULTIPLE TDCS ON MOOD 183

age, sex and the pre-test scores on Raven’s Advanced Progressive Matrices (the odd items of

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set II) were used to allocate each participant to one of the four intervention groups.

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Participants were blinded both in terms of stimulation and training group and experimenters

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were blinded in terms of stimulation. The participants were economically compensated with

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50 SEK per pre and post assessment occasion (10 occasions) and 100 SEK per occasion

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during the intervention phase (20 occasions). Pre- and post-testing included comprehensive

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cognitive testing, brain imaging, and several questionnaires. The intervention period extended

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over four weeks with 20 occasions of working memory/control training and parallel

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active/sham TDCS. See Nilsson, et al. (2017) for a detailed description of design and

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procedure.

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2.3. TDCS A saline-soaked anode (7x5cm) was placed on the scalp, targeting the left DLPFC,

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corresponding to the F3 in the 10-20 international system for EEG placement. To maximize

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peak current density underneath the F3 the anode was shifted slightly laterally, towards F5. In

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addition, a slight posterior shift ensured the minimum recommended inter-electrode distance

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of 8cm for all participants which minimizes the risk of shunting These modifications were

200

based on recommendations by Seibt, Brunoni, Huang, and Bikson (2015) and resulted in that

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the superior-anterior quarter section and not the centre of the anode was positioned over F3.

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The saline soaked cathode (7x5cm) was placed over the contralateral supraorbital area to

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minimize its possible deactivating effect The 10/20 BraiNet Placement Cap (Jordan

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NeuroScience, Inc, California, USA) was used for the electrode placement. Using the DC-

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STIMULATOR PLUS (neuroConn GmbH, Ilmenau, Germany), a constant direct current of

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2mA (current density 57.1 µA/cm2), was delivered for 25 minutes with an additional 8-

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second ramp-up and a 5-second ramp-down period. Impedance was confirmed to be below 20

EFFECT OF MULTIPLE TDCS ON MOOD 208

kΩ before any stimulation was initiated. For the sham version, the same procedure as in

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active TDCS was used with a 8-second ramp-up and a 5 second ramp down, but the

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stimulation lasted for only 30 seconds and was then followed solely by impedance control (a

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small current pulse every 550 ms: 110 µA over 15 ms, peak current of 3 ms). The 30 second

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stimulation was used to induce the same tingling sensation as experienced when initializing

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active TDCS (i.e., it was a way to mask whether active or sham TDCS was delivered). Before

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fixing the electrodes with rubber straps, the scalp was prepared by parting any hair, cleaning

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the skin with disinfectant and saline solution and subsequently ensuring that the scalp was

216

completely dry with the exception of the electrode areas.The ramp-up and ramp-down time

217

were fixed for the sham stimulation of the study mode of the DC-STIMULATOR PLUS

218

machine and the actual TDCS stimulation was set to have the same ramp-up and ramp-down

219

to mimic the sham stimulation in every aspect except for the stimulation duration. The length

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of the actual stimulation was set to increase the likelihood of longer lasting effects while still

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well below histological safety limits (Liebetanz, et al., 2009; Nitsche & Paulus, 2000; Ohn, et

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al., 2008). Participants guessed whether they had received the sham version or the actual

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TDCS. Side effects were evaluated at four occasions during the intervention weeks. At these

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occasions the participants were administered a 5-point Likert scale before, during and after

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the session (0 = “I did not experience the side effect at all,” 5 = “The side effect was so

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severe that I considered terminating or had to terminate the stimulation”) Five direct side

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effects were evaluated (pain, burning, heating, itching and pinching underneath the

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electrodes) as well as additionally six indirect side effects (see Supplement S14 for all side

229

effects).

230

EFFECT OF MULTIPLE TDCS ON MOOD 231

2.4. Measures of Mood

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Two measures of mood were the focus of the present study. As our main outcome, we

233

used the sum score scale of POMS 2 for adults called Total Mood Disturbance. We used the

234

latest short form of POMS 2 for adults (POMS 2-A Short) with a short time frame (i.e.,

235

participants were asked to rate each item given how they felt “right now”). The Total Mood

236

Disturbance scale is aggregated from adding the scores of the POMS 2 subscales Depression-

237

Rejection, Anger-Hostility, Fatigue-Inertia, Confusion-Bewilderment and Tension Anxiety,

238

and then subtracting the score of the Vigor-Activity subscale. The Total Mood Disturbance

239

scale ranges from -20 to 100, with a higher value indicating a higher mood disturbance.

240

Cronbach’s alpha was calculated to .94 in a normative population aged 50 years and above.

241

The adjusted test-retest reliability coefficient in a normative sample aged 18 and above was

242

.69 for the questionnaire administered one week apart and .54 for the questionnaire

243

administered 30 days apart (Heuchert & McNair, 2012). The participants answered POMS 2

244

once before the intervention and once at the end of each intervention week (i.e., five

245

measurement occasions in total).

246

As our secondary outcome of mood, we used the 10-point Likert scale question “How are you

247

feeling today?” (further on referred to as the Daily mood question) where a higher score

248

indicates greater mood. A red, sad smiley was printed above the number one, a green neutral

249

smiley was printed above the numbers five and six and a yellow smiling smiley was printed

250

above the number ten. This question was answered with a higher frequency than POMS 2 – at

251

five occasions before the intervention, at each of twenty intervention sessions, and at five

252

occasions after the intervention (i.e., in total at 30 occasions). In addition, the question –

253

“How alert do you feel today?” (Daily Alertness question) was also answered on a daily basis

254

but is however not the focus of the present investigation. Both the POMS 2 and the short

EFFECT OF MULTIPLE TDCS ON MOOD 255

questions were administered before any cognitive testing or intervention session.2.5 Working

256

memory and control training

257

The working memory training focused on updating and switching ability. Updating

258

ability was trained using n-back and running span exercises. Switching ability was trained

259

using task switching and rule switching exercises. The control training consisted of a

260

perceptual matching test. The training programs lasted 40 minutes per session and started five

261

minutes after the onset of TDCS or the sham stimulation to avoid distraction due to the start

262

of the stimulation. See Nilsson, et al. (2017) for a more detailed description of the working

263

memory training as well as the control training.

264 265 266

2.6. Statistical analysis SPSS 24 (IBM, Armonk, NY) was used for the descriptive statistics while R (R Core

267

Team, 2016) was used for all inferential statistics. We unfortunately lacked data on one or

268

several assessments for some individuals and training occasions (see Table A3-A10 in

269

Supplement for exact numbers). Since multilevel models are better at handling missing

270

values than traditional models such as ANOVA, while also allowing random effects (Field,

271

2009), we used multilevel models for all analyses. Multilevel models were specified for the

272

main outcome of POMS total mood and for the secondary outcome of Daily mood with both

273

random intercept and slope. The maximum likelihood method and an autoregressive moving

274

average (ARMA 1, 0) covariance structure (Holan, Lund, & Davis, 2010) were used for the

275

estimation. Both models included the main effect of time (occasion 1-5 for POMS total

276

mood, occasion 1-30 for Daily mood), TDCS (active, sham), and cognitive training (working

277

memory training, control training), as well as all possible two way-interactions and the three-

278

way interaction as fixed effects. The package nlme:lme (Pinheiro, Bates, DebRoy, Sarkar, &

279

Team, 2017) with the optimizer named optim was used. In the spirit of encouraging less

EFFECT OF MULTIPLE TDCS ON MOOD 280

dichotomous interpretations of parameter estimates without losing information as well as

281

achieving more robust confidence intervals, cluster bootstrapped confidence intervals were

282

calculated for all estimates and reported instead of p-values (samples = 2000, seed = 12345).

283

This was done using private code that can be made available on request. To decrease the risk

284

of false positive findings by multiple comparisons we set the alpha value to .05 for the

285

primary outcome of POMS total mood disturbance (corresponding to a 95% confidence

286

interval) but to .01 for the secondary outcome of the Daily mood question (corresponding to a

287

99% confidence interval).

288

The between group effects sizes (Cohen’s d) for the two way-interactions including

289

time were calculated using the mean of the standard deviations from the compared groups

290

post the intervention. In addition, the subscales of POMS and the Daily Alertness question

291

were similarly analysed (see the supplement for details).

292

Seven of the 123 participants who completed the trial had a baseline score of at least

293

eight on the Depression-Rejection subscale of the POMS questionnaire. The score of eight on

294

the subscale corresponds to 1.5 SD above the mean in a healthy population aged 50 (Heuchert

295

& McNair, 2012). In a study of the concurrent predictive validity of the Depression-Rejection

296

scale, the use of the cut off 1.5 SD above the mean correctly classified a SCID (Structured

297

Clinical Interview for DSM-IV) diagnosis of Major Depression Disorder with an overall

298

predictive value estimated to 80 % (Patterson, et al., 2006). To investigate whether higher

299

scores on the Depression-Rejection subscale affected our results in a substantial way, we did

300

two types of post-hoc sensitivity analyses. Firstly, we specified the same statistical models as

301

for the original sample but excluded the seven participants who scored eight or above.

302

Secondly, we specified models for the POMS Total Mood Disturbance as well as Daily mood

303

question with a three-way interaction between Time, Stimulation and the individual baseline

304

score on the subscale Depression-Rejection.

EFFECT OF MULTIPLE TDCS ON MOOD 305 306 307

3. Results The participants’ blinding to the type of stimulation they had received was successful

308

with 52% incorrect guesses and 48% correct guesses (p = .72 by binomial test). Reported side

309

effects were generally very small: the maximum average over the four occasions was 1.265

310

(SD = 1.200) for the outcome burning underneath the electrodes for the stimulation period

311

before the training started. No statistically significant difference was found between the

312

active and the sham group, collapsing the scores over time (all ps > .136 by Mann-Whitney U

313

test). See S14 in the Supplement for means and standard deviations of all side effects reported

314

before, during and after stimulation.

315

There was no main effect of stimulation (active, sham) or any interaction between time

316

(occasion 1-5: Pre to Week 4/Post in Figure 1) and stimulation (active, sham) for our main

317

outcome POMS total mood disturbance (i.e., all of the confidence intervals included zero).

318

Unstandardized parameter values for the main effect of stimulation; -0.46 (CI -7.61, 5.57)

319

and for the interaction time x stimulation; -0.30 (CI -1.52, 1.07). Between-group Cohen’s d

320

for total mood disturbance at post measure was 0.10 with a 95% confidence interval

321

including zero (-0.48, 0.28). As for our more explorative question of an interaction between

322

time, TDCS, and cognitive training, our analyses showed no support for any modulating

323

effect of cognitive training on the stimulation effect on mood for the POMS total mood

324

disturbance. Unstandardized parameter values for the interaction Time x Stimulation x

325

Training: -0.07 (CI -1.95, 1.59) See the supplement for details of the model.

326

There was also no significant main effect of stimulation (active, sham) or any

327

interaction between time (occasion 1-30: Pre-1-5, Session 1-20, Post 1- 5 in Figure 1) and

328

stimulation (active, sham) on the Daily mood question (i.e., all of the confidence intervals

329

included zero). Unstandardized parameter values for the main effect of stimulation; 0.06 (CI

EFFECT OF MULTIPLE TDCS ON MOOD 330

(-0.90, 1.10) and for the interaction time x stimulation; -0.01 (CI -0.04, 0.02). Between group

331

Cohen’s at post measure was - 0.06 with a 95% confidence interval including zero (-0.45,

332

0.34). Neither was there support for an interaction of time, TDCS, and cognitive training on

333

mood, as measured with the Daily Mood question. Unstandardized parameter values for the

334

interaction Time x Stimulation x Training: 0.02 (-0.02, 0.06). See the supplement for the

335

details of the model.

336

The sensitivity analyses which excluded the seven individuals who scored at least eight

337

on the POMS Depression-Rejection subscale, as well as the sensitivity analyses that used the

338

baseline score on the POMS Depression-Rejection subscale as a covariate, demonstrated the

339

same outcome. Furthermore, the POMS subscales and Daily Alertness question showed the

340

same pattern of non-significant findings. See the supplement for the details of these analyses

341

as well as descriptive statistics for all time points and outcome measures.

342

343 344 345 346

Fig 1. The effect of TDCS on POMS total mood disturbance. POMS: The Profile of Mood States. Note that the y-axis is broken, total possible range: -25, 100. A higher value indicates more mood disturbance. The error bars correspond to standard deviations. X-axis: time. TDCS: transcranial direct current stimulation.

EFFECT OF MULTIPLE TDCS ON MOOD 347

348 349 350 351

Fig 2. The effect of TDCS on the Daily mood question. Range 0-10 with a higher value indicating better mood. The error bars correspond to standard deviations. X-axis: time. TDCS: transcranial direct current stimulation

352

4. Discussion

353

This study is the first to investigate the effect of multiple prefrontal TDCS on mood in

354

older healthy participants. It greatly exceeds the previous studies in both number of

355

participants (123), number of stimulation sessions (20), and number of mood measurements

356

(5 for main outcome, 30 for secondary outcome). The analyses showed no statistical evidence

357

for enhancement of mood after multiple anodal TDCS over the left DLPFC on the primary

358

mood outcome (POMS total mood disturbance) or on the secondary mood outcome (Daily

359

mood question). There was also no evidence for a modulating effect of working memory

360

training on the TDCS effect on mood for any of the outcome measures.

361

Previous evidence of reduced depressive symptoms following anodal TDCS over the

362

DLPFC in major depressive disorder suggest that TDCS can influence emotional regulation

363

(Aldao, Nolen-Hoeksema, & Schweizer, 2010; Brunoni, et al., 2015; Meron, et al., 2015).

EFFECT OF MULTIPLE TDCS ON MOOD 364

However, the participants in our study were not depressed, which implies that their ability to

365

regulate emotions was at a well-functioning level already at baseline. It is therefore possible

366

that the lack of mood enhancement in the present and previous studies is due to a restriction

367

of mood enhancing effects of TDCS to populations with abnormal emotional regulation.

368

Additionally, effects on mood may be particularly unlikely in a healthy older population

369

given findings that older adults in general experience less negative affect, possibly due to

370

better emotional regulation relative to young adults (Kryla-Lighthall & Mather, 2009;

371

Nashiro, et al., 2012).

372

To enrich the discussion, we also need to consider the function of emotional regulation.

373

It is clear that both low levels of mood, as in depression, as well as excessive mood levels, as

374

in manic episodes, decrease well-functioning. Additionally, dysfunctional emotional

375

regulation has been related to a range of mood and anxiety disorders (Aldao, et al., 2010;

376

Carl, Soskin, Kerns, & Barlow, 2013; Coryell, et al., 1993). In other words, it seems in many

377

ways beneficial to have an emotional system that keeps mood at a relatively stable level,

378

including being fairly robust to external stimuli such as TDCS.

379

On the other hand, one could argue that the positive effects on well-being through

380

behavioural techniques showed by Bolier, et al. (2013) in mostly healthy samples, contradicts

381

such a conclusion. However, Bolier, et al. (2013) also found that the research field of

382

behavioural techniques for emotional regulation suffers from severe quality problems such as

383

only presenting completers-analyses as well as publication bias. This means that conclusions

384

about the alleged effects of behavioural techniques are less robust.

385

A related limitation of the present study is that we did not formally evaluate the

386

presence of depression in the screening phase, which means that the sample may not have

387

been entirely healthy in this regard. However, the variation in baseline mood allowed

388

sensitivity analyses to explore whether the initial mood of the participants affected the

EFFECT OF MULTIPLE TDCS ON MOOD 389

response to TDCS. As presented, we did not find support for an effect of baseline mood in

390

the present sample, but this can however not be interpreted conclusively as the sample was

391

relatively homogenous in this aspect. For a contrary result where baseline mood in healthy

392

older adults was reported to predict mood change after two sessions of the similar method

393

transcranial random noise stimulation (TRNS), see Evans, Banissy, and Charlton (2018)

394

We also acknowledge that a questionnaire with a higher test-retest reliability than what

395

has been estimated for POMS total mood disturbance (Heuchert & McNair, 2012) would

396

have enabled more precise measures of the participants’ mood, and that Likert scale question

397

“How are you feeling today?” has to be interpreted with some caution as it has not been

398

psychometrically evaluated. We also recognize that a power calculation based on the mood

399

outcomes rather than working memory, could have estimated another sample size.

400

Electrode placement may also have contributed to the results. Placement of the anode

401

over the left DLPFC and the cathode over the supraorbital area, or alternatively with the

402

placement of the cathode over the right DLPFC, has become the standard in studies of mood

403

(Brunoni, Ferrucci, Fregni, Boggio, & Priori, 2012; Remue, et al., 2016). All studies of

404

healthy individuals so-far have placed the anode according to this standard, but they have

405

differed in the cathodal placement. Newstead, et al. (2018) and Austin, et al. (2016) found

406

positive mood effects with a cathodal placement over the right cerebellum and the right

407

DLPFC, respectively. The cathodal placement can be motivated by findings of possible

408

hyperactivity in the right DLPFC in depression (Grimm, et al., 2008) and the cerebellum has

409

increasingly gained interest as region important for emotion (Newstead, et al., 2018).

410

However, Motohashi, et al. (2013) found no evidence of an effect on mood with a cathodal

411

placement over the orbital area, arguably consistent with the results reported here. Thus, it

412

cannot be excluded that the cathodal placements over the supraorbital region in the present

413

study rendered the stimulation ineffective for mood modulation. As for our placement of the

EFFECT OF MULTIPLE TDCS ON MOOD 414

anode, we aimed to increase influence in the left DLPFC by creating a peak of the electrical

415

field underneath F3. As demonstrated by Seibt, et al. (2015), this is enabled by anodal

416

placement over F5 (in their study combined with the cathode over F6). In line with that

417

conclusion, we shifted the anode slightly lateral towards F5 while placing the cathode where

418

no decrease in neuronal activation could be expected i.e., over the right supraorbital area. We

419

realize that this placement slightly differs from most clinical studies, where the anode is

420

placed centrally over F3, but find it reasonable to prioritize anodal placement reported to

421

most effectively enhance activity in the left DLPFC.

422

Recently, concerns have been raised as to whether conventional sham TDCS also has

423

the ability to induce neurobiological effects which would be problematic since it could

424

confound the results of TDCS studies using sham TDCS as a comparison group (Nikolin,

425

Martin, Loo, & Boonstra, 2018). Since none of the groups in the present study reliably

426

increased in mood over the intervention time, we judge that any possible neurobiological

427

affects due to sham TDCS have not confounded our results.

428

No other previous study has investigated the effect of multiple sessions of TDCS on

429

mood in a healthy older population and an important consideration is the neural changes that

430

come with age. Brain activity patterns are known to be different in older relative to younger

431

adults (Gunning-Dixon, et al., 2003; Roalf, et al., 2011), and normal aging has been linked to

432

several neural changes that affect plasticity negatively, particularly in hippocampal and

433

frontal regions (Burke & Barnes, 2006; Lovden et al., 2010). Given the uncertainty

434

concerning the precise neurophysiological mechanism of TDCS, particularly in non-motor

435

areas such as the DLPFC, it is difficult to speculate in how age may affect the physiological

436

response to TDCS (Heise, et al., 2014; Horvath, et al., 2015). Future research will be required

437

to discern how age may limit the potentially mood-enhancing effects of TDCS in the healthy

438

population.

EFFECT OF MULTIPLE TDCS ON MOOD 439

The present study had several strengths, including its randomized, double-blind, sham-

440

controlled design as well as its sample size. It is therefore reasonable to also consider the

441

possibility that a positive effect of anodal TDCS over the left DLPFC on mood is in fact

442

unlikely for healthy, older adults. Such an interpretation would follow the pattern of no

443

detectable effects on mood in healthy individuals following a single TDCS session (Remue,

444

et al., 2016). This interpretation can also be considered in the context of a number of recent

445

reviews and meta-analyses demonstrating no or very small effect of TDCS in the healthy

446

population for outcomes such as cognition (Nilsson, et al., 2017; Westwood & Romani,

447

2017). Concerns have recently been raised regarding the amount of inter- as well intra-

448

individual differences in response to TDCS as well as often overlooked variables such as

449

thick hair and sweat, that substantially can influence the effects of TDCS. Furthermore, the

450

physiological mechanisms and the overall efficacy of TDCS have also been questioned

451

recently (Horvath, Carter, & Forte, 2014; Horvath, et al., 2015) even though the validity of

452

that critique has it-self been questioned and later empirical studies have reported changes in

453

neural activity as an effect of TDCS (Antal, Keeser, Priori, Padberg, & Nitsche, 2015;

454

Nikolin, et al., 2018)

455 456 457

5. Conclusions The present study represents the first investigation of the effect of multiple sessions of

458

frontal TDCS in healthy older individuals. We found no evidence of a mood-enhancing effect

459

of twenty sessions of anodal TDCS over the left DLPFC. Although TDCS may be beneficial

460

in some contexts, for example for treatment of clinical depressive symptoms, we conclude

461

that the TDCS protocol used here is unlikely to improve mood in non-depressed older

462

individuals.

463

EFFECT OF MULTIPLE TDCS ON MOOD 464

Acknowledgements

465

We thank Anders Rydström, Linda Lidborg, Jakob Norgren, Helena Franzén, and Simon

466

Peyda for help with data collection and Marie Helsing for help with recruitment and

467

organization. We also thank Brjánn Ljótsson for kindly providing the R code for the cluster

468

bootstrapping and lastly but not least, our reviewers for valuable input.

469

This work was supported the European Research Council (ERC) under the European

470

Union’s Seventh Framework Programme (FP7/2007-2013) and ERC Grant No. 617280 -

471

REBOOT. Martin Lövdén was also supported by a Distinguished Young Researchers grant

472

from the Swedish Research Council (446-2013-7189).

473 474

Conflicts of interest: none.

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Aldao, A., Nolen-Hoeksema, S., & Schweizer, S. (2010). Emotion-regulation strategies across psychopathology: A meta-analytic review. Clinical Psychology Review, 30, 217-237. Antal, A., Keeser, D., Priori, A., Padberg, F., & Nitsche, M. A. (2015). Conceptual and Procedural Shortcomings of the Systematic Review "Evidence That Transcranial Direct Current Stimulation (tDCS) Generates Little-to-no Reliable Neurophysiologic Effect Beyond MEP Amplitude Modulation in Healthy Human Subjects: A Systematic Review" by Horvath and Co-workers. Brain Stimulation, 8, 846-849. Austin, A., Jiga-Boy, G. M., Rea, S., Newstead, S. A., Roderick, S., Davis, N. J., Clement, R. M., & Boy, F. (2016). Prefrontal electrical stimulation in non-depressed reduces levels of reported negative affects from daily stressors. Frontiers in Psychology, 7, 315. Beekman, A. T. F., Penninx, B. W. J. H., Deeg, D. J. H., Beurs, E. d., Geerlings, S. W., & Tilburg, W. v. (2002). The impact of depression on the well-being, disability and use of services in older adults: a longitudinal perspective. Acta Psychiatrica Scandinavica, 105, 20-27. Beraha, E., Eggers, J., Hindi Attar, C., Gutwinski, S., Schlagenhauf, F., Stoy, M., Sterzer, P., Kienast, T., Heinz, A., & Bermpohl, F. (2012). Hemispheric asymmetry for affective stimulus processing in healthy subjects – A fMRI study. PloS One, 7, e46931. Bolier, L., Haverman, M., Westerhof, G. J., Riper, H., Smit, F., & Bohlmeijer, E. (2013). Positive psychology interventions: a meta-analysis of randomized controlled studies. BMC Public Health, 13, 119. Boyes, M. E., Carmody, T. M., Clarke, P. J. F., & Hasking, P. A. (2017). Emotional reactivity and perseveration: Independent dimensions of trait positive and negative affectivity and differential associations with psychological distress. Personality and Individual Differences, 105, 70-77. Brunoni, A. R., Boggio, P. S., De Raedt, R., Benseñor, I. M., Lotufo, P. A., Namur, V., Valiengo, L. C. L., & Vanderhasselt, M. A. (2014). Cognitive control therapy and transcranial direct current stimulation for depression: A randomized, double- blinded, controlled trial. Journal of Affective Disorders, 162, 43-49. Brunoni, A. R., Ferrucci, R., Fregni, F., Boggio, P. S., & Priori, A. (2012). Transcranial direct current stimulation for the treatment of major depressive disorder: A summary of preclinical, clinical and translational findings. Progress in Neuropsychopharmacology and Biological Psychiatry, 39, 9-16. Brunoni, A. R., Moffa, A., Fregni, F., Palm, U., Padberg, F., Blumberger, D. M., Daskalakis, Z. J., Bennabi, D., Haffen, E., Alonzo, A., & Loo, C. K. (2015). Transcranial Direct Current Stimulation for Major Depression: A Meta-analysis of Individual Patient Data. Biological Psychiatry, 77, 22s-22s. Buhle, J. T., Silvers, J. A., Wager, T. D., Lopez, R., Onyemekwu, C., Kober, H., Weber, J., & Ochsner, K. N. (2014). Cognitive reappraisal of emotion: A meta-analysis of human neuroimaging studies. Cerebral Cortex, 24, 2981. Carl, J. R., Soskin, D. P., Kerns, C., & Barlow, D. H. (2013). Positive emotion regulation in emotional disorders: a theoretical review. Clinical Psychology Review, 33, 343-360. Charles, S. T., Mather, M., & Carstensen, L. L. (2003). Aging and emotional memory: The forgettable nature of negative images for older adults. Journal of Experimental Psychology: General, 132, 310-324. Christensen, K., Doblhammer, G., Rau, R., & Vaupel, J. W. (2009). Ageing populations: the challenges ahead. The Lancet, 374, 1196-1208.

23

Coryell, W., Scheftner, W., Keller, M., Endicott, J., Maser, J., & Klerman, G. L. (1993). The enduring psychosocial consequences of mania and depression. American Journal of Psychiatry, 150, 720-727. Crimmins, E. M., & Beltran-Sanchez, H. (2011). Mortality and morbidity trends: is there compression of morbidity? Journals of Gerontology. Series B: Psychological Sciences and Social Sciences, 66, 75-86. D'Esposito, M., Postle, B. R., & Rypma, B. (2000). Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies. Experimental Brain Research, 133, 3-11. Djernes, J. K. (2006). Prevalence and predictors of depression in populations of elderly: a review. Acta Psychiatrica Scandinavica, 113, 372-387. Evans, C., Banissy, M. J., & Charlton, R. A. (2018). The efficacy of transcranial random noise stimulation (tRNS) on mood may depend on individual differences including age and trait mood. Clinical Neurophysiology, 129, 1201-1208. Field, A. (2009). Discovering statistics using SPSS (and sex and drugs and rock 'n' roll) (3 ed.). London, UK: SAGE. Fitzgerald, P. B., Laird, A. R., Maller, J., & Daskalakis, Z. J. (2008). A meta-analytic study of changes in brain activation in depression. Human Brain Mapping, 29, 736. Gratz, K. L., & Roemer, L. (2004). Multidimensional Assessment of Emotion Regulation and Dysregulation: Development, Factor Structure, and Initial Validation of the Difficulties in Emotion Regulation Scale. Journal of Psychopathology and Behavioral Assessment, 26, 41-54. Grimm, S., Beck, J., Schuepbach, D., Hell, D., Boesiger, P., Bermpohl, F., Niehaus, L., Boeker, H., & Northoff, G. (2008). Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: An fMRI study in severe major depressive disorder. Biological Psychiatry, 63, 369-376. Gunning-Dixon, F. M., Gur, R. C., Perkins, A. C., Schroeder, L., Turner, T., Turetsky, B. I., Chan, R. M., Loughead, J. W., Alsop, D. C., Maldjian, J., & Gur, R. E. (2003). Agerelated differences in brain activation during emotional face processing. Neurobiology of Aging, 24, 285-295. Hamilton, J. P., Etkin, A., Furman, D. J., Lemus, M. G., Johnson, R. F., & Gotlib, I. H. (2012). Functional neuroimaging of major depressive disorder: A meta-analysis and new integration of base line activation and neural response data. The American Journal of Psychiatry, 169, 693. Heise, K.-F., Niehoff, M., Feldheim, J. F., Liuzzi, G., Gerloff, C., & Hummel, F. C. (2014). Differential behavioral and physiological effects of anodal transcranial direct current stimulation in healthy adults of younger and older age. Frontiers in Aging Neuroscience, 6, 146. Herrington, J. D., Heller, W., Mohanty, A., Engels, A. S., Banich, M. T., Webb, A. G., & Miller, G. A. (2010). Localization of asymmetric brain function in emotion and depression. Psychophysiology, 47, 442-454. Heuchert, J. P., & McNair, D. M. (2012). POMS 2: Profile of Mood States Second Edition Manual. Toronto, Canada: Multi-Health Systems Inc. Holan, S. H., Lund, R., & Davis, G. (2010). The ARMA alphabet soup: A tour of ARMA model variants. Statistics Surveys, 4, 232–274. Horvath, J. C., Carter, O., & Forte, J. D. (2014). Transcranial direct current stimulation: five important issues we aren't discussing (but probably should be). Frontiers in Systems Neuroscience, 8, 2. Horvath, J. C., Carter, O., & Forte, J. D. (2015). Evidence that transcranial direct current stimulation ( tDCS) generates little-to-no reliable neurophysiologic effect beyond

24

MEP amplitude modulation in healthy human subjects: A systematic review. Neuropsychologia, 66, 213-236. Jaworska, N., Yang, X.-R., Knott, V., & Macqueen, G. (2015). A review of fMRI studies during visual emotive processing in major depressive disorder. The World Journal of Biological Psychiatry, 16, 448. Kahn, M., Sheppes, G., & Sadeh, A. (2013). Sleep and emotions: bidirectional links and underlying mechanisms. International Journal of Psychophysiology, 89, 218-228. Kohn, N., Eickhoff, S. B., Scheller, M., Laird, A. R., Fox, P. T., & Habel, U. (2014). Neural network of cognitive emotion regulation — An ALE meta-analysis and MACM analysis. Neuroimage, 87, 345–355. Kryla-Lighthall, N., & Mather, M. (2009). Chapter: The role of cognitive control in older adults' emotional well-being. In Handbook of theories of aging., 2nd ed (pp. 323344). New York, NY: Springer Publishing Co; US ISBN 0-8261-6251-7 (Hardcover); 978-0-8261-6251-9 (Hardcover). Liebetanz, D., Koch, R., Mayenfels, S., Konig, F., Paulus, W., & Nitsche, M. A. (2009). Safety limits of cathodal transcranial direct current stimulation in rats. Clinical Neurophysiology, 120, 1161-1167. Mather, M., & Carstensen, L. L. (2003). Aging and attentional biases for emotional faces. Psychological Science, 14, 409-415. Meron, D., Hedger, N., Garner, M., & Baldwin, D. S. (2015). Transcranial direct current stimulation (tDCS) in the treatment of depression: Systematic review and metaanalysis of efficacy and tolerability. Neuroscience and Biobehavioral Reviews, 57, 46-62. Mondino, M., Thiffault, F., & Fecteau, S. (2015). Does non-invasive brain stimulation applied over the dorsolateral prefrontal cortex non-specifically influence mood and emotional processing in healthy individuals? Frontiers in Cellular Neuroscience, 9, 399. Motohashi, N., Yamaguchi, M., Fujii, T., & Kitahara, Y. (2013). Mood and cognitive function following repeated transcranial direct current stimulation in healthy volunteers: A preliminary report. Neuroscience Research, 77, 64-69. Nashiro, K., Sakaki, M., & Mather, M. (2012). Age differences in brain activity during emotion processing: Reflections of age-related decline or increased emotion regulation? Gerontology, 58, 156-163. Newstead, S., Young, H., Benton, D., Jiga-Boy, G., Andrade Sienz, M. L., Clement, R. M., & Boy, F. (2018). Acute and repetitive fronto-cerebellar tDCS stimulation improves mood in non-depressed participants. Experimental Brain Research, 236, 83-97. Nikolin, S., Martin, D., Loo, C. K., & Boonstra, T. W. (2018). Effects of TDCS dosage on working memory in healthy participants. Brain Stimulation, 11, 518-527. Nilsson, J., Lebedev, A. V., Rydstrom, A., & Lovden, M. (2017). Direct-Current Stimulation Does Little to Improve the Outcome of Working Memory Training in Older Adults. Psychological Science, 28, 907-920. Nitsche, M. A., & Paulus, W. (2000). Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. Journal of Physiology, 527 Pt 3, 633-639. Ochsner, K. N., Silvers, J. A., & Buhle, J. T. (2012). Functional imaging studies of emotion regulation: A synthetic review and evolving model of the cognitive control of emotion. Annals of the New York Academy of Sciences, 12511, E1-E24. Ohn, S. H., Park, C. I., Yoo, W. K., Ko, M. H., Choi, K. P., Kim, G. M., Lee, Y. T., & Kim, Y. H. (2008). Time-dependent effect of transcranial direct current stimulation on the enhancement of working memory. Neuroreport, 19, 43-47.

25

Patterson, K., Young, C., Woods, S. P., Vigil, O., Grant, I., & Atkinson, J. H. (2006). Screening for major depression in persons with HIV infection: The concurrent predictive validity of the Profile of Mood States Depression‐Dejection Scale. International Journal of Methods in Psychiatric Research, 15, 75-82. Pinheiro, J., Bates, D., DebRoy, S., Sarkar, D., & Team, R. C. (2017). _nlme: Linear and Nonlinear Mixed Effects Models_. R package version 3.1-130. In. Poreisz, C., Boros, K., Antal, A., & Paulus, W. (2007). Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients. Brain Research Bulletin, 72, 208-214. Priori, A., Hallett, M., & Rothwell, J. C. (2009). Repetitive transcranial magnetic stimulation or transcranial direct current stimulation? Brain Stimulation, 2, 241-245. R Core Team. (2016). R: A Language and Environment for Statistical Computing. In. Vienna, Austria: R Foundation for Statistical Computing. Remue, J., Baeken, C., & De Raedt, R. (2016). Does a single neurostimulation session really affect mood in healthy individuals? A systematic review. Neuropsychologia, 85, 184198. Reynolds, C., & Gatz, M. (2001). Age-related differences and change in positive and negative affect over 23 years. Journal of Personality and Social Psychology, 80, 136151. Roalf, D. R., Pruis, T. A., Stevens, A. A., & Janowsky, J. S. (2011). More is less: Emotion induced prefrontal cortex activity habituates in aging. Neurobiology of Aging, 32, 1634-1650. Sacher, J., Neumann, J., Fünfstück, T., Soliman, A., Villringer, A., & Schroeter, M. L. (2012). Mapping the depressed brain: A meta-analysis of structural and functional alterations in major depressive disorder. Journal of Affective Disorders, 140, 142-148. Segrave, R. A., Arnold, S., Hoy, K., & Fitzgerald, P. B. (2014). Concurrent Cognitive Control Training Augments the Antidepressant Efficacy of tDCS: A Pilot Study. Brain Stimulation, 7, 325-331. Seibt, O., Brunoni, A. R., Huang, Y., & Bikson, M. (2015). The pursuit of DLPFC: Nonneuronavigated methods to target the left dorsolateral pre-frontal cortex with symmetric bicephalic transcranial direct current stimulation (tDCS). Brain Stimulation, 8, 590-602. Tversky, A., & Kahneman, D. (1981). The framing of decisions and the psychology of choice. Science, 211, 453-458. Westwood, S. J., & Romani, C. (2017). Transcranial direct current stimulation (tDCS) modulation of picture naming and word reading: A meta-analysis of single session tDCS applied to healthy participants. Neuropsychologia, 104, 234-249. Vittengl, J. R., & Holt, C. S. (1998). Motivation and Emotion, 22, 255-275.

Highlights for the manuscript “No evidence for any effect of multiple sessions of frontal transcranial direct stimulation on mood in healthy older adults”

• • •

The first RCT of mood effects of multiple TDCS in healthy older adults (n = 123) 20 sessions of anodal TDCS or sham TDCS was delivered over the left DLPFC We found no effect on mood on any of our outcomes