Received: 15 April 2021 Revised: 10 August 2021 Accepted: 8 October 2021

DOI: 10.1111/ejn.15490

REVIEW ARTICLE

Non-invasive brain stimulation in modulation of mental

rotation ability: A systematic review and meta-analysis

Jitka Veldema1 | Alireza Gharabaghi1 | Petra Jansen2

1
Institute for Neuromodulation and
Neurotechnology, University Hospital and
University of Tübingen, Tübingen,
Germany
2
Faculty of Human Science, University of
Regensburg, Regensburg, Germany
Correspondence
Jitka Veldema, Institute for
Neuromodulation and Neurotechnology,
Department of Neurosurgery and
Neurotechnology, University Hospital and
University of Tübingen, Otfried-Mueller-
Str.45, 72076 Tuebingen, Germany.
Email: jitka.veldema@klinikum.uni-
tuebingen.de
Edited by: John Foxe
Abstract
Mental rotation, the ability to manipulate mental images, is an important
function in human cognition. This systematic review and meta-analysis
investigates the potential of non-invasive brain stimulation in modulation of
this component of visuo-spatial perception. The PubMed database was
reviewed prior to 31 September 2020 on randomized controlled trials investi-
gating the effects of repetitive transcranial magnetic stimulation (rTMS),
transcranial direct current stimulation (tDCS), and transcranial alternating
current stimulation (tACS) on the mental rotation ability in healthy persons.
A total of 17 studies (including 485 subjects) matched our inclusion criteria.
Within their scope, overall, 46 sham-controlled experiments were performed.
Methodology and results of each experiment are presented in a meta-analy-
sis. The data show a large variety of methods and effects. The influence of
(1) stimulation-technique (tDCS, tACS, and rTMS), (2) stimulation protocol
(anodal, cathodal, bilateral tDCS, tACS, high-frequency rTMS, low-frequency
rTMS, paired pulse rTMS, and theta burst stimulation), (3) stimulation
timing (preconditioning and simultaneous), (4) stimulation location (left,
right hemisphere, frontal, and parietal area), and (5) stimulus type (bodily
and non-bodily) is discussed. The data indicate a beneficial effect of anodal
tDCS and of tACS and no effect of cathodal tDCS on the mental rotation
ability. Bilateral tDCS protocols both improved and worsened the parameters

ABBREVIATIONS: aMT, active motor threshold; BOLD, blood-oxygen-level-dependent; CI, confidence interval; cm, centimetre; cTBS, continuous
theta burst stimulation; Cz, vertex; DLPC, dorsolateral prefrontal cortex; DMPC, dorsomedial prefrontal cortex; dPMC, dorsal premotor cortex; EEG,
electroencephalography; fMRI, functional magnetic resonance imaging; Fz, mesial fontal cortex; h, hour; Hz, hertz; I2, inconsistency test; IAF,
individual alpha frequency; IPS, intraparietal sulcus; iTBS, intermittent theta burst stimulation; LOTC, lateral occipitotemporal cortex; LPS, lobus
parietalis superior; M1, primary motor cortex; mA, milliampere; min, minute; MRI, magnetic resonance imaging; ms, millisecond; MSO, maximal
stimulator output; OF, offline; ON, online; Oz, occipital point; PET, positron emission tomography; PPC, posterior parietal cortex; pprTMS, paired-
pulse repetitive transcranial magnetic stimulation; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; pTPJ, posterior
temporo-parietal junction; rMT, resting motor threshold; rTMS, repetitive transcranial magnetic stimulation; s, second; SG, supramarginal gyrus;
SMA, supplementary motor area; SSC, somatosensory cortex; T, test; tACS, transcranial alternating current stimulation; tDCS, transcranial direct
current stimulation; TMS, transcranial magnetic stimulation; TPJ, temporoparietal junction.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Eur J Neurosci. 2021;54:7493–7512. wileyonlinelibrary.com/journal/ejn 7493


7494
assessed. The small effect sizes obtained in mostly rTMS experiments require
cautious interpretation.
KEYWORDS
mental rotation, non-invasive brain stimulation
1 | INTRODUCTION
1.1 | Mental rotation
Mental rotation is psychological operation in which a
mental image is rotated around some axis in three-
dimensional space (Zacks, 2008). Since first presented by
Shepard and Metzler (1971), numerous concepts were
developed to assess this component of visuo-spatial per-
ception (Figure 1). Current data repeatedly demonstrates
correlations between superior mental rotation abilities
and “success” in daily life. For example, optimal neuro-
development during the first few months of life is associ-
ated, among others, with good mental rotation ability at
age 6–10 years (Serdarevic et al., 2016). A higher mental
rotation performance is significantly correlated to better
mathematical achievement in boys between 7 and 9 years
old and thus has implications for school practice (van
Tetering, van der Donk, de Groot, & Jolles, 2019). Ath-
letes and artists may present above average mental rota-
tion performance (Sluming, Brooks, Howard, Downes, &
Roberts, 2007; Voyer & Jansen, 2017). For example, pro-
fessional musicians are 25% faster at mental rotation
tasks than academically educated peers (Sluming,
Brooks, Howard, Downes, & Roberts, 2007). Amateur
gymnasts and orienteers demonstrate 50% better perfor-
mance in mental rotation of cubes than contemporaries
who take no regular sports (Voyer & Jansen, 2017).
On the other hand, relationships were also found
between the reduction of mental rotation performance
and ageing- or illness-related decline. Elderly (63–
80 years) show significantly poorer mental rotation abil-
ity than young adults (17–29 years) (Techentin, Voyer, &
Voyer, 2014). People who suffered from a major depres-
sive disorder have a worse mental rotation performance
than healthy peers (Chen et al., 2014), and the severity of
depression symptoms correlates with the reduction of
mental rotation ability (Oshiyama et al., 2018). Stroke
victims show significantly poorer mental rotation perfor-
mance than healthy controls (Braun et al., 2017; Daprati,
Nico, Duval, & Lacquaniti, 2010), and the amount of sen-
sitivity (Braun et al., 2017) and motor (Daprati, Nico,
Duval, & Lacquaniti, 2010) deficits correlates with the
disruption of mental rotation performance. Pain-related
diseases are also associated with impaired mental
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VELDEMA ET AL.
rotation performance (Baarbé, Holmes, Murphy,
Haavik, & Murphy, 2016; Kohler et al., 2019).
1.2 | Neural background of mental
rotation
Several fMRI, PET, and EEG studies investigated the
neural background of mental rotation in the last few
decades (Hawes, Sokolowski, Ononye, & Ansari, 2019;
Searle & Hamm, 2017; Tomasino & Gremese, 2016;
Zacks, 2008). Taken together, the data demonstrate that
mental rotation is associated with extensive activation
within several cortical areas in both hemispheres
(e.g., inferior and superior parietal lobule, inferior fron-
tal gyrus, middle frontal gyrus, supplementary motor
area, inferior and middle occipital gyrus, and so forth)
and the cerebellum (Hawes, Sokolowski, Ononye, &
Ansari, 2019; Searle & Hamm, 2017; Tomasino &
Gremese, 2016; Zacks, 2008). Although bilateral activa-
tion was found for most areas (Hawes, Sokolowski,
Ononye, & Ansari, 2019; Searle & Hamm, 2017;
Tomasino & Gremese, 2016; Zacks, 2008), some data
also detected between-hemispheric asymmetries
(Tomasino & Gremese, 2016; Zacks, 2008). A previous
review demonstrates more consistent parietal cortex
activity in the right hemisphere and more consistent
frontal cortex activity in the left hemisphere
(Zacks, 2008). A more recent meta-analysis shows
stimulus-dependent between hemispheric differences
during mental rotation tasks (Tomasino &
Gremese, 2016). Mental rotation of “non-bodily” stimuli
(e.g., Shepard-Metzler objects) induce right-lateralized
activation, whereas “bodily” stimuli (e.g., hands and
feet) leads to the activation of the bilateral sensorimotor
network (Tomasino & Gremese, 2016). An advanced
review also refers stimulus-dependent differences of
neural processing (Searle & Hamm, 2017). BOLD acti-
vation within the ventral stream and the premotor cor-
tex increases linearly with stimulus discrepancies
during mirror/normal discriminations only during men-
tal rotation of bodily stimuli. Similarly, slow negativity
over centroparietal regions as recorded by EEG
increases for greater rotations only during mental rota-
tion of bodily stimuli. Higher difficulty during mental
 14609568, 2021, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.15490 by NHMRC National Cochrane Australia, Wiley Online Library on [07/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
VELDEMA ET AL. 7495

F I G U R E 1 Common strategies to assess mental rotation ability: (1) congruence determination (same/mirrored) of two stimuli, which
are rotated relative to each other (e.g., Shepard-Metzler objects, Shepard & Metzler, 1971; hands, Bode, Koeneke, & Jäncke, 2007),
(2) congruence determination (congruent/incongruent) of rotated items in relation to “standard item” (e.g., animals, Snodgrass &
Vanderwart, 1980; letters, Corballis & Sergent, 1989; cubes, Gittler & Glück, 1998), (3) laterality determination (right/left) of foots, hands
(Sekiyama, 1982), identifying which hand (right/left) was marked depending on the stimulus dot presented in the lower portion of the figure
(Ratcliff, 1979), and (4) paper folding and cutting task (determination of the item that represents what the folded and cut piece of paper will
look like when it is unfolded) (Oldrati, Colombo, & Antonietti, 2018)

rotation of non-bodily objects did not induce a higher
neural network activation (Searle & Hamm, 2017).
Some data explain the neurological background of
illness-related disruption of mental rotation (Kohler
et al., 2019; Yan et al., 2012). A magnet resonance
imaging study revealed that patients who suffer from
complex regional pain syndrome have a reduced activa-
tion in certain areas including the subthalamic nucleus,
nucleus accumbens, and putamen, during mental rota-
tion tasks (Kohler et al., 2019). An electroencephalogra-
phy study in stroke patients demonstrated a hypo-
activity in frontal and central areas of the ipsilesional
hemisphere, as well as hypo-activity of the frontal cor-
tex bilateral during a mental rotation task (Yan
et al., 2012). Thus, illness-induced reduction of the
mental rotation ability seems to be associated with
suppressed neural processing. In contrast, a superior
mental rotation performance appears to be linked to
enhanced neural processes. A fMRI study found that
orchestral musicians have a significantly increased acti-
vation in Broca’s area during a mental rotation task, in
addition to the visuospatial network, which was acti-
vated in both musicians and non-musicians (Sluming,
Brooks, Howard, Downes, & Roberts, 2007).
1.3 | Non-invasive brain stimulation in
modulation of neural and cognitive
processing
Repetitive transcranial magnetic stimulation (rTMS) and
transcranial direct current/alternating current stimula-
tion (tDCS/tACS) are innovative methods that can modu-
late neural processing within the cortex (Giordano

7496
et al., 2017; Herrmann, Rach, Neuling, & Strüber, 2013;
Siebner & Rothwell, 2003) and have therefore the poten-
tial to influence the mental rotation ability. TDCS/tACS
consists of the application of a low-intensity direct cur-
rent/alternating current that flows between two elec-
trodes (anode and cathode) (Herrmann, Rach,
Neuling, & Strüber, 2013; Nasseri, Nitsche, &
Ekhtiari, 2015). One of the electrodes is positioned over
the target area (active electrode), the other (reference
electrode) over another cranial or extracranial position.
TMS is produced by passing short high-current pulses
through an insulated coil of wire held over the scalp. The
electric pulse induces a rapidly changing magnetic field
with lines of flux running perpendicular to the coil
(Lang & Siebner, 2007; Siebner & Rothwell, 2003). Acute
physiological effects of non-invasive brain stimulation
techniques distinguish tDCS/tACS from TMS. TMS pro-
duces high intensities of short-lasting electromagnetic
currents that lead to a supra-threshold activation of the
neurons. In contrast, tDCS/tACS does not generate action
potentials in neurons, but bi-directionally modifies their
spontaneous firing activity via subthreshold activation
(Yavari, Jamil, Mosayebi Samani, Vidor, &
Nitsche, 2018). Potentially oversimplifying, the basic idea
is (i) anodal tDCS (anode over the target area) and facili-
tatory rTMS (high-frequency rTMS [≥5 Hz], intermittent
theta burst stimulation [iTBS], and paired-pulse rTMS
[pprTMS] [inter-stimulus interval >5 ms]) increase neu-
ronal excitability and may consequently enhance cogni-
tive performance; (ii) cathodal tDCS (cathode over the
target area), inhibitory rTMS (low-frequency rTMS
[1 Hz], continuous theta burst stimulation [cTBS], and
pp rTMS [inter-stimulus interval ≤ 5 ms]) decreases
neuronal excitability and subsequently worsen cognitive
performance (Fertonani & Miniussi, 2017; Lang &
Siebner, 2007). Indeed, the factors influencing the inter-
individual variability of the effect of brain stimulation on
neural and cognitive processing are not completely
understood. Recent studies show, for example, high inter-
individual variability regarding the neural responses to
“up” and “down” regulating brain stimulation protocols
(Hamada, Murase, Hasan, Balaratnam, & Rothwell, 2013;
Wiethoff, Hamada, & Rothwell, 2014). It was also demon-
strated that stimulation-timing (preconditioning/preced-
ing versus simultaneously application) plays a critical
role on stimulation effects on cognition (Hill,
Fitzgerald, & Hoy, 2016; Yeh & Rose, 2019). In the past
few years, there has been a rapid increase in the applica-
tion of non-invasive brain stimulation techniques in
modulation of mental rotation in healthy persons. This
systematic review aims to investigate if non-invasive
brain stimulation is effective in supporting this relevant
visuo-spatial ability.
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VELDEMA ET AL.
2 | METHODS
2.1 | Study selection
The PubMed database was reviewed up to 31 September
2020 for papers reporting the use of non-invasive brain
stimulation in modulation of mental rotation ability in
healthy subjects. The screening was performed according
to the PRISMA guidelines. Search term (1) “transcranial
direct current stimulation” and “mental rotation,”
(2) “transcranial alternation current stimulation” and
“mental rotation,” and (3) “repetitive transcranial mag-
netic stimulation” and “mental rotation” were used.
Studies matching the following criteria were included:
(1) human-studies, (2) prospective studies, (3) healthy
subjects, (4) modulation of mental rotation ability by
non-invasive brain stimulation, and (5) placebo-
controlled study or study with at least two experimental
groups/treatments. The screening was performed by two
independent reviewers (JV and AE). Disagreements were
resolved by consensus.
2.2 | Data extraction and risk of bias
Outcomes reported were (1) participants characteristics
(age and gender), (2) methodological approach (number
of participants, crossover/parallel groups design, assess-
ments, number and scheduling of evaluations, and stimu-
lation positioning techniques), (3) intervention
characteristics (stimulation protocol, stimulation dura-
tion, stimulated area, and number of sessions), and
(4) outcomes (assessments and between-group differ-
ences). The Oxford quality scoring system was applied to
evaluate the methodological quality of trials included,
such as random allocation, subjects and assessor blinding
and description of dropouts and withdrawal (Jadad
et al., 1996). Its overall score ranges between 0 and 5. The
higher the score, the better the methodological quality of
the study. Oxford quality score for studies enrolled in our
meta-analysis is presented in Table 1 (tDCS/tACS) and
Table 2 (TMS).
2.3 | Data synthesis and statistical
analysis
Effect size and 95% confidence interval were calculated
for each study and each assessment. On this basis, means
were calculated for each stimulation technique (tDCS/
tACS and rTMS), stimulated hemisphere (left, right, bilat-
eral, and central), stimulated area (frontal, parietal,
frontal +parietal, and cerebellum), stimulation timing
 TABLE 1 Studies investigating tDCS/tACS in modulation of mental rotation, included in our meta-analysis
Number of
Reference/Oxford participants/gender/ Study design/blinding/positioning Results (group*time effect/
quality scoring scale age techniques Stimulation protocol Number of sessions/evaluations performed tests)
VELDEMA ET AL.

Moghadas Tabrizi
et al., 2019/2
Kasten et al., 2018/2
Oldrati et al., 2018/2
Kikuchi et al., 2017/3
60/30 males, 30 Parallel groups (15 + 15 + 15 + 15) (1) Anodal 1.5-mA tDCS (15 min) over 5 sessions, evaluations: T1 before Anodal 1.5 mA tDCS over right F4
females/24  0 years /subjects blinded/10–20 EEG right DLPF (F4), cathode over left treatment, T2 post treatment and right P4 significantly better
system supraorbital area than sham tDCS: Hands (reaction
time and accuracy)
(2) Anodal 1.5 mA tDCS (15 min) over
right PPC (P4), cathode over left
supraorbital area
(3) Sham 1.5-mA tDCS (15 min, current
turned off after 30 s) over right
DLPF (F4), cathode over left
supraorbital area
(4) Sham 1.5 mA tDCS (15 min, current
turned off after 30 s) over right PPC
(P4), cathode over left supraorbital
area
20/12 males, 8 Parallel groups (10–10)/subjects (1) IAF tACS (20 min), at individual 1 session, evaluations: T1 before IAF tACS at individual intensity, and
females/26  3 years blinded/10–10 EEG system intensity (0.715 mA at mean), and treatment, T2 post treatment frequency significantly better:
frequency (10.5 Hz at mean), over Shepard-Metzler objects
Oz, cathode over Cz (accuracy)
(2) sham tACS (20 min, current turned No significant differences: Shepard-
off after 30 s), anode over Oz, Metzler objects (reaction time)
cathode over Cz
27/9 males, 18 Parallel groups (10–9–8)/subjects (1) Anodal 1.5-mA tDCS (20 min) over 1 session, evaluations: T1 24 h before Anodal 1.5 mA tDCS over left DLPC
females/27  6 years blinded/10–20 EEG system left DLPC (F3), cathode over right treatment, T2 24 h after treatment coupled with visuospatial skill
deltoid muscle coupled with training significantly better than
visuospatial skill training sham tDCS, and anodal 1.5 mA
tDCS over left DLPC followed by
(2) Anodal 1.5-mA tDCS (20 min) over
visuospatial skill training: Paper
left DLPC (F3), cathode over right
folding and cutting task (accuracy)
deltoid muscle followed by
visuospatial skill training
(3) Sham tDCS (20 min, current turned No significant differences: Shepard-
off after 5 s), anode over left DLPC- Metzler objects (accuracy)
F3, cathode over right deltoid
muscle coupled with/followed by
visuospatial skill training
40/40 males, 0 Parallel groups (20–10–10)/subjects (1) Simultaneously 2.0-mA tDCS 1 session, evaluations: T1 during Simultaneously 2.0 mA tDCS with
females/20–43 years blinded/10–10 EEG system unilateral (20 min), anode over treatment anode over right LOTC, and
right LOTC (PO8), cathode over cathode over right DLPC
right DLPC (F4) significantly better than
(2) Simultaneously 2.0-mA tDCS simultaneously 2.0 mA tDCS, with
anode over right DLPC, and
unilateral (20 min), anode over
(Continues)
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 TABLE 1 (Continued)
7498

Number of
Reference/Oxford participants/gender/ Study design/blinding/positioning Results (group*time effect/
quality scoring scale age techniques Stimulation protocol Number of sessions/evaluations performed tests)

van Elk et al., 2017/1
Date et al., 2015/1
right DLPC (F4), cathode over right
LOTC (PO8)
(3) Sham tDCS (20 min, current turned
off after 5 s), the same electrodes-
positions as during active tDCS
45/45 males, 0 Parallel groups (16–15–14)/subjects (1) Simultaneously 1-mA tDCS bilateral
females/21  3 years blinded/10–20 EEG system (20 min) with anode over right SG
(CP6), and cathode over left SSC
(C3)
(2) Simultaneously 1-mA tDCS bilateral
(20 min) with anode over left SSC
(C3), and cathode over right SG
(CP6)
(3) Sham tDCS (20 min, current turned
off after 60 s), anode over right SG
(CP6), and cathode over left SSC
(C3)
28/14 males, 4 Crossover (28–28)/subjects blinded/ (1) Anodal 1-mA tDCS (10 min) over
females/24  4 (20– TMS left M1, cathode over right
37) years supraorbital area
(2) Sham tDCS (10 min, current turned
off after 20 s) anode over left M1,
cathode over right supraorbital
area
1 session, evaluation: T1 during
treatment
1 session, evaluations: T1 before
treatment, T2 post treatment
cathode over right LOTC: Hands
(accuracy)
Bilateral 1 mA tDCS with anode over
right SG, and cathode over left
SSC significantly poorer than
sham, and bilateral 1 mA tDCS,
with anode over left SSC, and
cathode over right SG: Avatar
(reaction time for stimuli with
high angular disparity ([180 ] and
for stimuli rotated along x and y
axis)
No significant differences: Avatar
(reaction time for stimuli with low
angular disparity ([0 , 60 , 120 ]
and for stimuli rotated along z
axis)
Anodal 1 Hz tDCS significantly better:
Hands (reaction time)
No significant differences: Hands
(accuracy)

Foroughi et al., 2015/2
45/11 males, 34 Parallel groups (15–15–15)/subjects (1) Anodal 2-mA tDCS (30 min) over 1 session, evaluations: T1 before Anodal 2 mA tDCS over right PPC
females/20  2 years blinded/10–5 EEG system right PPC, cathode over left upper treatment, T2 during treatment significantly improved between T1
arm and T2: Shepard-Metzler objects
(accuracy)
(2) Cathodal 2-mA tDCS (30 min) over Cathodal 2 mA tDCS over right PPC
right PPC, anode over left upper significantly deteriorated between
arm T1 and T2: Shepard-Metzler
objects (accuracy)
(3) Sham tDCS (30 min, current turned No significant differences: Sham tDCS
off after 5 s) over right PPC, over right PPC
reference over left upper arm

Note: Cz, vertex; DMPC, dorsomedial prefrontal cortex; DLPC, dorsolateral prefrontal cortex; EEG, electroencephalography; h, hour; Hz, Hertz; IAF, individual alpha frequency; LOTC, lateral occipitotemporal cortex; mA,
milliampere; min, minute; M1, primary motor cortex; Oz, occipital point; PPC, posterior parietal cortex; s, second; SG, supramarginal gyrus; SSC, somatosensory cortex; tACS, transcranial alternating current stimulation; tDCS,
VELDEMA ET AL.

transcranial direct current stimulation; T, test; TPJ, temporoparietal junction.

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 TABLE 2 Studies investigating rTMS in modulation of mental rotation, included in our meta-analysis
Number of
Reference/Oxford participants/gender/ Study design/blinding/positioning Results (group * time effect/
quality scoring scale age techniques Stimulation protocol Number of sessions/evaluations performed tests)
VELDEMA ET AL.

Zeugin et al., 2020/0 30/15 males, 15 Crossover (30–30) /subjects (1) 1-Hz rTMS (1200 pulses, 90% rMT) 1 session, evaluations: T1 immediately 1 Hz rTMS over right TPJ significantly
females/25  5 years blinded/10–20 EEG system over right TPJ after rTMS better than sham rTMS: faces
(2) Sham rTMS (1-Hz rTMS, 1200 (reaction time)
pulses, 90% rMT, coil at the same
position) over Cz
Cona et al., 2017/0 15/5 males, 10 Crossover (15–15–15)/subjects blinded/ (1) 10-Hz rTMS (112  5 pulses, 100% 1 session, evaluations: T1 during rTMS 10 Hz rTMS over right dPMC
females/25 (21–31) neuronavigation, MRI scan rMT) over right dPMC (350 ms after each stimulus onset 5 significantly poorer than sham
years rTMS pulses applied) rTMS: Shepard-Metzler objects
(accuracy for the same stimuli),
hands (reaction time for the same
stimuli)
(2) 10-Hz rTMS (112  5 pulses, 100% 10 Hz rTMS over right dPMC
rMT) over left dPMC significantly poorer than sham
rTMS and 10 Hz rTMS over left
(3) Sham rTMS (10 Hz rTMS, 112  5
dPMC: Shepard-Metzler objects
pulses, 100% rMT, coil at 45 ) over
(reaction time for the same
Cz
stimuli), hands (reaction time for
the same stimuli)
10 Hz rTMS over left dPMC
significantly poorer than sham
rTMS: Shepard-Metzler objects
(accuracy for the same stimuli)
No significant differences: Shepard-
Metzler objects (accuracy and
reaction time for the mirror
stimuli), hands (accuracy for the
same and the mirror stimuli,
reaction time for the mirror
stimuli)
Cona et al., 2016/1 16/5 males, 11 Crossover (15–15–15)/subjects blinded/ (1) 10-Hz rTMS (112  5 pulses, 110% 1 session, evaluations: T1 during rTMS 10-Hz rTMS over left SMA
females/24 (21–30) M1 determined by TMS, SMA rMT) over left SMA (350 ms after each stimulus onset 5 significantly better than sham
years determined in relation to vertex rTMS pulses applied) rTMS and 10-Hz rTMS over left
(2) 10-Hz rTMS (112  5 pulses, 110%
(3 cm anterior, 0.5 cm left) rMT) over left M1 M1: Shepard-Metzler objects
(reaction time for the same
stimuli, accuracy for the same
stimuli with high angular disparity
[100 , 150 ]), hands (reaction time
for the same stimuli, accuracy for
the same stimuli with high angular
disparity [100 , 150 ])
(Continues)
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 TABLE 2 (Continued)
7500

Number of
Reference/Oxford participants/gender/ Study design/blinding/positioning Results (group * time effect/
quality scoring scale age techniques Stimulation protocol Number of sessions/evaluations performed tests)
(3) Sham rTMS (10 Hz rTMS, 112  5 No significant differences: Shepard-
pulses, 110% rMT, coil at 45 ) over Metzler objects (accuracy and
Cz reaction time for the mirror
stimuli and for the same stimuli
with low angular disparity [0 ,
50 ]), hands (accuracy and
reaction time for the mirror
stimuli and for the same stimuli
with low angular disparity [0 ,
50 ])

Wang et al., 2016/0 15/6 males, 9 females)/2 Crossover (15–15)/subjects blinded/ (1) 0.2-Hz pprTMS (80  2 pulses, 1 session, evaluations: T1 during No significant differences: Avatar
(21–37) years neuronavigation, MRI scan separated by 100 ms, 110% rMT) ppTMS (1st pulse at 300 s and 2st (reaction time)
over right pTPJ pulse at 400 s after stimulus onset)
(2) Sham TMS (acoustics click sounds
played binaurally via ear phones)

Picazio et al., 2013/1
42/18 males, 24 Two experiments with parallel groups
females/28  4 (19– (7–7–7, 7–7–7)/subjects blinded/
35) years position determined in relation to
inion (1 cm inferior, 3 cm left)
(1) 50-Hz cTBS (200  3 pulses, 80%
aMT) over left lateral cerebellum
(2) 50-Hz cTBS (200  3 pulses, 80%
aMT) over right lateral cerebellum
(3) Sham cTBS (200  3 pulses, 80%
aMT, coil angled) over vermian
surface
1 session, evaluations: T1 following 50-Hz cTBS over left lateral cerebellum
cTBS significantly poorer than sham
TBS, and 50 Hz TBS over right
lateral cerebellum: Embodied
mental rotation task (reaction
time), abstract mental rotation task
(reaction time)
No significant differences: Embodied
mental rotation task (accuracy),
abstract mental rotation task
(accuracy)

Pelgrims et al., 2009/0
20/20 males, 0 Crossover (20–20–20–20–20)/subjects (1) 10-Hz rTMS (60  5 pulses, 65% 1 session, evaluations: T1 during rTMS 10-Hz rTMS over right SG significantly
females/26 years blinded/MRI scan MSO) over right LPS (100 ms after each stimulus onset 5 poorer than sham rTMS: Hands
rTMS pulses applied) (reaction time)
(2) 10-Hz rTMS (60  5 pulses, 65%
MSO) over left LPS
(3) 10-Hz rTMS (60  5 pulses, 65% 10-Hz rTMS over left SG significantly
MSO) over right SG poorer than sham rTMS: Hands
(reaction time)

(Continues)
VELDEMA ET AL.

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 TABLE 2 (Continued)
Number of
Reference/Oxford participants/gender/ Study design/blinding/positioning Results (group * time effect/
quality scoring scale age techniques Stimulation protocol Number of sessions/evaluations performed tests)
VELDEMA ET AL.

(4) 10-Hz rTMS (60  5 pulses, 65%

MSO) over left SG

(5) Sham rTMS (no stimulation, coil at 10-Hz rTMS over right LPS
the same position) significantly poorer than sham
rTMS: Letters (reaction time)
10-Hz rTMS over left LPS significantly
poorer than sham rTMS: Letters
(reaction time)

Feredoes & 20/10 males, 10 Crossover (20–20–20–20)/subjects (1) 20-Hz rTMS (38  4 pulses, 60% 1 session, evaluations: T1 during rTMS 20-Hz rTMS over right PPC
Sachdev, 2006/0 females/25 years blinded/10–20 EEG system MSO) over right PPC (400 ms after each stimulus onset 4 significantly poorer than sham
rTMS pulses applied) rTMS: Shepard-Metzler objects
(accuracy for stimuli with angular
disparity 120 )
(2) 20-Hz rTMS (38  4 pulses, 60%
MSO) over left PPC
(3) Sham rTMS (20-Hz rTMS, 38  4 20-Hz rTMS over left PPC significantly
pulses, 60% MSO, handle poorer than sham rTMS: Shepard-
perpendicular) over right PPC Metzler objects (accuracy for
stimuli with angular disparity of
180 )
(4) Sham rTMS (20 Hz rTMS, 38  4 No significant differences: Shepard-
pulses, 60% MSO, handle Metzler objects (accuracy for
perpendicular) over left PPC stimuli with angular disparity of 0
and 60 )

Harris & 33/16 males, 17 Four crossover experiments (9–9, 9–9, (1) 20-Hz rTMS (32 or 64  4 pulses, 1 session, evaluations: T1 during rTMS 20-Hz rTMS over right LPS applied
Miniussi, 2003/0 females/31 (20–51) 9–9, 6–6)/subjects blinded/ 110% rMT) over right LPS ((a)200-400 ms, (b) 400-600 ms, (c) 400–600 ms after stimulus onset
years navigator software 600-800 ms after each stimulus significantly poorer than sham:
onset 4 rTMS pulses applied) Alphanumeric characters (reaction
time)
(2) 20-Hz rTMS (32 or 64  4 pulses, No significant differences between (a)
110% rMT) over left LPS sham rTMS and 20 Hz rTMS over
left LPS applied 200–400 ms and
600–800 ms after stimulus onset,
and (b) sham rTMS and 20 Hz
rTMS over left LPS applied 200–
400 ms, 400–600 ms, and 600–
800 ms after stimulus onset:
Alphanumeric characters (reaction
time)

(Continues)
7501

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 TABLE 2 (Continued)
7502

Number of
Reference/Oxford participants/gender/ Study design/blinding/positioning Results (group * time effect/
quality scoring scale age techniques Stimulation protocol Number of sessions/evaluations performed tests)
(3) Sham rTMS (20 Hz rTMS, 32 or
64  4 pulses, 110% rMT, coil at
45 and reverse) over posterior
midline location

Klimesch et al., 2003/2
15/6 males, 9 females) Crossover (15–15–15–15–15–15–15– (1) IAF + 1-Hz rTMS (24 pulses, 110% 1 session, evaluations: T1 immediately IAF  1 Hz rTMS over right IPS
/25 (18–30) years 15–15)/subjects blinded/10–20 rMT) over right IPS (P6) after rTMS significantly better than sham
EEG system rTMS: Cubes (accuracy)
(2) IAF - 3-Hz rTMS (24 pulses, 110%
rMT) over right IPS (P6)
(3) 20-Hz rTMS (24 pulses, 110% rMT) IAF  1 Hz rTMS over Fz significantly
over right IPS (P6) better than sham rTMS: Cubes
(accuracy)
(4) IAF + 1-Hz rTMS (24 pulses, 110%
rMT) over Fz
(5) IAF – 3-Hz rTMS (24 pulses, 110% No significant differences between
rMT) over Fz sham rTMS and (a) IAF – 3-Hz
rTMS over right IPS, (b) IAF –
3-Hz rTMS over Fz, (c) 20-Hz
rTMS over right IPS, and (d) 20-Hz
rTMS over Fz: Cubes (accuracy)
(6) 20-Hz rTMS (24 pulses, 110% rMT)
over Fz
(7) Sham rTMS (IAF + 1-Hz rTMS, 24
pulses, 110% rMT, coil at 90 ) over
left IPS (P6)
(8) Sham rTMS (IAF – 3-Hz rTMS, 24
pulses, 110% rMT, coil at 90 ) over
left IPS (P6)
(9) Sham rTMS (20 Hz rTMS, 24
pulses, 110% rMT, coil at 90 ) over
left IPS (P6)

Bestmann 14/11 males, 3 Crossover (14–14–14)/subjects (1) 20-Hz rTMS (100  4 pulses, 120% 1 session, evaluations: T1 during rTMS 20-Hz rTMS over right PPC
et al., 2002/1 females/27  6 years blinded/10–20 EEG system rMT) over right PPC (P4) (100 ms after each stimulus onset 4 significantly poorer than sham:
rTMS pulses applied) Centre-out pointing task (reaction
time for large angles of rotation
[105 and 140 ])
(2) 20-Hz rTMS (100  4 pulses, 120%
rMT) over left PPC (P3)

(Continues)
VELDEMA ET AL.

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VELDEMA ET AL. 7503

(preconditioning = offline, simultaneous = online), and

20-Hz rTMS over left PPC significantly

No significant differences: Centre-out

stimuli (bodily and non-bodily). The effects on mental

pointing task (accuracy, reaction

time for small angles of rotation
pointing task (reaction time for

frequency; IPS, intraparietal sulcus; LPS, lobus parietalis superior; MRI, magnetic resonance imaging; ms, millisecond; MSO, maximal stimulator output; M1, primary motor cortex; pprTMS, paired-pulse repetitive transcranial
Note: aMT, active motor threshold; cm, centimetre; cTBS, continuous theta burst stimulation; Cz, vertex; dPMC, dorsal premotor cortex; EEG, electroencephalography; Fz, mesial fontal cortex; Hz, Hertz; IAF, individual alpha
poorer than sham: Centre-out

large angles of rotation [105 ,

Results (group * time effect/ rotation ability were classified using Cohen’s effect size

magnetic stimulation; PPC, posterior parietal cortex; pTPJ, posterior temporo-parietal junction; rMT, resting motor threshold; rTMS, repetitive transcranial magnetic stimulation; s, second; SG, supramarginal gyrus; SMA,
definition (d < 0.2 “no effect,” d = 0.2–0.49 “small
effect,” d = 0.5–0.79 “medium effect,” and d ≥ 0.8 “large
effect”) (Campbell, Machin, & Walters, 2007). The homo-
performed tests)

[0 , 35 , 70 ])

geneity of effects across studies was evaluated using the
inconsistency test (I 2), where values above 50% were con-

140 ])
sidered indicative of high heterogeneity (Higgins,
Thompson, Deeks, & Altman, 2003).
Number of sessions/evaluations

3 | RESULTS

In total, 56 articles were identified for the above search

procedure. Thirty-nine of them were excluded because of
inappropriate article type, outcome, intervention, and/or
population. The remaining 17 manuscripts corresponded
with our inclusion criteria and were selected for this sys-
tematic review and meta-analysis. The detailed summary
of the literature search is depicted in Figure 2. Overall,
(3) Sham rTMS (20 Hz rTMS, 100  4

485 subjects were enrolled. There are no reports of seri-

ous adverse events. The trials show a high variability
pulses, 120% rMT) over Cz

regarding stimulation parameters, participant’s charac-

Stimulation protocol

teristics, methodological approach, and effects of non-

invasive brain stimulation on mental rotation perfor-
mance (Figure 3). Table 3 demonstrates relationships
between stimulation-induced effects on mental rotation
ability and stimulation technique used, stimulation loca-
tion and timing and stimuli used. Greater effects of men-
tal rotation ability are associated with (1) tDCS and
Study design/blinding/positioning

tACS, (2) stimulation of right hemisphere, (3) combined

stimulation of frontal and parietal areas, and (4) using
bodied stimuli. For more clarity, we split our presenta-
tion into studies investigating tDCS/tACS and studies
investigating rTMS below.
techniques

supplementary motor area; T, test; TPJ, temporo-parietal junction.

3.1 | Transcranial direct current/

alternating current stimulation
participants/gender/

Seven studies evaluated the effect of tDCS/tACS on men-

tal rotation performance. Within their scope, overall,
12 sham-controlled experiments were performed
Number of

(Table 1).
age
(Continued)

3.1.1 | Methods
quality scoring scale
Reference/Oxford

Overall 265 persons (161 males, 104 females), aged

TABLE 2

between 18 and 43 years, were enrolled. One study

applied five tDCS sessions over 15 min (Moghadas
Tabrizi, Yavari, Shahrbanian, & Gharayagh, 2019). The

7504
remaining trials performed a single session of tDCS/tACS
over 10–30 minutes. Anodal tDCS, (Date, Kurumadani,
Watanabe, & Sunagawa, 2015; Foroughi, Blumberg, &
Parasuraman, 2015; Moghadas Tabrizi, Yavari,
Shahrbanian, & Gharayagh, 2019; Oldrati, Colombo, &
Antonietti, 2018), cathodal tDCS (Foroughi, Blumberg, &
Parasuraman, 2015), simultaneous tDCS bilateral (anodal
tDCS over one hemisphere coupled with cathodal tDCS
over the other hemisphere) (van Elk, Duizer, Sligte, &
van Schie, 2017), simultaneous tDCS unilateral (anodal
tDCS over one area coupled with cathodal tDCS over
another area of the same hemisphere) (Kikuchi
et al., 2017), and individual alpha frequency tACS (IAF
tACS) (Kasten, Maess, & Herrmann, 2018) were evalu-
ated. Exact stimulation parameters and stimulation loca-
tion are presented in Table 1 and Figure 3. Four trials
evaluated the mental rotation ability before and after
tDCS application (offline) (Date, Kurumadani,
Watanabe, & Sunagawa, 2015; Kasten, Maess, &
Herrmann, 2018; Moghadas Tabrizi, Yavari,
Shahrbanian, & Gharayagh, 2019; Oldrati, Colombo, &
Antonietti, 2018). Two studies applied only evaluation
during tDCS (online) (Kikuchi et al., 2017; van Elk,
Duizer, Sligte, & van Schie, 2017). One trial tested before
and during tDCS stimulation (online) (Foroughi,
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VELDEMA ET AL.
F I G U R E 2 Summary of literature
search results based on PRISMA guidelines
Blumberg, & Parasuraman, 2015). All studies included
sham control. Five studies also compared two different
stimulation protocols (Foroughi, Blumberg, &
Parasuraman, 2015; Kikuchi et al., 2017; Moghadas
Tabrizi, Yavari, Shahrbanian, & Gharayagh, 2019;
Oldrati, Colombo, & Antonietti, 2018; van Elk, Duizer,
Sligte, & van Schie, 2017). All studies except one (van
Elk, Duizer, Sligte, & van Schie, 2017) were randomized
trials. Only one study was double-blind (Kikuchi
et al., 2017).
3.1.2 | Effects
Table 1 presents the effects of tDCS/tACS on mental rota-
tion ability as detected in the enrolled studies. The data
indicate supporting effects of anodal tDCS and of tACS
(Date, Kurumadani, Watanabe, & Sunagawa, 2015;
Foroughi, Blumberg, & Parasuraman, 2015; Kasten,
Maess, & Herrmann, 2018; Moghadas Tabrizi, Yavari,
Shahrbanian, & Gharayagh, 2019; Oldrati, Colombo, &
Antonietti, 2018) and a worsening effect of cathodal tDCS
(Foroughi, Blumberg, & Parasuraman, 2015) on the men-
tal rotation ability. Opposite effects were demonstrated
for reverse electrode positioning during simultaneous
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VELDEMA ET AL. 7505

F I G U R E 3 Forest plot of 40 stimulation protocols investigating the effects of non-invasive brain stimulation on mental rotation ability
in scope of 16 placebo-controlled studies. Note: CI, confidence interval; cTBS, continuous theta burst stimulation; Hz, Hertz; IAF, individual
alpha frequency; mA, milliampere; OF, offline; ON, online; pprTMS, paired-pulse transcranial magnetic stimulation; rTMS, repetitive
transcranial magnetic stimulation; , rTMS; ■, tDCS

stimulation (Kikuchi et al., 2017; van Elk, Duizer, 3.2.1 | Methods

Sligte, & van Schie, 2017). Anodal tDCS over the right
parietal cortex coupled with cathodal tDCS over the right
frontal cortex induces an increase, reverse electrode
placement a decrease of mental rotation ability (Kikuchi
et al., 2017). Anodal tDCS over the left parietal cortex
coupled with cathodal tDCS over the right parietal cortex
induces a significant worsening in comparison to a
reverse protocol (van Elk, Duizer, Sligte, & van
Schie, 2017). The effect size calculation (Figure 3)
detected statistically relevant effects in a most experi-
ments that reported significant intervention-induced
changes within their cohorts (Table 1).
3.2 | Repetitive transcranial magnetic
stimulation
Ten studies tested rTMS on influencing the mental rota-
tion ability. In total, 34 placebo-controlled experiments
were applied (Table 2).
Overall 220 subjects (112 males, 108 females), aged 19–
51 years, were included. All studies tested single rTMS
session. Between 24 and 1200 rTMS pulses were applied
per intervention; 10-Hz rTMS (Cona, Marino, &
Semenza, 2016; Cona, Panozzo, & Semenza, 2017;
Pelgrims, Andres, & Olivier, 2009), 20-Hz rTMS
(Bestmann, Thilo, Sauner, Siebner, & Rothwell, 2002;
Feredoes & Sachdev, 2006; Harris & Miniussi, 2003;
Klimesch, Sauseng, & Gerloff, 2003), 1 Hz rTMS (Zeugin,
Notter, Knebel, & Ionta, 2020), individual alpha
frequency-based rTMS (Klimesch, Sauseng, &
Gerloff, 2003), ppTMS (Wang, Callaghan, Gooding-Wil-
liams, McAllister, & Kessler, 2016), and cTBS (Picazio,
Oliveri, Koch, Caltagirone, & Petrosini, 2013) were
applied. Exact stimulation parameters and stimulation
locations are presented in Table 2 and Figure 3. Most tri-
als evaluated the mental rotation ability during rTMS
application (online). Two to five TMS pulses were applied
100–800 ms after each stimulus presentation in these
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7506 VELDEMA ET AL.

TABLE 3 Cross-tabulation for studies evaluating non-invasive brain stimulation in the modulation of the mental rotation ability

Stimulation induced effects on mental rotation (number of studies)

tDCS/tACS rTMS

No Small Medium Large No Small Medium Large

effect effect effect effect effect effect effect effect
Overall
2 6 1 3 21 5 1 1
Stimulated hemisphere
Right 1 1 1 3 10 2 0 1
Left 0 3 0 0 11 3 1 0
Bilateral 1 1 0 0 0 0 0 0
Central 0 1 0 0 0 0 0 0
Stimulated areas
Frontal 0 3 0 1 8 0 0 0
Parietal 2 3 1 0 11 0 0 1
Frontal 0 0 0 2 0 4 0 0
+ parietal
Cerebellum 0 0 0 0 2 1 1 0
Stimulation timing
Preconditioning 0 3 1 1 2 1 0 1
Simultaneous 2 3 0 2 19 4 1 0
Stimuli
Bodied 1 2 1 3 8 2 1 1
Non-bodied 1 4 0 0 13 3 0 0

Note: No effect (d < 0.2); small effect (d = 0.2–0.49); medium effect (d = 0.5–0.79); large effect (d ≥ 0.8).

studies. Only three trials performed evaluation after
rTMS completion (offline) (Klimesch, Sauseng, &
Gerloff, 2003; Picazio, Oliveri, Koch, Caltagirone, &
Petrosini, 2013; Zeugin, Notter, Knebel, & Ionta, 2020). A
sham control was performed in all studies. Furthermore,
all studies except for two (Wang, Callaghan, Gooding-
Williams, McAllister, & Kessler, 2016; Zeugin, Notter,
Knebel, & Ionta, 2020) compared the effects of two or
more different stimulation protocols. Only some trials
mentioned a randomized allocation (Bestmann, Thilo,
Sauner, Siebner, & Rothwell, 2002; Cona, Marino, &
Semenza, 2016; Klimesch, Sauseng, & Gerloff, 2003;
Picazio, Oliveri, Koch, Caltagirone, & Petrosini, 2013).
No study was double-blind.
3.2.2 | Effects
Table 2 presents the effects of rTMS on mental rotation
ability as detected in the included trials. Online 10-Hz
rTMS over frontal lobes led to (i) improving (left SMA
stimulation) and (ii) deterioration (right and left dPMC
stimulation) or no significant changes (M1 stimulation)
(Cona, Marino, & Semenza, 2016) of mental rotation abil-
ity. Online 10-Hz rTMS over both the right and the left
posterior lobes induced deterioration of the observed
parameters (Pelgrims, Andres, & Olivier, 2009). Online
20-Hz rTMS over both the left (PPC stimulation) and the
right (PPC and LPS stimulation) parietal lobe deterio-
rated mental rotation ability (Bestmann, Thilo, Sauner,
Siebner, & Rothwell, 2002; Feredoes & Sachdev, 2006;
Harris & Miniussi, 2003). However, online 20-Hz RTMS
over left parietal cortex (LPS stimulation) did not induce
significant changes (Harris & Miniussi, 2003). Online
ppTMS over the right posterior cortex showed no effect
(Wang, Callaghan, Gooding-Williams, McAllister, &
Kessler, 2016). Offline 1-Hz rTMS over this area
improved the mental rotation ability (Zeugin, Notter,
Knebel, & Ionta, 2020). Offline rTMS in the individual
alpha frequency + 1 Hz (IAF + 1-Hz rTMS) applied over
both central frontal cortex and the right parietal cortex
increased mental rotation performance (Klimesch,

VELDEMA ET AL.
Sauseng, & Gerloff, 2003). Offline rTMS in individual
alpha frequency 3 Hz (IAF 3-Hz rTMS) and 20-Hz rTMS
over the same areas induced no effects (Klimesch,
Sauseng, & Gerloff, 2003). Offline cTBS deteriorated men-
tal rotation when applied over the left cerebellum but
induced no changes by application over the right cerebel-
lum (Picazio, Oliveri, Koch, Caltagirone, & timing may relevantly impact stimulation effects of cog-
Petrosini, 2013). Despite the intervention-induced
changes reported in individual trials (Table 2), the effect
size calculation (Figure 3, Table 3) detected statistically
relevant effects only in a small part of the experiments.
4 | DISCUSSION
The aim of this systematic review and meta-analysis
was to investigate whether non-invasive brain stimula-
tion can support the mental rotation ability in healthy
subjects. The available data demonstrate great inhomo-
geneity of effects across the experiments and indicate
that non-invasive brain stimulation can both support
and deteriorate this important visuo-spatial ability. In
fact, the effect size calculation detected a relevant
intervention-induced improvement of mental rotation
in nine protocols. In contrast, eight protocols evoked a
relevant worsening of this ability. The remaining 23 pro-
tocols did not have a clear effect (Figure 3, Table 3).
The reasons for these inconsistencies may be the high
heterogeneity of experiments regarding stimulation
techniques (tDSC/tACS and rTMS), stimulation parame-
ters (different protocols, durations, and intensities),
stimulation location (different brain areas and hemi-
spheres), stimulation timing (online and offline), and
mental rotation objects (bodily and non-bodily). We will
discuss how these factors may influence the effects of
non-invasive brain stimulation on the mental rotation
ability.
4.1 | Stimulation technique-dependent
effects
The effect size calculation demonstrated that tDCS/
tACS induced greater effects on mental rotation ability
than rTMS. In fact, only two rTMS protocols but
10 tDCS/tACS protocols induced relevant effects
(Figure 3, Table 3). It is not clear whether and to what
extent the differences reflect the differential impact of
the various techniques on the human brain and cogni-
tion, and which role other factors (such as patient char-
acteristics, study design, etc.) play. The included tDCS/
tACS studies differ considerably from rTMS studies
regarding the applied methodological approaches. A
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7507
major part of the rTMS studies performed stimulation
during the cognitive task (online). In contrast, tDCS/
tACS studies performed simultaneous and
preconditioning stimulation equally frequently
(Figure 3). This is an important point because previous
reviews and meta-analyses indicate that stimulation-
nitive performance (Hill, Fitzgerald, & Hoy, 2016;
Yeh & Rose, 2019). Moreover, most rTMS studies did
not perform a conventional repetitive application of
TMS pulses with a constant frequency. Instead, short
sequencies of two to five pulses (with a given fre-
quency) were time locked to the stimulus presentation
during the cognitive task. A repetitive application of
38–200 sequencies were performed in each subject
within a few minutes (Table 1, Figure 3). The question
is whether those protocols can be clearly considered as
repetitive application of TMS? In contrast, a conven-
tional uninterrupted stimulation was performed in all
tDCS/tACS studies. Given these inconsistencies, we will
discuss the rTMS and the tDCS/tACS studies separately.
4.2 | TDCS/tACS for modulation of the
mental rotation ability
The effect size calculation indicates that tDCS/tACS is
effective in the modulation of mental rotation (Figure 3,
Table 3). However, the effects are highly inhomogeneous.
We will discuss how stimulation-timing, electrodes-polar-
ity, stimulation location and type of stimuli may influ-
ence the effectiveness.
4.2.1 | Stimulation-timing dependent effects
Overall 12 placebo-controlled experiments investigated
tDCS in the modulation of the mental rotation ability.
Only two protocols did not induce any relevant effect
on the observed parameters (Foroughi, Blumberg, &
Parasuraman, 2015; van Elk, Duizer, Sligte, & van
Schie, 2017). Interestingly, both ineffective protocols
performed simultaneous stimulation (online). Similarly,
an earlier review and meta-analysis demonstrated that
only offline (but not online) anodal tDCS significantly
supports working memory in healthy populations (Hill,
Fitzgerald, & Hoy, 2016). Interestingly, an opposite
effect (supportive influence of online, but not offline
anodal tDCS) was observed in neuropsychiatric
populations (Hill, Fitzgerald, & Hoy, 2016). In any case,
the available data indicate that tDCS/tACS timing may
significantly influence the stimulation effect on human
cognition.

7508
4.2.2 | Electrodes-polarity dependent effects
Our data show polarity-dependent effects in accordance
with the oversimplified theory that indicates that
anodal tDCS/tACD improves and cathodal tDCS/tACS
deteriorates cognitive performance (Fertonani &
Miniussi, 2017). Similar results are presented in an ear-
lier systematic review and meta-analysis that investi-
gates the effect of tDCS over the dorsolateral prefrontal
cortex on human cognition (Dedoncker, Brunoni,
Baeken, & Vanderhasselt, 2016). Only anodal stimula-
tion supported cognitive processing in both healthy and
neuropsychiatric samples. Cathodal protocols did not
induce significant effects (Dedoncker, Brunoni,
Baeken, & Vanderhasselt, 2016). The data also show
that a reverse positioning of electrodes during simulta-
neous unilateral stimulation evokes reverse cognitive
changes (Kikuchi et al., 2017). While anodal stimulation
over the right parietal cortex and cathodal stimulation
over the right frontal cortex improves the mental rota-
tion ability, the reverse electrode placement leads to its
deterioration (Kikuchi et al., 2017). This result is
supported by a previous systematic review and meta-
analysis that detected between-hemispheric asymmetries
during mental rotation tasks (Zacks, 2008). Parietal cor-
tex activity is somewhat more consistently observed in
the right hemisphere, whereas frontal cortex activity is
more consistently observed in the left hemisphere
(Zacks, 2008). This explains the supportive effect of
anodal (and not of cathodal) tDCS over the right parie-
tal regions.
4.2.3 | Stimulation-location dependent
effects
Our data indicate that the positioning of the active
electrode over the right hemisphere is more effective
than both left hemispheric and simultaneous bilateral
stimulation (with the anode over one hemisphere and
the cathode over the other) (Figure 3, Table 3).
Finally, simultaneous application over the right hemi-
sphere (with electrodes over parietal and frontal corti-
cal areas) induces greater effects than all another
protocols (Kikuchi et al., 2017). In accordance, a pre-
vious meta-analysis emphasizes the superior role of
the right hemisphere during some mental rotation
tasks (Tomasino & Gremese, 2016). Whereas mental
rotation of bodily stimuli (e.g., hands and feet) leads
to the activation of the bilateral sensorimotor network,
non-bodily stimuli (e.g., Shepard-Metzler objects)
induce right lateralized activation (Tomasino &
Gremese, 2016).
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VELDEMA ET AL.
4.2.4 | Stimulus-type dependent effects
The effect size calculation indicates that tDCS/tACS is
more effective in modulation of the mental rotation of
bodily stimuli than in the modulation of non-bodily
objects. A previous review refers to stimulus-dependent
differences of neural-processing (Searle & Hamm, 2017).
BOLD activation within the ventral stream and the
premotor cortex increases linearly with stimulus discrep-
ancies during mirror/normal discriminations, but only
during mental rotation of bodily stimuli. Similarly, slow
negativity over centroparietal regions as recorded by EEG
increases for greater rotations only during mental rota-
tion of bodily objects. Higher difficulty during mental
rotation of non-bodily stimuli did not induce higher acti-
vation of the neural network (Searle & Hamm, 2017). It
is conceivable, that stronger activation of the neural net-
work during mental rotation tasks provides more oppor-
tunity for modulation with non-invasive brain
stimulation and has thus greater effects on cognitive
performance.
4.3 | rTMS for modulation of the mental
rotation ability
The effect size calculation demonstrates that rTMS has
only limited effectiveness in the modulation of the men-
tal rotation ability (Figure 3, Table 3). From a total of
28 experiments, only two protocols induce relevant
effects. However, Table 2 shows that any part of mental
rotation tasks could be significantly influenced by this
method. We will discuss how different factors influence
the effectiveness of rTMS.
4.3.1 | Stimulation-timing dependent effects
The effect size calculation demonstrates relevant changes
of mental rotation ability in one-half of the experiments
that applied preconditioning stimulation and only in one-
fifth of experiments that performed a simultaneous stim-
ulation (Figure 3, Table 3). Thus, offline application
seems to have more potential to influence the visuo-
spatial ability. Similarly, a meta-analysis detected timing-
dependent effects of rTMS for modulation of working
memory (Yeh & Rose, 2019). Offline 20-Hz rTMS induces
an improvement and online 20-Hz rTMS a deterioration
of the observed parameters (Yeh & Rose, 2019). More-
over, in the framework of online stimulation, the timing
of rTMS pulses in relation to cognitive tasks significantly
impacted their effects. A study demonstrated that 20-Hz
rTMS that was applied over the right lobus parietalis

VELDEMA ET AL.
superior 400–600 ms after stimulus onset affected the
reaction time during mental rotation of alphanumeric
characters (Harris & Miniussi, 2003). The same protocol
applied 200–400 ms and 600–800 ms after stimulus onset
did not induced any effects (Harris & Miniussi, 2003).
4.3.2 | Stimulation-frequency dependent
effects
The data did not demonstrate frequency-dependent
effects in accordance with the assumed supportive effects
of high-frequency (≥5 Hz) and deteriorating effects of
low-frequency (1-Hz) rTMS (Siebner & Rothwell, 2003).
The studies show both supportive and disruptive effects
of high-frequency protocols (Table 2). Ten-hertz rTMS
induced worsening (Cona, Panozzo, & Semenza, 2017;
Pelgrims, Andres, & Olivier, 2009) as well as improve-
ment of the mental rotation ability (Cona, Marino, &
Semenza, 2016). Twenty-hertz rTMS evoked deterioration
(Feredoes & Sachdev, 2006; Harris & Miniussi, 2003) or
no changes of the assessed parameters (Klimesch,
Sauseng, & Gerloff, 2003). Individual alpha frequency
+ 1-Hz rTMS improved the mental rotation ability
(Klimesch, Sauseng, & Gerloff, 2003). Individual alpha
frequency–3-Hz rTMS did not affect the visuo-spatial per-
formance (Klimesch, Sauseng, & Gerloff, 2003). Only one
study tested a low-frequency stimulation protocol up to
now. Its results show supporting effects of 1-Hz rTMS on
the mental rotation ability (Zeugin, Notter, Knebel, &
Ionta, 2020). One trial applied 50-Hz cTBS and demon-
strated worsening of the mental rotation ability (Picazio,
Oliveri, Koch, Caltagirone, & Petrosini, 2013). This is in
accordance with the simplified concept that indicates
supporting effects of iTBS and impeding effects of cTBS
on neural and cognitive processing (Siebner &
Rothwell, 2003); 0.2-Hz pp rTMS did not modulate the
performance during the visuo-spatial task (Wang,
Callaghan, Gooding-Williams, McAllister, & Kessler, 2016)
and contradicts the positive role of paired-pulse rTMS with
inter-stimulus interval >5 ms on neural and cognitive
processes (Siebner & Rothwell, 2003). In accordance with
our findings, the available systematic reviews and meta-
analyses demonstrate that effects of diverse rTMS protocols
for modulation of human cognition and behaviour are
often contrary to the conventional frequency-dependent
view (Siebner & Rothwell, 2003). A recent meta-analysis
indicates a disruptive effect of 10-Hz and 20-Hz rTMS and
no effect of 1 Hz or 5 Hz on attention, executive, language,
memory, motor, and perception (Beynel et al., 2019).
Another meta-analysis shows both improving and
deteriorating effects of 20-Hz rTMS on working memory
depending on the stimulation-timing (Yeh & Rose, 2019).
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7509
In contrast, only positive effects were found for 1-Hz rTMS
(Yeh & Rose, 2019).
4.3.3 | Stimulated hemisphere-dependent
effects
The effect size calculation did not detect relevant effects
regarding the stimulated hemisphere (right versus left)
on rTMS effectiveness (Figure 3, Table 3). However, a
closer look at our studies detected some hemisphere-
dependent effects (Table 2). On the one hand, 10-Hz
rTMS over both the right and the left dorsal premotor
cortex impaired accuracy for the same stimuli during
mental rotation of Shepard-Metzler objects (Cona,
Panozzo, & Semenza, 2017). Only right hemispheric stim-
ulation delayed reaction time for the same stimuli during
mental rotation of both Shepard-Metzler objects and
hands (Cona, Panozzo, & Semenza, 2017). This result
contradicts the findings of an earlier meta-analysis that
detected a more consistent parietal cortex activity in the
right hemisphere, and frontal cortex activity in the left
hemisphere during mental rotation tasks (Zacks, 2008).
On the other hand, 20-Hz rTMS applied over the right
lobus parietalis superior 400–600 ms after stimulus onset
affected reaction time for alphanumeric characters
(Harris & Miniussi, 2003). The same stimulation over the
homologous area did not evoke any changes (Harris &
Miniussi, 2003). This finding confirms the prominent role
of right parietal areas (in comparison to the left hemi-
sphere) during neural control of visuo-spatial tasks
(Zacks, 2008). Another study indicates the prominent role
of the left lateral cerebellum (in comparison to the
homologous area) during mental rotation (Picazio,
Oliveri, Koch, Caltagirone, & Petrosini, 2013). Fifty-hertz
cTBS over left but not over the right hemisphere delayed
reaction time during embodied and abstract mental
rotation tasks (Picazio, Oliveri, Koch, Caltagirone, &
Petrosini, 2013). One study demonstrates a differential
involvement of both hemispheres depending on the
stimuli angular disparity (Feredoes & Sachdev, 2006).
Twenty-hertz rTMS over both the right and the left poste-
rior parietal cortex impaired mental rotation of Shepard-
Metzler objects (Feredoes & Sachdev, 2006). While the
right hemispheric stimulation influenced stimuli with
angular disparity of 120 , the left hemispheric stimula-
tion affected stimuli with angular disparity of 180 . Stim-
uli with angular disparity of 0 and 60 were not affected
(Feredoes & Sachdev, 2006). The differential involvement
of the hemispheres depending on the stimuli angular dis-
parity is a new finding, which has not been described in
previous reviews and meta-analyses (Beynel et al., 2019;
Yeh & Rose, 2019).

7510
4.3.4 | Stimulated area-dependent effects
The effect size calculation shows no relevant impact of
the stimulated region (frontal versus parietal) on rTMS
effects (Figure 3, Table 3). However, some studies found
significant stimulated area-dependent effects (Table 2).
The data indicate that a simple subdivision of brain net-
work in either “frontal” or “parietal” is too coarse to
detect the effective involvement of specific brain regions
during mental rotation tasks (Cona, Marino, &
Semenza, 2016; Pelgrims, Andres, & Olivier, 2009). Ten-
hertz rTMS over both the right and the left lobus
parietalis superior delayed the reaction time during men-
tal rotation of letters but not hands (Pelgrims, Andres, &
Olivier, 2009). The same protocol applied over both the
right and the left supramarginal gyrus slowed reaction
time during mental rotation of hands but not letters
(Pelgrims, Andres, & Olivier, 2009). Similarly, 10-Hz
rTMS over the left supplementary motor area improved
reaction time and accuracy during mental rotation of
Shepard-Metzler objects and of hands (Cona, Marino, &
Semenza, 2016). Ten-hertz rTMS over the left primary
motor cortex did not induce any changes (Cona,
Marino, & Semenza, 2016).
4.3.5 | Stimulus-type dependent effects
The effect size calculation shows relevant effects in one
third of the experiments that used bodied stimuli and
only in one fifth of experiments that used non-bodied
stimuli (Figure 3, Table 3). Similar effects were also
detected for tDCS/tACS studies. The reason for this phe-
nomenon may be stimulus-dependent differences of neu-
ral processing as described on a previous review
(Searle & Hamm, 2017). Increased difficulty during men-
tal rotation of bodily stimuli induces an increased activa-
tion of the neural network. Higher difficulty during
mental rotation of non-bodily stimuli did not induce any
effects (Searle & Hamm, 2017).
5 | C ON C L U S I ON S
The systematic review and meta-analysis presented
here shows that non-invasive brain stimulation is effec-
tive in modulating the mental rotation ability. The
available data indicates a supportive effect of anodal
tDCS and of tACS and no effect of cathodal tDCS.
Bilateral tDCS/tACS both supported and deteriorated
the visuospatial performance. Only small effects were
obtained in most rTMS experiments. Stimulation
timing, stimulation location and stimulus type are
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VELDEMA ET AL.
factors that impact the effects of both tDCS/tACS and
rTMS. Future research may apply these methods in
cohorts with impaired mental rotation ability, such as
major depressive disorder, stroke, and pain-related
diseases.
A C KN O WL ED G EME N T S
We acknowledge Arne Engelhardt for his support in data
acquisition.
This research received no specific grant from any
funding agency in the public, commercial, or not-for-
profit sectors.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
AUTHOR CONTRIBUTIONS
JV and PJ concepted and designed the study. JV and AE
performed the data acquisition. JV analysed and inter-
preted the data and wrote the first version of the manu-
script. PJ and AG contributed to data interpretation and
reviewed the manuscript.
PE ER RE VI EW
The peer review history for this article is available at
https://publons.com/publon/10.1111/ejn.15490.
DA TA AVAI LA BI LI TY S T ATE ME NT
The datasets generated during and/or analysed during
the current study are available from the corresponding
author on reasonable request.
ORCID
Jitka Veldema https://orcid.org/0000-0002-9184-9776
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How to cite this article: Veldema, J.,
Gharabaghi, A., & Jansen, P. (2021). Non-invasive
brain stimulation in modulation of mental rotation
ability: A systematic review and meta-analysis.
European Journal of Neuroscience, 54(10),
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