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Efficacy of repetitive transcranial magnetic
stimulation combined with visual scanning
treatment on cognitive and behavioral
symptoms of left hemispatial neglect in
right hemispheric stroke patients: study
protocol for a randomized controlled trial
Francesco Di Gregorio
1
, Fabio La Porta
2*
, Emanuela Casanova
2
, Elisabetta Magni
2
, Roberta Bonora
2
,
Maria Grazia Ercolino
2
, Valeria Petrone
2
, Maria Rosaria Leo
3
and Roberto Piperno
2
Abstract
Background: Left hemispatial neglect (LHN) is a neuropsychological syndrome often associated with right
hemispheric stroke. Patients with LHN have difficulties in attending, responding, and consciously representing the right
side of space. Various rehabilitation protocols have been proposed to reduce clinical symptoms related to LHN, using
cognitive treatments, or on non-invasive brain stimulation. However, evidence of their benefit is still lacking; in
particular, only a few studies focused on the efficacy of combining different approaches in the same patient.
Methods: In the present study, we present the SMART ATLAS trial (Stimolazione MAgnetica Ripetitiva Transcranica
nell’ATtenzione LAteralizzata dopo Stroke), a multicenter, randomized, controlled trial with pre-test (baseline), post-test,
and 12 weeks follow-up assessments based on a novel rehabilitation protocol based on the combination of brain
stimulation and standard cognitive treatment. In particular, we will compare the efficacy of inhibitory repetitive-
transcranial magnetic stimulation (r-TMS), applied over the left intact parietal cortex of LHN patients, followed by visual
scanning treatment, in comparison with a placebo stimulation (SHAM control) followed by the same visual scanning
treatment, on visuospatial symptoms and neurophysiological parameters of LHN in a population of stroke patients.
(Continued on next page)
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* Correspondence: fabiolaporta@mail.com
Names of protocol contributors
Francesco Di Gregorio^, Fabio La Porta*, Emanuela Casanova*, Roberto
Piperno*
^Azienda Unità Sanitaria Locale, Bologna,
*IRCCS Istituto delle Scienze Neurologiche di Bologna, UO di Medicina
Riabilitativa e Neuroriabilitazione, Bologna, Italy
2
IRCCS Istituto delle Scienze Neurologiche di Bologna, UO di Medicina
Riabilitativa e Neuroriabilitazione, Casa dei Risvegli Luca de Nigris, Via Giulio
Gaist, 6, 40139 Bologna, Italy
Full list of author information is available at the end of the article
Di Gregorio et al. Trials (2021) 22:24
https://doi.org/10.1186/s13063-020-04943-6
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(Continued from previous page)
Discussion: Our trial results may provide scientific evidence of a new, relatively low-cost rehabilitation protocol for the
treatment of LHN.
Trial registration: ClinicalTrials.gov NCT04080999. Registered on September 2019.
Keywords: Stroke rehabilitation methods, Transcranial magnetic stimulation, Brain pathology, Brain physiology,
Functional laterality, Randomized controlled trial
Background
Left hemispatial neglect (LHN) is a disabling neuro-
psychological syndrome, which occurs in about 30% of
persons with stroke [1]. LHN is a well-known predictor
of poor long-term functional outcome [2], as it may be
associated with more extended in-hospital stay, long
term limitations in activities of daily living, and an in-
creased risk of falling [3]. About 90% of persons with
LHN have suffered a right hemispheric stroke [1]. Patients
with LHN present deficits in perceiving, responding, con-
sciously representing, and orienting attention toward the
contralesional hemifield, usually the left hemifield [4,5].
Consequently, this specific condition leads to a lack of
awareness for objects, persons, and even for their own
body parts in the left hemifield. Furthermore, LHN can be
associated with a deficit in other clinical domains. Indeed,
motor deficits involving the body’s contralateral side (i.e.,
left hemiplegia) are often present. This clinical picture can
be aggravated by a lack of awareness for cognitive and
motor deficits (i.e., anosognosia), particularly influencing
rehabilitation and daily living activities [6]. Thus, the com-
plexity of symptoms in LHN requires broad assessments
and specific rehabilitation protocols.
Clinically, LHN is investigated with paper and pencil
neuropsychological tests (e.g., lines bisection, letter, or star
cancelation), which assess the ability to search for stimuli
in space. Recently, however, neurophysiological diagnostic
procedures were introduced for the functional evaluation
of LHN. Specific paradigms indeed use visual evoked po-
tentials (VEPs) [7,8] to assess biases in the processing of
lateralized (i.e., right or left) presented stimuli. These stud-
ies evidenced a correlation between visual-spatial attention
deficits in LHN and a reduction in amplitude and later la-
tencies of the N100 component for stimuli presented in
the left neglected hemifield. N100 anomalies are observed
both at the left and right parietal cortices and on fronto-
parietal areas. These results suggest that functional im-
pairments in LHN involve both hemispheres and the
cerebral network involved in spatial attention orientation
[1,9]. Indeed, influential theories sustained the idea that
LHN is related to a dysfunction in the neural network
subtending attentive spatial processing. In particular, sev-
eral studies report an imbalance in interhemispheric activ-
ity due to hyperactivity of the left hemisphere in LHN
patients [1,10–12].
In the rehabilitation of LHN, it is possible to distin-
guish protocols based on cognitive treatments and non-
invasive brain stimulation, such as repetitive transcranial
magnetic stimulation (r-TMS) [13,14]. Conventional
cognitive treatments (CCT) of LHN involve different
types of exercises aimed at reducing attentional bias for the
ipsilesional space (e.g., prism adaptation) and promoting
contralesional space awareness (e.g., visual scanning train-
ing) [15]. Although several studies demonstrated the effi-
cacy of CCTs on improving short and medium-term LHN
symptoms, the debate is still open about these treatments’
long-term efficacy [16]. Thus, over the past 20 years, the
interest in rehabilitation approaches based on non-invasive
brain stimulation has increased. In particular, transcranial
magnetic stimulation (TMS) is a non-invasive method to
modulate the cerebral cortex’s excitability. For instance,
Brighina et al. (2003) [17] applied low-frequency (1 Hz) in-
hibitory repetitive TMS (r-TMS) in the healthy contrale-
sional areas. The r-TMS treatment improved the clinical
symptoms of LHN after ten treatment sessions. Improve-
ments were stable even 15 days after treatment. This study
provided encouraging initial evidence on the efficacy of in-
terventions based on TMS. Indeed, several studies also in-
vestigated the combined and additive effects of various
rehabilitation techniques on the same patient (i.e., TMS
and CCT) [18–20] to potentiate the intervention.
However, methodological limitations emerged from
these studies, such as reduced sample sizes, the lack of
blindness of assessors, the lack of a general assessment
of activities of daily living, and long-term follow-up.
Thus, it is still necessary to understand whether the
combination of different therapeutic approaches can
have a clinically significant additive effect in reducing
the severity of symptoms of LHN. Furthermore, com-
bined protocols need to be studied in terms of their
neurophysiological correlates to quantify better their ef-
fects over the interhemispheric imbalance and in terms
of long-lasting clinical results.
This study’s central hypothesis is that, as observed in
previous studies for right hemispheric strokes, clinical
symptoms of LHN are correlated to an imbalance in in-
terhemispheric activity due to hyperactivity of the left
hemisphere [1,10–12]. Inhibitory r-TMS on the intact
left parietal cortex reduces the left hemisphere activation
and can rebalance interhemispheric activity. Indeed, the
Di Gregorio et al. Trials (2021) 22:24 Page 2 of 11
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most used TMS paradigms for the rehabilitation of LHN
are based on the concept of interhemispheric rivalry [21,
22]. According to this model, the two hemispheres exert
a reciprocal inhibition. In particular, the right and left
parietal cortices are part of an interhemispheric and
intrahemispheric frontal-parietal pathway that controls
the orientation of attention in space [1]. Thus, the right
parietal cortex’s damage causes disinhibition of the left
parietal cortex and, therefore, a pathological over-
activation of the latter. This left over-activation conse-
quently inhibits the right contralateral hemisphere by in-
creasing the healthy hemisphere’s inhibitory activity on
the damaged hemisphere. TMS treatments, therefore,
aims at rebalancing interhemispheric rivalry by stimulat-
ing the parietal interhemispheric pathway, specifically
inhibiting the areas of the left healthy parietal cortex [5,
23]. Thus, should r-TMS administered before a cognitive
treatment, it might reduce the interhemispheric imbal-
ance. Consequently, r-TMS may increase brain activity
toward the left neglected hemifield and boost the effects
of cognitive training. Specifically, in the present study,
we hypothesize that a combined r-TMS and cognitive
training protocol could be efficient in rehabilitating clin-
ical and cognitive symptoms of LHN, reducing inter-
hemispheric imbalance with a positive impact on
activities of daily living.
Aims and objectives
The aims of this study are: (1) to test the central hypoth-
esis by assessing the immediate and long-term efficacy
of a combined treatment based on r-TMS and visual
scanning training (a conventional cognitive protocol
based on the administration of a structured series of
tasks aiming at improving spatial exploration abilities
[13,24] on the cognitive and behavioral manifestation of
LHN in a population of patients with right-hemisphere
stroke), (2) to assess the immediate and long-term effi-
cacy of the proposed treatment on independence in ac-
tivities of daily living, and (3) to investigate the clinical
responsiveness of neurophysiological correlates and in-
dexes based on visual evoked potentials (VEPs).
Our operational objectives and outcome measures are di-
vided into primary and secondary outcomes to reach all
these aims. The primary outcome is represented by (1) a
specific assessment of visual-spatial attentive functions and
behavioral symptoms of LHN with the Behavioral Inatten-
tion Test (BIT) [24]. The secondary endpoints consider the
impact of the protocols on other clinical and neurophysio-
logical indexes. In particular, we aim to test (2) the degree
of functional independence with the Catherine Bergegò
Scale, which considers the impact of LHN symptoms dur-
ing activities of daily living (ADL) [25]. Furthermore, we
test mobility with Motricity Index, Trunk Control Test, and
Functional Independence Measure (FIM) [2,26]thatare
measures of motor impairments, attentive functions with
the Test of Attentional Performance (TAP), that is a com-
puterized attention assessment. Finally, we tested (3) neuro-
physiological indexes of interhemispheric imbalance based
on the latencies (IHTT, interhemispheric transmission
time) and amplitudes (vABI, Visuospatial Attention Bias
Index) of the N100 components of the VEPs.
Methods
Trial design and study design
We present the SMART ATLAS trial (Stimolazione
MAgnetica Ripetitiva Transcranica nell’ATtenzione
LAteralizzata dopo Stroke; in English: repetitive trans-
cranial magnetic stimulation in lateralized attention
after stroke), a multicenter, randomized, controlled trial
with pre-test (baseline), post-test, and 12 weeks follow-
up assessments aiming at comparing the efficacy of
inhibitory r-TMS, applied over the left intact parietal
cortex of LHN patients, followed by visual scanning
treatment (VS) [27], in comparison with a placebo
stimulation (SHAM control) followed by the same vis-
ual scanning treatment, on visuospatial symptoms of
LHN in a population of stroke patients. Our methodo-
logical approach provides two parallel groups (active r-
TMS and SHAM placebo groups) with a 2:2 randomized
allocation ratio in a superiority trial design. Figure 1and
Table 1show the study flowchart and the study time
points, respectively.
Participants
Patients with LHN due to stroke will be recruited in the
Neurorehabilitation Unit of the IRCCS Istituto delle
Scienze Neurologiche di Bologna (coordinating center)
and the Villa Bellombra rehabilitation Hospital in Bol-
ogna (Italy). Subjects will be recruited accordingly to the
following eligibility criteria:
Inclusion criteria:
1. Diagnosis of ischemic stroke of the right medial
cerebral artery or right intracranial hemorrhagic
stroke, confirmed by encephalic CT scan or MRI;
2. Diagnosis of LHN with specific screening test
(asymmetry score in the Bells test > 3);
3. Inpatient or outpatient rehabilitation setting;
4. Age between 18 and 80 years;
5. Time after stroke between 3 weeks and 12 weeks;
and
6. Adequate language comprehension to give informed
consent.
Exclusion criteria:
1. Medical instability at the time of enrollment,
defined as the acute onset of an unexplained
Di Gregorio et al. Trials (2021) 22:24 Page 3 of 11
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derangement of one or more vital parameters
(temperature, blood pressure, pulse rate, respiratory
rate, oxygen saturation, level of responsiveness)
outside the normal range (e.g., fever, cardiac
arrhythmias, respiratory insufficiency) and/or the
onset of any new medical condition requiring
unexpected additional diagnostic procedures and
treatments (e.g., severe pain, reduction of urinary
output);
2. Presence of epileptogenic alterations of the EEG
and/or previous epileptic seizures;
3. Presence of intracranial implants of a metallic
material;
4. Presence of devices that could be altered by r-TMS,
such as pacemakers, ventriculoperitoneal deriva-
tions, or baclofen infusion pumps;
5. Absence of bone flap following decompressive
craniectomy;
6. Presence of alteration in the consciousness-vigilance
rhythm;
7. Cortical blindness and/or visual agnosia;
8. Previous psychiatric disorders and/or history of
substance abuse;
9. Pregnancy state;
10. Severe deafness not compensated by hearing
devices;
11. Severe reduction of visual acuity not compensated
by optic lenses; and
12. Previous diagnosis of cognitive impairment.
Before enrollment in the study, the principal investiga-
tor (PI) will check the eligibility criteria. In particular,
after verifying the eligibility criteria, the PI (or a dele-
gate) will provide the potentially eligible person with all
the information and details relative to the study in a
simple language during an interview that will preferably
take place in the presence of a caregiver.
Intervention
Based on previous studies [5,17,23], seven sessions of
r-TMS will be administered over 15 days [17]. In detail,
the parameters used in each session will be:
1. International 10/20 system for the location of the
target area (non-lesioned left posterior parietal
cortex);
2. 60% power;
3. Frequency: 1 Hz; and
Fig. 1 Study flowchart. r-TMS, repetitive transcranial magnetic
stimulation; VS, visual scanning
Table 1 Study time points
Study period
Stages ➔Enrolment Pre-allocation Allocation Post-allocation Follow-up
Weeks W0 W0 W0 W1 W2 W3 W15
Time points T
0
T
1
T
2
Eligibility Screening X
Informed Consent X
Allocation X
Treatment XX
Assessments XXX
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4. Ninety pulse trains with ten pulses each (total 900
stimuli) resulted in a whole stimulation period of
15 min.
The stimulation coil will be positioned tangentially on
the target area. Each r-TMS session will last 15 min and be
administered every other day (e.g., Monday-Wednesday-
Friday, Monday-Wednesday-Friday, Monday).
Following the rTMS, the visual scanning treatment will
be administered by speech and language therapists and
cognitive therapists, who will administer various visual
scanning tasks, increase the patient’s awareness of the
LHN clinical manifestations, and teach the participant
strategies to improve spatial exploration abilities [23]. In
particular, three different training protocols will be used:
1. Visuospatial training;
2. Reading and copying training; and
3. Copying of line drawings on a dot matrix.
All training protocols include three increasing levels of
difficulty, thus giving nine possible test-difficulty combi-
nations. Each level of difficulty will be practiced until the
subject will reach a level of accuracy of 75%. The train-
ing will be carried out in 50 min sessions for 5 days a
week within 15 days [23], for a total of 11 sessions. On
the days when the r-TMS is also carried out, the visual
scanning protocol administration will follow the brain
stimulation.
Control
In the control group, where a SHAM placebo stimula-
tion is implemented, the stimulation parameters will be
the same, but the coil of the r-TMS will be positioned at
90° on the target area. Thus, no specific cortical modula-
tion will be implemented (SHAM stimulation). The
visual scanning protocol will be administered with the
same modalities and time frame for this group, as de-
tailed for the intervention group. All routine care is per-
mitted for both groups during the study period.
Outcomes
Primary endpoint
The Behavioral Inattention Test (BIT), a neuropsycho-
logical battery for visual and cognitive assessment of
LHN in standard paper and pencil form, represents the
primary outcome. The BIT consists of two subscales
(cognitive and behavioral) with standardized scores,
where lower ratings indicate a more severe visual-spatial
impairment.
Clinical secondary endpoints
In this context, subtests from the TAP battery (Test of
Attentional Performance) will be administered to test
the attention levels of LHN patients. In particular, we
will administer the following subtest from the TAP:
Alertness and Visual Field/Neglect. The Catherine
Bergegò Scale (CBS) assesses specifically the presence
and severity of LHN in the activities of daily living (i.e.,
eating or reading biases). Motricity Index (MI) and
Trunk Control Test (TCT) will be used to measure
motor impairments, whereas the motor scale of the
FIM™will assess dependence in ADL and mobility. In
this way, it will be possible to evaluate different clinical
aspects related to LHS and control other improvements
induced by the rehabilitation protocol.
Neurophysiological secondary endpoints
Finally, in the present study, lateralized visual proces-
sing’s neurophysiological correlates are collected to in-
vestigate the common interhemispheric imbalance in
LHN [1,10,28]. In this study, the EEG will be recorded
while patients perform a visual detection task (Fig. 2)
seated at a distance of 50 cm from the computer’s
screen. Patients will be prompted to fix a central fixation
cross on a screen while visual stimuli are presented.
Stimuli will be small yellow squares (1 cm × 1 cm) shown
in a black background to detect color contrast between
the stimuli and the background easily. Each trial will
start with a white central fixation cross over a black
background. Then, after a varying stimulus onset asyn-
chrony between 640 and 960 ms (steps of 80 ms), a
stimulus will be presented randomly on the right or the
left of the fixation cross on a view distance angle 28°
along the midline. Stimuli will be displayed for 96 ms;
before the subsequent trial, a black background with the
fixation cross will be presented for 1000 ms (Fig. 2). In
general, the visual detection task consists of a passive
visual task with lateralized stimuli, and participants will
be prompted to keep the fixation during all tasks [7,8].
Whenever participants lose the fixation, feedback will be
provided to recover it. Overall, 256 stimuli will be pre-
sented in 4 blocks of 64 stimuli, where the overall task
will have an average duration of 20 min. The EEG will
be recorded from 18 Ag/AgCl-cup electrodes according
to the 10/20 system referenced to the linked ear lobes.
The EEG signal will be recorded from electrodes: Fz, Cz,
Pz, C4, C3, P4, P3, F4, F3, Oz, O1, O2. Impedance for
EEG and electrooculogram (EOG) electrodes will be
kept below 10 kΩ. Off-line, the amplitude in microvolt
(μv), and the latency in milliseconds (ms) of the negative
peak of the N100 VEP component will be analyzed sep-
arately for left and right-presented stimuli in corres-
pondence of posterior electrodes [8]. Then, indexes of
interhemispheric imbalance will be extracted. In particu-
lar, here we propose the Visuospatial Attention Bias
Index (vABI), which is based on N100 peak amplitude
and interhemispheric transmission time (IHTT) [29,30],
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which is a further index of hemispheric imbalance, based
on N100 peak latency.
Note. The vABI will be calculated as a lateralization
index [31] for the N100 amplitude. The vABI will be ex-
tracted in two steps. First, N100 for left and right pre-
sented stimuli will be calculated in the averaged activity
from posterior electrodes (i.e., mean of P3 and P4) to
have a signal of the two hemispheric activations after
lateralized stimulus presentation. Then, for each partici-
pant, the difference in the activations for lateralized
stimuli will be calculated as the difference between the
resulted N100 peaks for left and right-presented stimuli
(i.e., vABI = N100 amplitude for right stimuli −N100
amplitude for left stimuli). Such an index can measure
interhemispheric imbalance as it reflects the difference
in the activation of the two hemispheres in response to
lateralized stimuli. Similarly, based on N100 peak la-
tency, we will compute the IHTT [29,30], an indicator
of the EEG signal’s transmission times from one hemi-
sphere to the other. In particular, we will calculate the
IHTT as the difference between the latencies of the
negative peak of N100 for left presented stimuli on the
posterior electrodes P3 and P4 (i.e., IHTT = N100 la-
tency on P4 - N100 latency on P3), thus constituting a
single index in milliseconds of the interhemispheric
transmission times specifically for left presented stimuli.
Sample size
The sample size calculation was based on the results and
the population variance from previous studies, which
employed the BIT as a primary outcome measure [16,17,
28,32]. In particular, we calculated the sample size on the
BIT (primary endpoint) using the following formula:
N¼2z1−αðÞ
þz1−βðÞ
2σ2
δ2
where Nis the final sample size; σ
2
: population variance
established on previous studies [17] = 3.1; δ
2
: absolute
error allowed for parameter estimation = 2.84; z: con-
stant (corresponding to the value of the standardized
normal random variable) that depends on the level of
confidence desired for the estimation, fixing α= 0.05 and
1−β= 0.80, (Z
1−α
+Z
1−β
)
2
= 10.5. The sample size
resulting from the formula is 25.2. Consequently, the
minimum sufficient simple to reach our primary outcome
was established as 56 subjects (28 per group), to be en-
rolled over 2 years, assuming a 10% loss at follow-up.
Safety assessment
The stimulation protocol (i.e., the intervention) was de-
vised accordingly to the guidelines for stimulation by
Müri et al. 2013 [33]:
1. The application should be easy to implement
without neuroimaging and neuronavigation systems
for the localization of the target area. Many studies,
as an alternative to neuronavigation, adopt the
international 10/20 localization system.
2. The total application time of the daily rehabilitation
paradigm should not exceed ten sessions for
2 weeks. Indeed, protocols that provide everyday
applications for more than 2 weeks are difficult to
implement in rehabilitation centers and may not be
tolerated by patients.
Indeed, when the r-TMS is administered according
to the published international guidelines for brain
stimulation protocols [33], it is a safe technique. The
stimulation paradigm [17,20] we will use in this
study follows these guidelines. However, we will ad-
dress any possible adverse events reported in the lit-
erature, as follows:
Fig. 2 Visual detection task. Each trial starts with a central fixation cross for a jittered time between 640 and 960 milliseconds (ms), then a
stimulus is presented randomly either on the left or on the right of the fixation cross for 96 ms. After stimulus presentation, a fixation cross
remains for 1000 ms, and then a new trial starts
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1. Mild headache after the session, usually not
requiring any treatment (rather frequent). However,
if requested by the patient, analgesics will be
administered.
2. Some local annoyance in the stimulated area
(frequent): this effect rarely requires the suspension
of r-TMS, but should the discomfort reported to be
excessive, the session will be interrupted.
3. Temporary loss of hearing (rare) for the duration of
the stimulation session. In such a case, the session
will be interrupted.
4. Epileptic crises (actually rather rare) may occur in
predisposed individuals. To minimize this risk,
subjects who have suffered from seizures during the
acute phase or have a diagnosis of epilepsy will be
excluded from the trial (exclusion criterion).
Moreover, it is planned to have the EEG track
recorded during the neurophysiologic pre-test as-
sessment to exclude epileptiform anomalies. If epi-
leptiform abnormalities are present, the participant
will be excluded from the trial. Finally, should a
convulsive episode occurs during the 15 days of
treatment with r-TMS despite the above precau-
tions, the latter will be immediately suspended, and
the patient will be treated according to the standard
hospital protocols for epileptic seizures.
The PI will report any adverse event in an ad hoc CRF.
Should the treatment (either intervention or sham con-
trol) be suspended, the reason for the suspension will be
reported in the CRF. Data on adverse events will be ana-
lyzed appropriately and included in the study’s final
report.
Assignment of interventions
Allocation
The PI will generate a blocked randomization list (2,2
per group) using the online software QuickCalcs (www.
graphpad.com). Only the PI will have access to the
randomization list after its generation.
Blinding
To ensure a double-blind assessment, pre-treatment as-
sessments (T0) will be performed before randomization,
whereas post-test (T1) and follow-up (T2) assessments
will be carried out by an assessor who will not be aware
of the randomization group. The visual scanning proto-
col will be administered by therapists unaware of the pa-
tient’s allocation to intervention or control arms.
Patients themselves will be instructed not to reveal any
information to the assessors on the brain stimulation
treatment received.
To minimize biases deriving from inter-rater measure-
ment errors, the following interventions will be per-
formed before the start of the trial:
1. Collegial assessments of patients who are not
candidates for enrolment by the various assessors
involved in the trial to standardize the
administration modalities and resolve any
discrepancies between scoring procedures.
2. The subsequent development of an “assessment
manual”containing all information for
administering and scoring procedures.
Data collection and management
All data will be anonymized, and a specific alpha-
numeric code will be attributed to each subject after en-
rolment. All the assessors will be responsible for trans-
fers the data they have collected on paper CRF into the
corresponding electronic CRF in the study database
shortly after their collection. The study database is
configured so that only the PI will be aware of all patient
details, including the randomization group, and this in-
formation will not be visible to any of the assessors.
Statistical analyses over the complete dataset will be per-
formed at the end of data collection. However, interim
analyses approved by the local ethical committee may be
performed.
Statistical analysis
Changes in all endpoints will be assessed across groups
(r-TMS plus VS and SHAM plus VS) and across time (at
post-test and 12 weeks follow-up assessment). BIT, TAP,
CBS, and the motor function tests (MI, TCT, and
FIM
tm
) provide standard scores, separated for each test,
and scores including a general performance with cutoffs
that allow discriminating pathological performance.
vABI and IHTT are continuous variables based on
neurophysiological data. Differences in primary and sec-
ondary outcomes for each indicator will be analyzed be-
tween the pre-test baseline (T0), post-test(T1), and
follow-up (T2) phases for both groups of patients (group
r -TMS plus VS and SHAM plus VS group).
The pretest-posttest follow-up control group design is
often analyzed with the posttest and follow-up as
dependent variables and the pretest as covariate
(ANCOVA) [34,35] or with the difference between
posttest and pretest as dependent variable (CHANGE)
[36,37]. The choice of one of these two methods should
consider two assumptions: homogeneity vs. heterogen-
eity of the study population (i.e., group differences at
pretest) and normal data distribution.
In general, ANCOVA is preferable in randomized con-
trolled trials as treatment assignment is based on
randomization [34–36], and this may prevent data
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heterogeneity. However, in heterogeneous data, a meas-
ure of gain is preferable (i.e., CHANGE). Both methods
have more power if data are normally distributed [36].
In our study, we will verify first the two assumptions
mentioned above for each outcome measure and, after-
ward, we will adopt the appropriate approach:
1. Homogeneity vs. heterogeneity: For each outcome
measure, the ANCOVA assumption of homogeneity
of regression slopes will be verified [38]. In case the
assumption is violated, a CHANGE measure (i.e., a
score of gain in the specific outcome) will be
considered in a 2 × 2 mixed-model ANOVA with
the between factor group and the within factor time
(posttest and follow-up).
2. Normal distribution: Our primary outcome (the
Behavioral Inattention Test) data will be analyzed
after linear logistic transformation accordingly to
the Rasch calibration, which ensures normal data
distribution [39]. For the secondary outcomes, in
the case normal distribution is not verified, a linear
logistic transformation will be performed.
3. In the case assumptions are verified, a mixed-model
ANCOVA will be used with a 2 × 3 design, where
the “between”factor will be the randomization
group and the “within”factor will be the time of as-
sessment, with the covariate pre-test baseline (T0)
used to control for the LHN level before the begin-
ning of the rehabilitation protocols.
In all cases, a two-tailed ttest for independent samples
will be employed to investigate the differences between
groups. Data analysis will be performed using the
MatLab (The Mathworks Inc.) and SPSS (version 13)
softwares. We will accept a significance level of 5% (i.e.,
pvalue = .05) corrected for multiple comparisons when
needed. Data from all randomized patients will be in-
cluded in the analyses. Should data be missing at follow-
up, data will be analyzed according to the intention to
treat principle. However, participants will be contacted
by telephone in the proximity of follow-up to ensure
participant retention.
Oversight and monitoring
A dedicated member of the investigator team other than
the PI will assess the completeness of data collection
and be involved in monitoring all the clinical trial’s
organizational, ethical, and scientific aspects. The PI will
declare the end of the enrolment.
Dissemination plans
All data will be treated so that the participants’identities
will be kept anonymous. Before publication, the trial re-
sults will be discussed within the research group, and
authorship eligibility will be agreed upon with all con-
tributors before publication. Professional writers will not
be involved in the dissemination process. The trial data,
suitably anonymized, will be made available upon re-
quest at the end of the trial.
Ethical considerations
Treatments for LHN will be allowed after the post-test,
should severe LHN-related symptoms persist. Further-
more, during the trial, the standard care treatments will
be guaranteed within the inpatient rehabilitation setting
for all patients in the r-TMS intervention and SHAM
control groups.
Roles and responsibilities
Patients are being enrolled within two centers: the
Neuro-rehabilitation Unit of IRCCS Istituto delle
Scienze Neurologiche di Bologna (which is the coordin-
ating center) and the Intensive Rehabilitation Unit of
“Villa Bellombra Hospital”in Bologna. Both centers re-
ceived the required ethical approvals and authorizations
from the local ethics committee (CE/AVEC num.
0078006 and CE/AVEC num. 148456).
Discussion
Within the SMART-ATLAS study, we propose a new
combined protocol for the rehabilitation of LHN in right
hemispheric stroke patients. In particular, it combines
two potentially effective treatments for the rehabilitation
of cognitive and behavioral symptoms of left hemispatial
neglect to investigate the advantages of a combined
protocol compared to a single intervention. We will also
combine brain stimulation (inhibitory r-TMS on the left
intact parietal cortex) with a cognitive treatment (visual
scanning), which will follow the stimulation.
Many published studies have highlighted the efficacy
of the brain stimulation and cognitive treatments admin-
istered alone for the rehabilitation of LHN syndrome
after stroke [23]. However, the level of scientific evi-
dence for the efficacy of combined approaches (i.e., brain
stimulation and cognitive treatments) is still low because
of factors such as small sample size, methodological bias
(lack of double-blind studies or follow-up assessments),
and contradictory results. To control for these biases, we
will apply a double-blind, SHAM-controlled design
within the context of an RCT, in which assessors and
patients are blinded to the type of stimulation used, re-
ducing any source of potential bias. Moreover, our out-
comes consider several construct domains related to
LHN. Indeed, we consider cognitive and behavioral as-
pects of LHN, together with disabilities in the motor do-
main and the activity of daily living. Importantly, we
introduce indexes based on neurophysiological data to
monitor changes induced by the treatment at a
Di Gregorio et al. Trials (2021) 22:24 Page 8 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
neurophysiological level. Thus, our design can provide a
valuable comparison between the combined approach
and the cognitive treatment alone, thus evidencing spe-
cific brain stimulation effects and contributing to identi-
fying the most beneficial rehabilitation approach for
LHN patients.
This study’s central hypothesis is that clinical symp-
toms of LHN are correlated to an imbalance in inter-
hemispheric activity due to hyperactivity of the left
hemisphere [1,10–12]. Inhibitory r-TMS on the intact
left parietal cortex reduces the left hemisphere activation
and can rebalance interhemispheric activity. Therefore,
this RCT will provide evidence of the clinical efficacy of
the rebalancing effect of the r-TMS on a larger sample
of stroke patients. In particular, we expect to observe
better performances on clinical tests and batteries, indi-
cating more substantial improvements in cognitive and
behavioral symptoms of LHN in the r-TMS group com-
pared to the control SHAM group. Furthermore, we ex-
pect that these more significant clinical improvements in
the r-TMS group can also be reported in specific scales
assessing motor independence in the activities of daily
living. Finally, inhibitory r-TMS on the intact left par-
ietal cortex could point out the particular effect of r-
TMS protocols on neurophysiological correlates of LHN.
More in detail, we expect to observe in the r-TMS group
a more significant rebalancing effect than in the control
group, as demonstrated by smaller amplitudes of vABI
and earlier latencies of IHTTs at the post-test assess-
ment. Finally, we expect to observe the persistence of
this effect at follow-up.
Although both the visual scanning training and the r-
TMS protocols alone have been demonstrated to be ef-
fective in the rehabilitation of clinical symptoms related
to LHN, combinations of different therapies may boost
the therapeutic effect. The rationale behind this hypoth-
esis is that following a right hemisphere stroke, the neur-
onal loss may impair cognitive functions due to a
functional deactivation of the related neuro-functional
networks. Thus, the reactivation of those networks can
support the rehabilitation of the compromised functions
[40,41]. Indeed r-TMS can lead to neuronal activity
changes that outlast the stimulation itself and enable
empowerment of a specific network or neuronal circuit
[40]. This after-effect of the r-TMS can support cogni-
tive task execution, thus facilitating experiential learning
during cognitive training [40,41]. In our study, inhibi-
tory r-TMS is applied over the intact left parietal cortex;
thus, the r-TMS modulation concerns the preserved
areas and the interhemispheric connectivity [42–44]. As
a consequence, r-TMS could increase the “responsive-
ness”of the peri-lesional areas and the interhemispheric
connectivity [43] during a cognitive training protocol
(i.e., the visual scanning), increasing its effectiveness
compared to the SHAM condition, where only a placebo
stimulation is applied before the training.
Conclusions
The SMART-ATLAS protocol implements a novel
therapeutic approach for the rehabilitation of attentive
spatial deficits in stroke patients by combining brain
stimulation with cognitive treatments. The proposed ap-
proach is easily applicable and relatively low-cost.
Although a TMS stimulator is necessary for trial im-
plementation, the visual scanning protocol is very flex-
ible in terms of materials and tasks, and mainly paper
and pencil material is required. Moreover, visual scan-
ning can be implemented at the bedside, and also pa-
tients with severe motor impairments can easily carry
out the tasks.
Although this is a multicenter trial, only two centers
are involved. Thus, the generalizability of results may be
limited. Further studies and replications of our protocol
can improve results generalization. Should protocol effi-
cacy be demonstrated, it could be implemented in ordin-
ary clinical practice, thus providing an additional
therapeutic option to reduce the burden of LHN and im-
prove the clinical outcome of patients with right hemi-
spheric stroke.
Trial status
The protocol here presented is the same registered on
ClinicalTrials.gov (NCT04080999; title: “Repetitive
Transcranial Magnetic Stimulation in Spatial Attention
After Stroke”) on September 2019. Patient recruitment
began on March 2019, and the estimated study comple-
tion date is March 2021. Fourteen patients have been
screened, and ten patients were included in the study
and randomized. Five of those patients have already
completed the 12 weeks follow-up.
Abbreviations
BIT: Behavioral Inattention Test; CBS: Catherine Bergegò Scale;
CCT: Conventional cognitive treatment; CT: Computerized tomography scan;
EEG: Electroencephalography; EOG: Electrooculogram; ERP: Event-related
potentials; FIM™: Functional Independence Measure; IHTT: Interhemispheric
transmission time; LHN: Left hemispatial neglect; MI: Motricity Index;
MRI: Magnetic resonance imaging; PI: Principal investigator; r-TMS: Repetitive
transcranial magnetic stimulation; TAP: Test of Attentional Performance;
TCT: Trunk Control Test; vABI: Visuospatial Attention Bias Index; VEP: Visual
evoked potentials; VS: Visual scanning
Acknowledgements
The authors are grateful to all the Neurorehabilitation Unit staff of the
Maggiore Hospital and Villa Bellombra Hospital for logistic and work support.
We thank dr. Mauro Mancuso, MD, for his helpful comments on an earlier
version of the protocol.
Authors’contributions
EC is the principal investigator of the study and is responsible for the TMS
stimulation. FDG, EC, FLP, and RP provided the idea and designed the
protocol. FDG coordinates organizational, ethical, and scientific aspects of
the clinical trial. VP is responsible for neurophysiological assessments. FDG,
EC, and FLP are designated members of the data management team. FDG,
Di Gregorio et al. Trials (2021) 22:24 Page 9 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
FLP, and RP wrote the manuscript. All authors have read and approved the
final version of the paper.
Funding
There is no external financial funding.
Availability of data and materials
Not applicable. No data is available at this point because the study is in
process. The data will only be accessed at the end of the trial by the
research team’s designated members.
Ethics approval and consent to participate
The protocol has been approved by the local Ethics Committee (Bologna)
CE/AVEC num. 0078006. The PI or delegate will obtain written informed
consent from all patients before enrolment. All amendments are submitted
to the Ethics Committee for approval and communicated to all sites.
Consent for publication
All data are treated, keeping anonymous participants’identities.
Competing interests
Authors declare no competing interests.
Author details
1
Azienda Unità Sanitaria Locale, UOC di Medicina Riabilitativa e
Neuroriabilitazione, Bologna, Italy.
2
IRCCS Istituto delle Scienze Neurologiche
di Bologna, UO di Medicina Riabilitativa e Neuroriabilitazione, Casa dei
Risvegli Luca de Nigris, Via Giulio Gaist, 6, 40139 Bologna, Italy.
3
Villa
Bellombra rehabilitation Hospital, Bologna, Italy.
Received: 18 June 2020 Accepted: 1 December 2020
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