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S T U D Y P R O T O C O L Open Access
Clinical outcomes and neural correlates of
20 sessions of repetitive transcranial
magnetic stimulation in severe and
enduring anorexia nervosa (the TIARA
study): study protocol for a randomised
controlled feasibility trial
Savani Bartholdy
1†
, Jessica McClelland
1†
, Maria Kekic
1
, Owen G. O’Daly
2
, Iain C. Campbell
1
, Jessica Werthmann
1
,
Samantha J. Rennalls
2
, Katya Rubia
3
, Anthony S. David
4
, Danielle Glennon
5
, Nikola Kern
5
and Ulrike Schmidt
1,5*
Abstract
Background: Anorexia nervosa (AN) is a serious mental disorder with multiple comorbidities and complications. In
those with a severe and enduring form of the illness (SEED-AN), treatment responsivity is poor and the evidence
base limited. Thus, there is a need for novel treatment strategies. This paper describes the theoretical background
and protocol of a feasibility randomised controlled trial (RCT) of real versus sham (placebo) therapeutic repetitive
transcranial magnetic stimulation (rTMS) in SEED-AN. The aim of this trial is to obtain information that will guide
decision making and protocol development in relation to a future large-scale RCT of rTMS in this group of patients,
and also to assess the preliminary efficacy and neural correlates of rTMS treatment.
Design: Forty-four adults from the community with a DSM-5 diagnosis of AN, an illness duration >3 years and a
previous course of unsuccessful treatment will be randomly allocated to receive 20 sessions of either real or sham
rTMS, in a parallel group design. As this is a feasibility study, no primary outcome has been defined and a broad
range of outcome variables will be examined. These include weight/body mass index (BMI), eating disorder
psychopathology, other psychopathology (for example, depression, anxiety), quality of life, neuropsychological
processes (such as self-regulation, attentional bias and food choice behaviour), neuroimaging measures (that is,
changes in brain structure or function), tolerability and acceptability of rTMS, and additional service utilisation.
The feasibility of conducting a large-scale RCT of rTMS and the appropriateness of rTMS as a treatment for SEED-AN
will be evaluated through: assessment of recruitment and retention rates, acceptability of random allocation,
blinding success (allocation concealment), completion of treatment sessions and research assessments (baseline,
post-treatment and follow-up assessments). The acceptability and tolerability of the treatment will be assessed via
semi-structured interviews.
(Continued on next page)
* Correspondence: ulrike.schmidt@kcl.ac.uk
Savani Bartholdy and Jessica McClelland are joint first authors.
†
Equal contributors
1
Section of Eating Disorders, Department of Psychological Medicine, Institute
of Psychiatry, Psychology and Neuroscience, King’s College London, London,
UK
5
South London and Maudsley NHS Foundation Trust, London, UK
Full list of author information is available at the end of the article
© 2015 Bartholdy et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Bartholdy et al. Trials (2015) 16:548
DOI 10.1186/s13063-015-1069-3
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
(Continued from previous page)
Discussion: The effect sizes generated and other findings from this trial will inform a future large-scale RCT with
respect to decisions on primary outcome measures and other aspects of protocol development. Additionally, results
from this study will provide a preliminary indication of the efficacy of rTMS treatment for AN, the neural correlates
of the illness, and potential biomarkers of clinical response.
Trial registration: ISRCTN14329415. Date of registration: 23 July 2015.
Keywords: Anorexia nervosa, Treatment, Trial, Transcranial magnetic stimulation, Neuromodulation, Neuroimaging
Background
Anorexia nervosa (AN) is a disabling, deadly disorder
with a high disease burden [1–4]. Onset is usually peri-
pubertal and AN mainly affects females. The lifetime
prevalence of AN in women is 2–4 % [5], the median
duration is 5–7 years and 30 % have an illness duration
greater than 15 years [6]. AN is associated with func-
tional and structural brain changes and some studies
find that these correlate with chronicity [7–9]. Conver-
ging evidence suggests that after 3–5 years at low
weight, treatment responsivity of AN lessens and out-
comes become poorer, possibly due to neurotoxic effects
of starvation and stress hormones (cortisol) on the brain
[10, 11]. Thus, the first years after onset seem critical for
successful intervention [12]. For example, 60–70 % of
adolescents with AN who typically have a short illness
duration (that is, <3 years) make a full recovery with
family-based psychological treatments [13, 14], whereas
only about 10–30 % adults, who usually have a more en-
during form of AN, achieve full remission after a course
of the best available psychotherapy [15–18]. Pharmaco-
logical treatments (antidepressants, antipsychotics) are
largely ineffective and have low acceptability [19–22].
Cases of AN where there is a sustained (>3 years)
period of being significantly underweight (body mass
index (BMI) < 18.5 kg/m
2
), can be defined as a severe
and enduring eating disorder
1
(SEED) [23–25]. For this
group, treatment options are limited, especially as these
patients will often have had several previous unsuccess-
ful interventions [25]. A systematic review of treatments
for severe and enduring anorexia nervosa (SEED-AN
[25]) identified only one randomised controlled trial
(RCT) (N= 63) comparing two psychological therapies,
and reported limited improvements in both groups [23].
One further trial [26] evaluated dronabinol (a cannabin-
oid agonist) against placebo in patients with SEED-AN
(n= 25) and found a small but significant weight gain.
However, only 18% of those approached agreed to par-
ticipate. Finally, deep brain stimulation (DBS) has shown
promise in highly selected SEED-AN patients [27]. As
DBS is an invasive procedure, it may not be an appropri-
ate and/or desirable treatment option for the majority of
patients with SEED-AN. Thus, there is a strong need for
new, non-invasive treatment strategies for this group
[28]. Treatment advances are most likely to arise from
neuroscience-based interventions that probe and target
disease mechanisms [28, 29].
Functional neuroimaging studies of AN using symptom
provocation paradigms have proposed aberrant functioning
of ‘top-down’(evaluative) prefrontal regions (involved in
executive control) and/or subcortical regions promoting
‘bottom-up’(stimulus-driven) responses, including anxiety-
related mesolimbic circuits, reward-related regions (for ex-
ample, the striatum) and parietal somatosensory regions
[30, 31]. Such findings have been incorporated into disease
models that suggest that in AN, altered neural circuitry un-
derlies phenotypic difficulties in the regulation of appetite,
emotion and self-control [32–34] and the fact that AN
symptoms (such as food restriction and excessive exercise)
become rewarding, compulsive and/or habitual with in-
creasing illness duration [35, 36]. This may explain the
persistent nature of the illness [37]. Underpinning the hy-
pothesis that altered self-regulation plays a key role in the
development and/or maintenance of AN, a number of be-
havioural and neuroimaging studies have reported that in-
dividuals with AN show differences from other eating
disorders (EDs) and healthy individuals on tasks of motiv-
ational self-control (see, for example, [38]) and response
inhibition (see, for example, [39]). Neuroimaging research
using such tasks has implicated the dorsolateral prefrontal
cortex (DLPFC) in these cognitive processes [40–42]. Such
neural models of AN and the role of the DLPFC in self-
regulation provide a strong rationale for targeting the
DLPFC in treatment.
Neuromodulation techniques, such as repetitive trans-
cranial magnetic stimulation (rTMS), that directly alter
brain activity provide a promising avenue for delivering
precise brain-directed treatments for mental disorders,
such as EDs [27, 28, 43–46]. rTMS is a non-invasive pro-
cedure that can be used to stimulate (high frequency) or
inhibit (low frequency) cortical activity, and the DLPFC is
a widely used target. It has shown promising therapeutic
effects in several psychiatric disorders [47–51], leading to
its approval by the Food and Drug Administration (FDA)
as a second line treatment for depression in the USA. It
appears to increase neuroplasticity, that is, the ability of
the brain to form new nerve connections, and hence
rTMS is proposed to be of particular value in chronic or
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treatment-resistant neuro-circuit-based disorders [52],
such as SEED-AN.
Evidence is accumulating to support rTMS as safe,
well-tolerated, and of some benefit in the treatment of
EDs. Two recent reviews have summarised the effects of
neuromodulatory interventions, including rTMS, on ED
symptoms, body weight and food intake in human and
animal studies, and highlight the potential for treating
EDs [45, 46]. Proof-of-concept studies in EDs have
shown that in the short term, high-frequency rTMS ap-
plied to the left DLPFC reduces key symptoms [46, 53–
55]. A single-session sham-controlled RCT of rTMS in-
dicated that cue-elicited food craving can be reduced in
healthy women who have high levels of food craving [56].
In bulimia nervosa, a single session of rTMS has been re-
ported to reduce food craving, binge eating and salivary
cortisol levels, suggesting the effects of rTMS on food
craving involve the hypothalamic-pituitary-adrenal (HPA)
axis [53]. Evidence also suggests key symptoms of AN (for
example, urge to restrict food intake, feeling full/fat) are
reduced after a single session of rTMS to the left DLPFC
[57], McClelland J, Kekic M, Bozhilova N, Nestler S, Dew
T, Van Den Eynde F, David A, Rubia K, Campbell IC,
Schmidt U, unpublished observations, which appears to
occur alongside an improvement in motivational self-
control (that is, temporal foresight) [McClelland et al., un-
published observations]. A recent case series of thera-
peutic rTMS (20 sessions) found sustained improvements
(for at least 6 months) in ED symptomatology and/or
affective symptoms in five patients with SEED-AN who
had had multiple unsuccessful previous treatments [58].
Finally, studies in healthy participants have shown that
rTMS to the DLPFC can improve performance on self-
regulation tasks, and thus it may have promise in target-
ing the self-regulation difficulties in EDs [59]. Given
the success of rTMS to the DLPFC in treating other
neurocircuit-based disorders (such as treatment-
resistant depression) and the encouraging preliminary
dataonitseffectsonsymptomsofAN[46,58],
McClelland et al., unpublished observations, there is a
strong rationale for further exploring the therapeutic
potential of rTMS in SEED-AN.
In summary, the evidence base for treatment of SEED-
AN is limited [23, 25], and use of rTMS appears promis-
ing. To date, no sham-controlled RCT of therapeutic
rTMS in AN has been conducted. The proposed feasibility
study is an RCT comparing real (active) to sham (placebo)
high-frequency rTMS to the left DLPFC as an adjunct to
treatment as usual (TAU) in individuals with SEED-AN.
Participants will be randomly allocated to receive 20 ses-
sions of either real or sham rTMS. Participants’ED symp-
toms and other clinical outcomes will be measured before,
during, immediately after and 3 months after treatment.
Additionally, the effects of rTMS on neuropsychological
processes such as self-regulation, attentional bias and food
choice behaviour will be explored. Neuroimaging mea-
sures will be used pre- and post-treatment to explore
neural mechanisms underlying treatment effects. Lastly,
participants will be interviewed about their experiences of
this treatment.
Aims
The specific objectives of the proposed feasibility study
are to:
(1)establish the feasibility of conducting a large-scale
RCT of rTMS in patients with SEED-AN by assessing
recruitment, attendance and retention rates;
(2)determine the best instruments for measuring
outcomes in a full trial by examining the quality,
completeness and variability in the data;
(3)estimate the treatment effect sizes and standard
deviations for outcome measures to inform the
sample size calculation for a large-scale RCT;
(4)evaluate whether the treatment is operating as
designed by analysing process measures, for
example, within-session visual analogue scales (VAS)
of key ED symptoms;
(5)explore patients’views on the acceptability,
credibility, tolerability and experience of rTMS;
(6)obtain information about patients’willingness to
undergo random allocation to 20 sessions of real or
sham rTMS;
(7)investigate neurocognitive changes underlying
treatment response; and
(8)investigate neural mechanisms underlying treatment
response, including changes in structure, cerebral
blood flow and in regional activity and functional
connectivity at rest and during computer-based tasks
assessing behavioural control.
Tentative underpinning hypotheses are based on pilot
studies previously conducted by our group and others in
patients with EDs [53, 55, 58, McClelland et al., unpub-
lished observations] and other disorders that are fre-
quently comorbid with EDs, including depression [60–
62] and addictions [63]. It is predicted that, compared to
sham rTMS treatment, 20 sessions of high-frequency
rTMS applied to the left DLPFC will:
(1)reduce AN symptomatology, encourage an increase
in weight/BMI and improve related psychopathology
(such as depression, anxiety and stress) and quality
of life;
(2)improve self-regulatory control, emotion regulation,
attentional-bias processes, and food choice behaviour.
Improvements in self-regulatory control abilities will
be associated with changes in task-based neural
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activity and connectivity between the DLPFC and the
inhibitory control network (the right inferior frontal
gyrus, pre-supplementary motor area) and areas
implicated in reward processing (for example, the
ventral striatum [64]);
(3)alter neural activity in the DLPFC at rest (for
example, cerebral blood flow) and during task
performance during functional magnetic resonance
imaging (fMRI), which will be correlated with
symptom improvement; and
(4)be considered by patients as an acceptable and
useful treatment adjunct for AN.
Methods
Design
This is a parallel group, double-blind, two-arm RCT.
Participants with SEED-AN will be randomly allocated
to receive 20 sessions of either real rTMS (treatment
group) or sham rTMS (control group) on consecutive
weekdays. Participants will be recruited from the com-
munity and rTMS will be delivered in addition to TAU.
Outcomes will be measured at baseline, post-treatment
and 3-month follow-up. Selected clinical outcomes
assessing ED symptomatology will additionally be mea-
sured during treatment. Participants in the control
group will be offered the opportunity to receive real
rTMS after the 3-month follow-up. The protocol is out-
lined in Fig. 1, and Additional file 1 gives details of all
assessments and time points.
Setting
The study will be conducted at the Institute of Psych-
iatry, Psychology and Neuroscience (IoPPN) in a desig-
nated rTMS suite.
Ethical approval and trial registration
Ethical approval for the TIARA trial was obtained
from NRES Committee London - City Road & Hampstead
(REC ref: 15/LO/0196). The study is registered on
the International Standard Randomised Controlled
Trial Number (ISRCTN) registry (registration num-
ber: ISRCTN14329415).
Participants and recruitment
Participants will be recruited from the Eating Disorders
Unit in the South London and Maudsley NHS Founda-
tion Trust, through websites (such as IoPPN and Beat
[the UK’s leading EDs charity]), and through participa-
tion in our previous single session RCT (REC ref: 12/
LO/1525) or the Charlotte's Helix/BRC BioResource
project (REC ref: 09/H0606/84).
Inclusion criteria
Male or female participants will be included if they are
right-handed, have a current DSM-5 diagnosis of AN,
are aged 18 or over and meet the following criteria for
SEED-AN: (1) an illness duration of 3 years or more
(this is the minimum illness duration cited in the litera-
ture after which treatment outcomes tend to be poorer
[11, 25]); (2) a BMI between 14 and 18.5 kg/m
2
(the
upper BMI cut-off of 18.5 kg/m
2
was chosen pragmatic-
ally for comparability with other studies, for example,
[23] and the lower BMI limit of 14 kg/m
2
was selected
as a safety precaution); and (3) at least one previous ad-
equate course of ED treatment (for example, one 6-month
course of specialist outpatient psychotherapy, specialist
day care or in-patient treatment for refeeding). All partici-
pants must have agreement from their ED clinician or
their GP to take part.
Exclusion criteria
Exclusion criteria mainly relate to patients’safety. Partici-
pants will be excluded if they: have a BMI below 14 kg/m
2
;
are currently receiving inpatient treatment; are deemed
medically (for example, they have significant electrolyte ab-
normalities) or psychiatrically (for example, they exhibit
acute suicidality) unstable by their clinician; require imme-
diate inpatient treatment (for example, due to very low
weight and rapid weight loss); have a history of epileptic
seizures or head injury; have comorbid major other psychi-
atric disorders needing treatment in their own right; are on
a dose of psychotropic medication that has not been stable
for at least 14 days; or have metallic implants anywhere in
the body.
Sample size
As this is a feasibility study, no a priori sample calcula-
tion has been conducted. This study aims to provide ef-
fect sizes on which future large-scale studies can be
powered. Total sample sizes of N=24–50 have been rec-
ommended for feasibility trials with outcomes measured
on a continuous scale, mainly because estimates of the
standard deviation for normally distributed variables
tend to stabilise around this size [65, 66]. We have
chosen a sample size of N= 40 (that is, at the upper end
recommended for feasibility trials). Assuming the attri-
tion to follow-up rate is a = 0.10 (as found in our previ-
ous AN trials [15, 67], McClelland et al., unpublished
observations and applying an attrition correction factor
of 1/(1-a), we will need a total sample size of N= 44 (22
participants per group).
Randomisation
Generation and implementation of the randomisation
sequence will be conducted independently from the trial
team by the King’s Clinical Trials Unit (CTU). Once the
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Fig. 1 Schematic diagram of the TIARA study protocol
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baseline assessment has been carried out and the patient
is recruited and has consented to the trial, the researcher
will enter patient ID and stratification details into the
web-based CTU system. Patients will then be allocated
to one of the two trial arms using a restricted stratified
randomisation algorithm, stratifying by prognostic fac-
tors (type of AN - binge-purge or restricting; intensity of
TAU - low (outpatient) or high (daypatient)). The strati-
fication will be implemented by minimised randomisa-
tion with a random component. The first n cases (n will
not be disclosed) will be allocated entirely at random to
further enhance allocation concealment.
Intervention
Commonalities between both groups
In both groups participants will receive 20 real or sham
rTMS sessions over 20 consecutive weekdays. Testing/
experimental sessions will last between 40–60 minutes,
including preparation time, 20 minutes of rTMS and
questionnaire administration. Throughout the study,
participants will be able to access or continue TAU as
recommended by their treating team. TAU will range
from GP care only to specialist eating disorder care
(day-care or outpatient only).
Preparation for rTMS sessions
Localisation of the DLPFC Both groups of participants
will undergo a structural magnetic resonance imaging
(MRI) scan to locate the left DLPFC (using Brainsight™
neuronavigation software). The protocol includes a high-
resolution sagittal 3D T1-weighted volume (voxel size
1.1 × 1.1 × 1.2 mm
3
) based on the well-validated ADNI
protocol (http://adni.loni.usc.edu/methods/documents/mri-
protocols/).
Determining the intensity of the rTMS stimulation
Through mapping of the first dorsal interosseous (FDI)
muscle, the intensity of the rTMS will be acquired by
obtaining the individual’s motor threshold (MT), which
represents membrane-related excitability of cortical
axons. To ensure safety and efficacy, the MT will be
assessed weekly for each participant during participants’
20 rTMS treatment sessions. Using the motor evoked
potential method (MEPM), the MT is established by de-
termining the minimum stimulator output intensity re-
quired to obtain five out of ten motor evoked potentials
(MEPs) greater than 50 μV.
TMS sessions
A Magstim Rapid
2
device (Magstim®, UK) and Magstim
D70-mm air-cooled real/sham coil will be used to ad-
minister real and sham rTMS. Before each rTMS deliv-
ery, participants in both groups will watch a short film
showing highly palatable foods, which will function as
cue exposure to disorder-related stimuli.
Delivery of real rTMS Patients in this group will re-
ceive 20 sessions of high-frequency rTMS (10 Hz) at 110
% of their individual MT, consisting of twenty 5-second
trains with 55-second inter-train intervals delivered to
the left DLPFC [Talairach co-ordinates x = −45 y =45
z = 30 [58, 68].
Delivery of sham rTMS Sham stimulation will be given
at the same parameters as the real rTMS; however, a sham
coil will be used. The sham coil makes the same noise as
the real coil but does not produce a magnetic field.
Therapist training and supervision, safety monitoring,
side effects, untoward events and study withdrawal All
study procedures and parameters are in accordance with
the current safety and application guidelines for rTMS
[69]. Treatment will be delivered by personnel trained in
the administration of rTMS. A case record form for each
trial patient will be kept to monitor session attendance
and any side effects or adverse events according to pre-
specified criteria. Any protocol violations will also be re-
corded here. In the event of mild side effects (such as a
slight headache) patients will not be withdrawn, but will
be able to discontinue rTMS treatment if they wish.
rTMS will be immediately halted if the participant expe-
riences a more serious adverse event (such as an epilep-
tic seizure), if their BMI falls below 14 kg/m
2
or if any
other indicators of serious medical risk emerge. Treat-
ment will only be restarted if it is deemed safe to con-
tinue by a medical professional.
To ensure safety, patients’weight, blood pressure
(sitting and standing) and pulse will be monitored
weekly. Routine blood tests including full blood
count, liver and renal function tests will be taken at
the start of treatment and repeated at least once dur-
ing treatment (at approximately session 8) or more
frequently if clinically indicated.
Procedure
A flowchart outlining the study procedures is presented
in Fig. 1. For further information about the time sched-
ule of enrolment, interventions and study assessments,
please see Additional file 1.
Screening
Potential participants will be referred to the study by their
clinician or if they self-refer will have to provide their ED
team’sorGP’s agreement. Study researchers will screen
participants for eligibility. Screening questionnaires in-
clude the Eating Disorder Diagnostic Scale (EDDS), the
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Structured Clinical Interview for DSM Disorders (SCID)
screening module, the TMS Adult Safety Screen, an MRI
safety screen questionnaire developed at King’s College
London and a short inclusion/exclusion screen specific to
this study, including an assessment of medical and psychi-
atric history, and medication dosage and stability. Once
eligibility has been confirmed, the patient’s written in-
formed consent will be obtained. Thereafter, participants
will be offered a session in a mock MRI scanner to famil-
iarise them with the MRI environment. In line with the
CONSORT guidelines [70, 71], we will record the number
and reasons for any participants we must exclude, or any
who decline consent or withdraw from the study.
Baseline assessment
Eligible participants will be weighed and asked to
complete a battery of questionnaires relating to ED
symptomatology and mood, as well as neuropsycho-
logical computer tasks that assess behavioural control,
attentional bias and food choice behaviour. In addition a
one-hour MRI scan will be conducted. The scan will in-
clude structural MRI, fMRI (including the Stop Signal
Task (SST) and temporal discounting (TD) task), resting
state fMRI and arterial spin labelling (ASL).
Once the baseline assessment is complete, participants
will be randomly allocated to the treatment (real rTMS)
or control (sham rTMS) group.
Post-treatment assessment
The post-treatment assessment will take place in the week
following the last rTMS session, and will include the same
elements as the baseline assessment.
Follow-up
Three months after the post-treatment assessment a
follow-up session will be conducted. This session will re-
peat baseline and post-treatment assessments, except
that no MRI scan will be conducted. A qualitative semi-
structured interview will also be undertaken with partici-
pants (minimum of n = 10 from each real/sham group)
to ascertain their views on and experience of this treat-
ment. Finally, blinding success will be evaluated by ask-
ing participants and researchers to guess the treatment
allocation. Participants will be unblinded and individuals
in the sham rTMS group will then be offered the real
rTMS treatment.
Measures
Screening measures
(a)BMI (kg/m
2
)
(b)Screening questionnaires:
(1)Eating Disorder Diagnostic Scale (EDDS) [72]:
This will be used to confirm ED diagnosis. A
revised version of the original EDDS
incorporating the diagnostic changes in the
DSM-5 will be used, although this has not yet
been validated [73].
(2)Screening module of the Structured Clinical
Interview for DSM Disorders –Researcher
Version (SCID) [74]: This short semi-structured
psychiatric interview will be used as a diagnostic
screen to assess the presence of psychiatric
comorbidities.
(3)MRI Safety Screen: This was created at the
Centre for Neuroimaging Sciences at King’s
College London and will be used to ensure the
participant is safe to undergo an MRI scan.
(4)TMS Adult Safety Screen [75]: This will be
conducted to check for contraindications to
rTMS.
(c)Other safety assessments: physical observations:
blood pressure (sitting and standing), pulse, and
routine blood tests.
Within-session measures
In all rTMS sessions, participants will complete several
VASs before and after rTMS. These will assess perceived
levels of stress, anxiety, feeling full, feeling fat, urge to
restrict, urge to exercise, urge to binge, urge to purge
and mood. At the end of each week, ED and mood
symptomatology will be assessed using three short ques-
tionnaires: the Eating Disorder Examination Question-
naire short version (EDE-QS) [76], the Fear of Food
Measure (FoFM) [77] and the 21 item Depression, Anx-
iety and Stress Scales (DASS-21) [78].
Outcome measures
Since this is a feasibility study, a broad range of outcome
measures are included to help determine which are most
sensitive to detecting a treatment effect. This will enable us
to determine primary outcome(s) for a future large-scale
RCT. However, the Eating Disorder Examination Ques-
tionnaire (EDE-Q) and DASS-21 scores are the most likely
candidates (based on our pilot data) [58].
Clinical outcomes
(1)ED-related measures: BMI and ED symptomatology
(measured by the EDE-Q version 6.0 [79], FoFM,
and the Self-Starvation Scale (SS) [80] will be
completed at baseline, post-treatment and at 3-month
follow-up. Within each session, VAS regarding current
ED experiences (urge to restrict, urge to binge, urge
to purge, urge to exercise, feeling full, feeling fat, urge
to eat, feeling low, level of stress, level of anxiety, level
of tension, and current hunger) will be completed
pre- and post-real/sham rTMS. The FoFM and the
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EDE-QS will additionally be completed weekly during
treatment.
(2)Other symptomatology will be measured by
questionnaires including the DASS-21, Positive and
Negative Affect Schedule (PANAS) [81], Profile of
Mood States (POMS) [82] and Intolerance of Uncer-
tainty Scale (IUS) [83] at baseline, post-treatment and
3-month follow-up. The DASS-21 will additionally be
completed weekly during treatment.
(3)Offline neuropsychological tasks assessing: i)
inhibitory control as assessed by a proactive
inhibition task [84] will be completed at baseline,
post-treatment and 3-month follow-up, while ii)
attentional bias to food using the visual probe task
(VPT) [85,86] and iii) food choice behaviour tasks
(FCT) [87] will be conducted at baseline and post-
treatment.
(4)Questionnaires assessing: i) impulsivity/compulsivity
and self-regulation, that is, Delaying Gratification
Inventory (DGI) [88], Barratt Impulsiveness Scale
(BIS-11) [89] and Obsessive-Compulsive Inventory
(OCI-R) [90], and ii) cognitive control of emotions
and self-efficacy, including the Eating Disorder
Recovery Self-Efficacy Questionnaire (EDRSQ) [91],
Emotion Regulation Questionnaire (ERQ) [92] and
the Cognitive Flexibility Scale (CFS) [93] assessed at
baseline, post-treatment and 3-month follow-up, and
iii) quality of life (EuroQol Quality of Life Scale EQ-
5D-5 L [94]) and illness impact (Clinical Impairment
Assessment (CIA)) [95,96] will be assessed at base-
line and 3-month follow-up.
Intervention/service related outcomes
(1)Treatment expectations, tolerability and acceptability
of rTMS will be assessed by VAS and thematic
analysis of semi-structured interviews.
(2)Service utilisation of treatments and services other
than rTMS will be assessed with a self-report version
of the Clinical Service Receipt Inventory (CSRI) [97].
Neuroimaging outcomes Magnetic resonance imaging
(MRI) measures at baseline and post-treatment include:
(1)Structural MRI for neuronavigation of the rTMS
coil and for assessing whole-brain structural changes
after rTMS using T1 weighted images acquired
through a magnetisation-prepared 180 degree radio-
frequency pulse and rapid gradient-echo (MPRAGE)
sequence (voxel size: 1.1 × 1.1 × 1.2 mm, TR:
7.312 ms, TE: 3.016 ms, number of slices: 196, slice
thickness: 1.2 mm, slice gap: 1.2 mm, FOV: 11, flip
angle: 11°, matrix: 256 × 256 mm);
(2)fMRI involving paradigms assessing inhibitory motor
control in a Stop Signal Task (SST) [98] and
motivation control, that is, temporal foresight and
reward-related decision making in a temporal
discounting (TD) task [99,100]), using an echo
planar imaging (EPI) sequence for both tasks (TR:
2,000 ms, TE: 30 ms, number of slices: 40, slice
thickness: 3 mm, slice gap: 3.3 mm, number of
volumes: SSRT = 193, TD = 363, FOV: 240, flip angle:
75°, matrix: 64 × 64 mm);
(3)Resting state fMRI to study neural networks at rest
(TR: 2,500 ms, TE: 28 ms, number of slices: 32, slice
thickness: 3 mm, slice gap: 4 mm, FOV: 240, flip
angle: 80°, matrix: 64 × 64 mm);
(4)ASL to obtain a quantitative measure of cerebral
blood flow at rest (TR: 5,135 ms, TE: 11.088 ms,
number of slices: 56, slice thickness: 3 mm, slice gap:
3 mm, FOV: 240, flip angle: 111°, matrix: 512 × 8 mm).
Blinding
Participants and the researchers conducting assessments
and delivering the rTMS will be blinded to treatment al-
location throughout; that is, the study will be conducted
in a triple-blind fashion. To assess whether allocation
concealment has been successful, participants and the
researcher will be asked to guess the treatment alloca-
tion at the end of the rTMS treatment and to indicate
how certain they are of this guess. Participants (but not
rTMS therapists in order for them to remain blinded
throughout the study) will be debriefed and unblinded
to group allocation upon completion of the 3 month
follow-up. At that point participants in the sham condi-
tion will be offered real rTMS treatment following the
same protocol as described above.
Analyses
Feasibility
The decision as to whether to progress the study to a fu-
ture large-scale RCT will be based on a number of cri-
teria. These include the number of patients we are able
to recruit, the proportion of patients retained in the
study, the proportion of patients completing the real
rTMS/sham intervention, the acceptability of real rTMS/
sham intervention and the effect sizes of treatment out-
comes. At the end of the study, these factors will be used
by the study team to decide the case for progressing to a
substantive RCT.
Clinical outcomes
Analyses will use the intention-to-treat principle. To deter-
mine quality, completeness and variability of the outcome
measures, descriptive statistical analyses and graphical
methods will be used. The size of the treatment ef-
fect on each outcome measure (BMI, questionnaires,
neuropsychological processes) will be the difference
in outcome data between those in the two treatment
Bartholdy et al. Trials (2015) 16:548 Page 8 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
conditions at post-treatment and follow-up. Group
differences will be estimatedusinglinearmixedef-
fects regression models, controlling for the baseline
level of the outcome. The aim of the analysis is to estab-
lish a suitably precise effect size for the primary outcome
in a future large-scale RCT at the post-treatment assess-
ment. Additionally, multiple regression models will permit
exploration of the relationship between changes in the
varying neuroimaging measures and symptom improve-
ment on questionnaire and task-based outcomes.
Service utilisation data
A cost-consequences approach (CCA) [101] will be used
which presents the mean values of each cost category
(treatment, other services use) and outcomes in each
group together with appropriate measures of central ten-
dency. A CCA does not formally analyse cost-
effectiveness. Instead, it provides descriptive information
that can be used to generate economic hypotheses for fu-
ture definitive studies of cost-effectiveness.
Qualitative data
Interviews will be conducted with a minimum of ten par-
ticipants from each of the groups, recruited according to
key characteristics (such as previous treatment history),
until theoretical saturation is reached. Interviews will ex-
plore initial expectations of the intervention, perceived
strengths and weaknesses, and suggestions for improve-
ments. Interviews will be recorded, transcribed and ana-
lysed using thematic analysis [102].
Neuroimaging analysis
Structural MRI Voxel-based morphometry (VBM) ana-
lyses will be conducted to evaluate any morphological
changes resulting from the series of rTMS.
ASL ASL data will be evaluated in a similar manner to
the structural MRI. Following pre-processing, second-
level models (such as ANOVAs) will be used to test for
an effect of treatment.
Resting state MRI Hypothesis-led seed-based connect-
ivity (DLPFC seed) analyses will be conducted before
and after treatment to explore the effect of rTMS on
cortico-cortical and thalamo-cortical connectivity. Note,
scans will not immediately follow rTMS and therefore
will not be affected by acute effects of rTMS.
fMRI Mass univariate analysis will be implemented
within SPM12 under the standard generalised linear
model (GLM). Contrasts of parameter estimates for sep-
arate conditions will provide context-specific maps of
neural activity for each participant/session. These will
include neural activation to delayed compared to imme-
diate choices in the TD task. In the SST, the main con-
trasts of interest will include (a) failed stop versus
successful stop trials; (b) failed stop versus successful go
trials; (c) successful stop versus successful go trials.
Common elements For all modalities, separate images
(connectivity maps, task-related activation, structural pa-
rameters such as grey matter volume) will be taken forward
into a second-level random effects analysis, implemented
within SPM12. This will necessitate a factorial ANOVA
model, with group (real versus sham) and time (pre
versus post), with a significant interaction the primary
contrast of interest, as with the clinical and question-
naire data. Significance will be defined as correction
for multiple comparisons (pFWE < 0.05) at a given
height threshold of Z-score of 2.3.
Discussion
Treatment outcomes for psychotherapies are modest for
adults with AN, and there is currently no gold-standard
treatment [103]. Given the paucity of effective treat-
ments for adult AN, specifically SEED-AN, new treat-
ments are needed. In light of this, and with the growing
understanding of the neural underpinnings of AN, re-
search into novel non-invasive brain-directed thera-
peutic approaches is warranted [28, 45, 46]. This paper
has outlined the protocol for a feasibility trial that will
inform future studies (for example, provide effect sizes
for a large RCT) and add to the evidence for brain-
directed interventions for AN [57, 58, 104], McClelland
et al., unpublished observations. Strengths of the study
include the use of an individualised (neuronavigated)
neuromodulation technique. Moreover, the protocol is
designed to probe disease mechanisms (that is, with the
inclusion of multiple structural and functional neuroim-
aging measures) and will provide important insight into
the neural correlates of the therapeutic effect. Finally,
the protocol adheres to guidance on the optimal conduct
of neuromodulation trials [105–107].
Several potential practical and operational issues may
pose challenges to the timely completion of this study,
particularly with regards to recruitment and attrition. Pa-
tients with AN are often ambivalent about treatment and
this is reflected in poor take-up rates of certain treatments
(for example, medications leading to weight gain) and high
drop-out rates [108]. Whilst rTMS appears promising in
AN, it is unclear what the take-up, attendance, and reten-
tion rates will be if this is offered to SEED-AN patients.
Although participants who took part in our previous
single-session rTMS trials [McClelland et al., unpublished
observations] showed interest in having rTMS therapeut-
ically, adherence and completion of the treatment may
prove challenging, for example, if the participant believes
Bartholdy et al. Trials (2015) 16:548 Page 9 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
they are receiving sham, if the treatment is too uncomfort-
able or if the research is too cumbersome.
Although we are using the most up-to-date equipment
with an improved sham coil that elicits a more realistic
TMS-like sensation, it is not clear whether participants,
especially those who may have previous experience of
rTMS in other research studies, will be able to distin-
guish between the real and sham treatment and what
impact this will have on attrition rates. However, in our
previous RCT of a single rTMS session in people with
AN there was no difference between groups in the abil-
ity to correctly guess stimulation type [McClelland et al.,
unpublished observations].
It will be important to ascertain patients’willingness
to undergo random allocation to real or sham rTMS.
This is not trivial, as rTMS is a relatively demanding
treatment, requiring daily attendance for an extended
period. However, this type of RCT is considered the
gold-standard method of evaluating the clinical efficacy
of rTMS treatment in other disorders, such as depres-
sion [50]. Providing participants who were randomised
to receive sham rTMS with the opportunity to receive
real rTMS after they have completed the study is
thought to be critical in encouraging recruitment and
participant retention. Addressing these challenges will
be particularly useful in informing the development of
future large-scale RCT of rTMS in EDs.
In summary, research into novel treatments for SEED-
AN is essential. rTMS is a promising neuromodulatory
technique that has shown preliminary benefit in AN, in-
cluding individuals with SEED-AN. This innovative
feasibility RCT will be the first to systematically assess
the acceptability, efficacy and neural correlates of this
promising treatment in comparison to an active control
condition. This will provide a foundation for the devel-
opment of future large-scale RCTs and, if the results are
positive, will provide support for the implementation of
this as a treatment adjunct in clinical practice.
Trial status
Participant recruitment and data collection for this study
began in August 2015.
Endnotes
1
Some authors have reserved this term for people with
an illness duration > 7 to 10 years [23, 24].
Additional file
Additional file 1: TIARA study schedule of enrolment,
interventions and assessments. This table presents the time
schedule of enrolment, interventions and assessments, consistent with the
figure provided in the SPIRIT Statement (2013) recommendations for
reporting protocols. (DOCX 20 kb)
Abbreviations
AN: Anorexia Nervosa; ASL: arterial spin labelling; BIS: Barratt Impulsiveness
Scale; BN: Bulimia Nervosa; CFS: Cognitive Flexibility Scale; CIA: Clinical
Impairment Assessment; CSRI: Clinical Service Receipt Inventory; DASS-21: 21
item Depression, Anxiety and Stress Scale; DGI: Delayed Gratification
Inventory; EDs: Eating Disorders; EDDS: Eating Disorder Diagnostic Scale;
EDEQ: Eating Disorder Examination Questionnaire; EDRSQ: Eating Disorder
Recovery Self-Efficacy Questionnaire; EQ-5D-5 L: EuroQol Quality of Life Scale;
ERQ: Emotion Regulation Questionnaire; FCT: Food Choice Task;
fMRI: functional magnetic resonance imaging; FoFM: Fear of Food Measure;
GNG: Go/No-Go Task; IUS: Intolerance of Uncertainty Scale; MRI: magnetic
resonance imaging; OCI: Obsessive-Compulsive Inventory; PANAS: Positive
and Negative Affect Schedule; POMS: Profile of Mood States;
RCT: randomised controlled trial; rTMS: repetitive Transcranial Magnetic
Stimulation; SCID: Structured Clinical Interview for DSM Disorders; SEED-
AN: severe and enduring Anorexia Nervosa; SS: Self-Starvation Scale;
SST: Stop Signal Task; TAU: treatment as usual; TD: temporal discounting;
VAS: visual analogue scale; VPT: Visual Probe Task.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
SB, JM and US drafted the manuscript. OOD, ICC, JW, SJR, KR, ASD, DG and
NK revised the manuscript critically for important intellectual content. Ethical
approval was obtained by SB, JM, MK and US. Funding from NIHR was
obtained by US, JM and ICC. Funding from the NIHR BRC was obtained by
SB, JM, MK, OOD, ICC and US. JM, SB and US registered the trial on the
ISRCTN registry. JM, SB, MK, US, DG and NK are involved in participant
recruitment. SB, JM, MK, JW and SJR are involved in data collection. rTMS
treatment is provided by SB, JM and MK. All authors contributed to the
design and conception of the study, were involved in drafting, critiquing
and approving of the manuscript, and accept responsibility for the accuracy
and integrity of this work.
Acknowledgements
This project is supported by an NIHR Research for Patient Benefit (RfPB) grant
(RB-PG-1013-32049) and Infrastructure Support for Pilot studies from the
National Institute for Health Research (NIHR) Biomedical Research Centre
(BRC) at South London and Maudsley NHS Foundation Trust (SLaM) and
King’s College London (KCL). Savani Bartholdy is supported by a studentship
awarded by the NIHR Mental Health BRC at SLaM. Iain Campbell, Anthony
David and Ulrike Schmidt receive salary support from the BRC. The project
is co-sponsored by KCL and SLaM. The views expressed are those of the
author(s) and not necessarily those of the NHS, the NIHR or the Department
of Health. The authors would like to thank Joanna Steinglass and Karin
Foerde for their permission to include the food choice task.
Author details
1
Section of Eating Disorders, Department of Psychological Medicine, Institute
of Psychiatry, Psychology and Neuroscience, King’s College London, London,
UK.
2
Centre for Neuroimaging Sciences, Department of Neuroimaging,
Institute of Psychiatry, Psychology and Neuroscience, King’s College London,
London, UK.
3
Department of Child and Adolescent Psychiatry, Institute of
Psychiatry, Psychology and Neuroscience, King’s College London, London,
UK.
4
Department of Psychosis Studies, Institute of Psychiatry, Psychology and
Neuroscience, King’s College London, London, UK.
5
South London and
Maudsley NHS Foundation Trust, London, UK.
Received: 13 August 2015 Accepted: 18 November 2015
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