Neuromodulation Treatment for Anorexia Nervosa: A Brief Review
Gloria Villalba1,3*, Azucena Justicia2,3 and Victor Pérez-Sola2,3
1Department of Neurosurgery, Hospital del Mar, Spain
2Institute of neuropsychiatry and addictions, Hospital del Mar, Spain
3Universitat autonoma de Barcelona, Spain
Submission: October 14, 2019;Published: November 19, 2019
*Corresponding author: Gloria Villalba Martínez, Department of Neurosurgery Passeig Marítim 25-29, Hospital del Mar, 08339, Barcelona, Spain
How to cite this article: Gloria Villalba, Azucena Justicia, Victor Pérez-Sola. Neuromodulation Treatment for Anorexia Nervosa: A Brief Review. Open
Access J Neurol Neurosurg. 2019; 12(2): 555831.
To date, three different neuromodulation techniques have been used to treat a total of 154 patients with anorexia nervosa. In the present review, we describe these techniques and the treatment outcomes reported in the relevant literature. Although the reported results are good overall, the results must be interpreted cautiously due to the heterogeneity of this disorder and the limitations (methodology, sample sizes) of those studies.
Keywords: Anorexia Nervosa Neuromodulation Deep Brain stimulation Transcranial Magnetic Stimulation Transcranial Current Direct Stimulation
Abbrevations: AN: Anorexia Nervosa; BMI: Body Mass Index; DBS: Deep Brain Stimulation; DLPFC: Dorsolateral Prefrontal Cortex; MD: Major Depression; NAcc: Nucleus Accumbens; OCD: Obsessive Compulsive Disorder; RCP: Randomized Controlled Trial; SGC: Subgenual Cingulate; TDCS: Transcranial Direct Current Stimulation; TMS: Transcranial Magnetic Stimulation
Anorexia Nervosa (AN) is the most important eating disorder, with a prevalence ranging from 0.7%-3%. In addition to the central symptoms of the disorder, a large proportion of these patients also present comorbid psychopathology, including with high rates of comorbid mental disorders. Of all mental disorders, AN is associated with has the highest rates of morbidity and mortality rates of all mental disorders. Approximately 20% of patients are resistant to conventional treatment. Although the precise causes of this disorder are not fully well-understood, it is widely believed to be a multifactorial disorder, including genetic, personality, environmental, and neurobiological factors [1,2]. The neurobiological component likely in particular is believed to plays a major role in the development of AN. Several different hypotheses related to this factor have been proposed to explain the underlying neurobiological pathophysiology of AN. The most widely accepted hypothesis is a dysfunctional cortico-limbic dysfunction system leading to alterations in the regulation of food-related emotions, rewards, and behaviors [2,3]. Based on data from imaging studies indicate that, the
brain regions most closely areas involved in the pathophysiology of this disorder are the insula, the parietal cortex, the anterior and Subgenual Cingulate (SGC), the ventral striatum (Nucleus Accumbens; NAcc), and the left dorsolateral prefrontal cortex (DLPFC) . In recent years, there has been a growing interest in identifying and offering non-pharmacological alternatives to patients with treat mental illnesses that fail to do not respond to conventional treatment. One such approach is neuromodulation, which encompasses several different techniques by in which brain function is stimulated or inhibited by specific techniques, without damaging the brain tissue. These such techniques are classified as invasive if they require surgery or non-invasive if they can be applied externally, without surgery [4,5].
The aim of the present review article is to review the various approaches in neuromodulation that are currently carrying out for AN patients treatment.
To perform the review, we searched the Medline and Scopus databases using the following key words: Anorexia nervosa,neuromodulation. This search identified (18 articles), and
three different types of Neuromodulation techniques have been
applied in patients with AN, including:
a) Deep brain stimulation (DBS),
b) Transcranial magnetic stimulation (TMS), and
c) Transcranial current direct stimulation (tDCS).
Below we describe each technique and the evidence base
to support their clinical use in the treatment of AN. There is
currently no approval for any neuromodulation technique
(neither by the FDA nor by the CE marking) for AN patients.
DBS is an invasive stimulation technique in which two
electrodes (generally 4 contacts/electrode) are inserted
bilaterally in deep areas of the brain using a stereotactic
technique. The electrodes are connected to an internal pulse
generator, which is inserted subcutaneously. This generator
sends electrical impulses to the electrodes. Although the precise
mechanism of action is not well-understood, DBS is believed
to act by inhibiting a malfunctioning brain circuit. Currently,
the only mental illness for which DBS has been approved (FDA
and CE marking) is Obsessive Compulsive Disorder (OCD). Our
literature search identified a total of nine publications (26
patients), as follows: four case reports, two case series, two
clinical trials and one clinical trial protocol publication. Overall,
26 patients with AN have been treated by DBS. In these studies,
three different brain sites have been targeted: the SGC, the NAcc,
and the Bed Nucleus of the Stria Terminalis (BNST) [6-11].
Of the nine studies, three applied to DBS to the SGC. In one
study-a case report by Israel et al.  DBS was administered
to a patient with Major Depression (MD) and comorbid an
with a Body Mass Index (BMI) of 19.65. In that patient, DBS
was applied unilaterally using an intermittent approach (130
Hz, 91 ms, 5 mA mp). At 30 months of follow-up, the patient
successfully maintained BMI . In the year . reported
initial results from a pilot clinical trial involving six patients with
chronic AN and DBS in SGC (follow-up 9 months). Four of the six
patients had good response to DBS. That trial was subsequently
expanded to 16 patients (including the original six), with results
reported in 2017.The larger trial also had a longer follow-up
(one year). The DBS parameters were 130 Hz, 90 ms, 5-6 V.
Numerous different variables were assessed, including BMI,
psychometric measures, Quality of Life (QoL), and imaging data
obtained by fluorodeoxyglucose-positron emission tomography
(FDG-PET). All 16 patients in that trial showed improvement,
including the patients who had not responded at 9 months,
in BMI, psychometric results and QoL. In addition, all of the
patients presented changes in cerebral metabolism at 6 months.
Complications included the following: epileptic seizure (n=1),surgical wound infection (n=1), worsening mood (n=1), air
embolism (n=1), and pain (n=5) [8,9,13].
The first reported case of a patient with AN treated with DBS
to the ventral striatum was published in 2013 by McLaughlin et
al. . The patient (BMI, 18.5), who had OCD and comoborbi
AN, received DBS (120 Hz, 120 ms, 7.5 V) to the ventral striatum,
which resulted in a modest increase in BMI, from 18.5 to 19 . In
that same year, Wang et al,  performed DBS in two adolescents
(BMI ≤ 13). The stimulation parameters were 2.5-3.8 V, 135-
185 Hz, 120-210 ms to the NAcc. At 12 months of follow-up, the
patients had no complications and showed improvement in BMI
values, psychometric measures, and . In another case series,
Wu et al.  performed DBS in four adolescents (BMI < 13) using
the following DBS stimulation parameters: 180 Hz, 90 micro sg.
Follow-up ranged from 9-50 months. All patients gained a mean
of 65% of body weight (BMI,) [17-22] together with significant
improvement in psychometric measures, with no complications
. Recently, Park et al.  published a protocol for a clinical
trial involving six patients with chronic AN and comorbid OCD.
That trial includes a double-blind phase with image evaluation
by magnetoencephalography. The planned follow-up after DBS
is 13 months. Results are pending .
Blomsted et al.  described a patient with MD and
comorbid AN. The DBS parameters were 130 Hz, 120 ms, 4.3 V.
At 12 months of follow up, although there was no improvement
in BMI, they did observe a reduction in food-related anxiety .
In Manuelli et al,  described a patient who underwent DBS
to the BNST (parameters: 130 Hz, 4V, 60 ms). The patient’s mean
BMI increased from 16.3 (baseline) to 18.98 at 6 months post-
TMS is a technique in which a magnetic field is generated
through a coil placed on the skull. The electrical current that
is generated penetrates the skull to depolarize the neurons in
the tissue located immediately below the coil. Depending on the
parameters used, the cortex can either be stimulated (> 1 Hz)
or inhibited (< 1 Hz). A repeated TMS technique (rTMS) with a
low frequency is commonly used. The duration of the immediate
effects on the brain is short. We identified a total of seven studies
(111 patients) describing the use of this technique to treat AN, as
follows: one case report, two case series, one trial protocol, and
three clinical trials. The stimulation target was the same (left
DLPFC) in all seven studies. The first report, published by ,
described the case of a 24-year old patient with AN and comorbid
depression. The treatment protocol consisted of 41 sessions of
TMS at 10 Hz with 2000 pulses. At 3 months of follow-up, the
patient’s BMI increased from 12.4 to 16 . In published the
results of a pilot study involving 10 patients with AN (age range,18-44 years). Treatment consisted of a single session of 10 Hz
(10000 pulses). Although BMI did not increase, a reduction was
observed in levels of feeling full, fat, and anxious .
In that same year, McClelland et al,  reported one-month
results from two patients treated with TMS for AN. The treatment
protocol was 20 sessions of high frequency pulses. Although BMI
did not improve, central symptoms of AN and mood improved
in both patients . Barholdy et al,  published a clinical
trial protocol (TIARA, randomized trial) for a study involving 44
patients with chronic (>3 years of duration) AN. The treatment
protocol called for 20 high frequency sessions. Outcome
measures include BMI, psychopathology, central symptoms of
AN, QoL, and neuroimaging data. Results are pending. In ,
McClelland et al,  reported results from a study involving
5 patients with AN (age range, 23-52 years). The treatment
protocol was 10,000 pulses in 20 sessions (20 min/session). At
12 months of follow-up, the patients had lost weight, but both
affective and central symptoms of the disorder had improved.
In that same year, the same authors  reported results from
a Randomized Controlled Trial (RCT) involving 49 patients who
underwent TMS (treatment protocol: single 20-minute session
at 10 Hz, 100,000 pulses).
However, they observed no significant improvement
in symptoms of depression or anxiety, and only a modest
improvement in central symptoms of the disorder . Jassova
et al,  described the case of a patient who received 10 days
of TMS (10 Hz, 15 steps/day 100 pulses/train); unfortunately,
there was no improvement in any of the disorder-related factors
. Finally, Dalton et al.  conducted an RCT comprising 34
patients diagnosed with chronic (> 3 years duration) AN. The
protocol consisted of 20 sessions of daily TMS over 4 weeks. At
4 months of follow up, BMI and central symptoms were virtually
unchanged; however, there was a moderate improvement in QoL
and a marked improvement in mood.
TDCS is a technique in which two surface electrodes are
placed on the scalp. A weak electrical current is then applied to
the scalp to restore the neuronal excitability of the underlying
cortex. The effect can be excitatory or inhibitory, depending on
whether the anode or cathode is used to deliver the current. The
duration of the immediate effects on the brain are short.
Two studies involving a total of 17 patients have been
reported to date, both targeting the left DLPFC. In Khedr et al,
 reported results from a series of 7 patients with AN (age
range, 16-39 years). The treatment protocol was 2 mA mp,
anodal, 10 sessions of 25 minutes for 10 days. At one month of
follow up, three of the seven patients showed improvement in
central symptoms of AN and mood. Strumila et al,  recently
reported the results of a clinical trial (STAR study) involving
10 patients. In that trial, the treatment protocol was an anode
current to the left DLPFC and a cathode to the right DLPFC. Thetreatment consisted of 20 sessions of 2 mAM twice daily (20 min/
application) for 23 weeks, twice daily, resulting in significant
improvements in central symptoms of AN and mood .
Currently, a wide range of neuromodulation techniques are
under investigation for the treatment of refractory AN. Due to the
non-invasive nature of TMS and tDCS, it is possible to evaluate
a larger number of patients. However, these techniques have
important limitations, mainly that the duration of the effects of
treatment is limited and targets located deep within the brain
cannot be reached. By contrast, although DBS is invasive and
expensive, the results can be maintained over a longer period
of time, and a wide range of brain regions can be targeted for
To date, RCTs have been performed only with TMS, and
those trials did not yield any improvement in BMI, with little
to no effect on symptoms. Given the relative lack of RCTs in
this area, together with the wide heterogeneity of the disorder
(type and severity, associated comorbidities) and important
differences in study design (e.g., chronic versus non-chronic
patients, stimulation targets, outcome measures) and the small
sample size of these studies, it is difficult to draw any definitive
conclusions about the efficacy of neuromodulation as a
treatment for AN. Despite the aforementioned limitations in the
evidence base, the results reported to date are generally positive
and encouraging. However, more data are needed, preferably
from large RCTs.
Lispman N, Lam E, Volpini M, Sutandar K, Twose R (2017) Deep brain stimulation of the subcallosal cingulate for treatment -refractory anorexia nervosa: 1-year follow-up of an open-label trial. Lancet (23): 1-10.
Dalton B, Bartholdy S, McClelland J (2018) Randomized controlled feasibility trial of real versus sham repetitive transcranial magnetic stimulation treatment in adults with severe and enduring anorexia nervosa: the TIARA study. BMJ Open 8: e021531.