Deep Brain Stimulation in Patients with Chronic Treatment Refractory Anorexia Nervosa: a Pilot Study

The Department of Psychiatry of the AMC has the intention to start a pilot
study with the objection to assess the efficacy and safety of Deep Brain
Stimulation (DBS) in treatment-refractory anorexia nervosa (AN) patients.

Anorexia nervosa is a serious psychiatric disorder constituting a major public
health problem. In about 20% of the cases the disease takes on a chronic course
(Steinhausen 2002). With a crude mortality rate of 5,6% per decade (Sullivan
1995), AN has the highest mortality of all psychiatric disorders (Attia 2010).
Up to date, there is no evidence-based treatment for AN (Agras e.a. 2008;
Morris e.a. 2007; Guarda 2007).

Many parallels with regard to symptomatology between anorexia nervosa and
obsessive compulsive disorder have been drawn. There is a high rate of
comorbidity between eating disorders and anxiety disorders (Kaye e.a. 2006;
Godart e.a. 2003; Speranza e.a. 2001). Numerous observers have documented the
importance of the mesolimbic reward system in the pathophysiology of anorexia
nervosa. The reward system is considered to be involved in several psychiatric
disorders, a.o. obsessive compulsive disorder and addiction.

It is hypothesized that in anorexia nervosa there is a dysregulation of the
reward system, in which 1) hyperactivity of cognitive networks in the dorsal
neurocircuit directs motivated actions when the ability of the ventral striatal
pathways to direct more automatic or intuitive motivated responses is impaired,
or 2) the limbic-striatal information processing in the ventral circuit is too
strongly inhibited by the dorsolateral prefrontal cortex and the parietal
cortex.

Because of the many similarities between obsessive compulsive disorder and
anorexia nervosa, both with regard to symptomatology and with regard to the
brain systems and adaptive responses involved, it is conceivable that
significant relapse and failure rates of current anorexia nervosa treatments
may be at least in part the result of a dysregulated reward system.

Deep Brain Stimulation (DBS) is an innovative and promising approach for the
treatment of patients with therapy-refractory reward-related psychiatric
disorders by modulating the reward-circuitry in the brain (Bewernick e.a. 2010;
Denys e.a. 2009; Schlaepfer e.a. 2008; Okun e.a. 2007; Greenberg e.a. 2006;
Sturm e.a. 2003). The department of psychiatry of the Academical Medical Centre
(AMC) Amsterdam is one of the few centers in Europe performing DBS for complex
psychiatric disorders. Currently, our center has experience in
obsessive-compulsive disorder, addiction and major depressive disorder. In all
these disorders, DBS targets reward related brain areas such as the nucleus
accumbens and the ventral striatum.

Modulating the reward circuitry in the brain in an attempt to *re-regulate*
this dysregulation of the reward system, by means of deep brain stimulation of
the ventral anterior limb of the internal capsula (theorizing that this has a
positive influence on the reward deficits in anorexia nervosa, as well as
positive effect on the overactivity of the corticolimbic mechanisms of the
brain reward system), may provide significant and sustained improvement in
anorexia nervosa symptoms and associated comorbidities and complications.

We propose to introduce DBS for chronic, therapy refractory anorexia nervosa
(a) based on our clinical experience with DBS as a safe and effective treatment
for therapy-refractory reward-related psychiatric disorders, (b) based on the
literature on the (reward) neurocircuits involved in anorexia nervosa and (c)
based on the existing knowledge of animal models and human imaging studies on
anorexia nervosa.

Based on indications from clinical and animal studies, we have chosen the area
above the nucleus accumbens (the ventral limb of the capsula interna) as target
for stimulation.

The aims of this research project are:
1) to establish the efficacy and feasibility of DBS as a last resort treatment
in patients with chronic, treatment refractory AN.

2) to associate the efficacy and functional effects of DBS in patients with
chronic, treatment refractory AN with changes in cerebral perfusion in response
to specific tasks using functional MRI and with electrophysiologic assessement
through electro-encephalography (EEG).

3) to assess safety of DBS in patients with chronic, treatment refractory AN
assessing changes in neuropsychological functioning.

In this pilot study of Deep Brain Stimulation in patients with chronic
treatment refractory anorexia nervosa, 6 adult patients (age 25-65) with
chronic treatment refractory AN will be included, after written informed
consent has been obtained, to participate in a 18 month prospective trial using
high frequency DBS of the ventral anterior limb of the internal capsula.

The complete study comprises four sequential phases: (1) preparatory phase; (2)
surgery phase; (3) optimization phase;; and (4) maintenance treatment phase.

Phase 1: Preoperative phase
The preparatory phase (T-1) is the period before the actual surgery, needed for
the recruitment, selection and assessment of the patients. Neuroimaging,
psychometric/psychiatric assessments, neuropsychological tests and affective
information processing tasks will be conducted during this period.
Standard somatic and psychiatric care will be available to all patients
throughout this period and if necessary patients may be hospitalized at the
PsychMedUnit (PMU) of the psychiatric department of the AMC.



Phase 2: Surgery phase
During this phase (T0) the implantation of the electrodes and the stimulator
will be performed according to standard procedures. The patient is admitted the
day before surgery, and will be discharged from the department of neurosurgery
one or several days after the procedure, depending on the psysical condition of
the patient.
The implantation procedure is carried out entirely under general anaesthesia.
After anaesthesia is started, a stereotactic frame will be applied to the head
in order to facilitate the stereotactic electrode implantation. After frame
application, a high resolution structural MRI is made to guide the surgeon in
the planning of the operation. Then two electrodes (Medtronic Quad 3389) are
implanted bilaterally with the tip of the electrodes in the core of the NAc.
The selected target point for the electrodes will be chosen in accordance with
the atlas of Mai et al. (Mai et al., 2004; J.K. Mai, J. Assheuer and G.
Paxinos, Atlas of the Human Brain (2nd ed.), Elsevier Academic, San Diego;
Videen e.a. 2008) and transformed to the corresponding position in the
patient*s brain.
After electrode implantation, the stereotactic frame is removed, and both
electrodes are then connected via a subcutaneous extension cable to a
neurostimulator, which is implanted in the infraclavicular region (see figure
3). The correct position of the electrodes will be comfirmed directly
postoperatively with a CT-scan, and after several months with an MRI-scan.
If necessary, prolonged clinical observation is possible after surgery in the
AMC (Psychiatric Medical Unit, or Department of Neurosurgery).

Phase 3: Optimization phase
The optimization phase lasts between 3 and 9 months. Immediately after recovery
from surgery, the neurostimulator will stay in off mode during three weeks in
order to prevent interference with the effects from surgery that may complicate
the fine-tuning of the stimulation parameters (location, frequency, voltage).
After these three weeks, the neurostimulator is switched *on* (T1) and
fine-tuning/optimization of the neurostimulation will be performed during 3-6
months. If, thereafter, clinical improvement is still expected with additional
changes in neurostimulator settings, a continuation of the fine-tuning phase is
possible for 3 more months (until a maximum total duration of the optimization
phase of 9 months), with assessments of improvement every 2 weeks until a
plateau of effectiveness is reached. During the optimization phase the
psychiatric and somatic condition and the potential development of a refeeding
syndrome will be monitored closely by regular physical examination and
laboratory tests. If necessary, patients can be admitted to the Psychiatric
Medical Unit of the AMC.
Patients enter the next phase of the study after the optimization period is
completed, which is (1) after at least three months of trial stimulation during
which the stimulation parameter settings are determined that give the best
clinical improvement, or (2) when after an extension of the optimization phase
no (further) clinical improvement can be achieved. Clinical improvement will be
quantified with 1) sustained weight improvement/BMI change, 2) score change
from baseline on the Yale-Brown-Cornell Eating Disorder Scale ( YBC-EDS), 3)
the Clinical Global Impressions Scale (CGI, Busner e.a. 2007; clinical
improvement is defined as a CGI-Improvement (CGI-I) score of 1 or 2).

Phase 4: Maintenance period
The maintenance phase (T2) consists of a period of 12 months following the
optimization period, with the stimulator *on*, to assess the long term effect
of DBS on weight/BMI, comorbidity, and eating behaviour. During this period,
when required, further optimization of stimulation parameters is allowed. After
6 months (T3) an interim-analysis will be performed.

The intervention of this study will be Deep Brain Stimulation (DBS) in the
ventral limb of the capsula interna. Deep Brain stimulation is an adjustable,
reversible, non-destructive intervention using a surgically implanted medical
device to deliver carefully controlled electrical pulses to precisely targeted
areas of the brain. The stimulation can be programmed and adjusted
non-invasively by a trained physician to maximize symptom control and minimize
side effects. The ventral limb of the capsula interna has been chosen because
both animal and human studies indicate that this location is promising for DBS
treatment of anorexia nervosa and because this location has shown to be safe in
DBS studies among humans with other psychiatric/reward-related disorders such
as OCD, depression, and addiction. In addition, the AMC has ample experience
with DBS in this brain region, since more than 40 patients with OCD and with
major depressive disorder have been treated following the same protocol.

Obviously the greatest burden on the patient during this study is the
intervention itself. During the various phases of the study, the time burden on
the patient varies and consists of ca. 30 hours in the preoperative phase, ca.
20 hours in the 1 week surgery phase and . Patients will be admitted to the
hospital for 1-2 days during the surgery phase. .

In general, potential risks involved in DBS include the risks associated with
the surgical procedure, including the risk of intracranial haemorrhage or
infection and the associated neurological consequences. Studies on DBS in
movement disorders have reported a 0% to 5% risk of intracerebral hemorraghe
(de Koning e.a. 2011). Recent AMC-data show a rate of intracerebral hemorraghe
of 1% and a rate of intracerebral infection of 2%. In addition, some patients
may show some temporary neurological symptoms (e.g. eye movement abnormalities,
transient diminished concentration and verbal perseverations) that generally
disappear spontaneously or after some fine-tuning of the stimulator.
Acute mood changes during the first few days of stimulation of the ALIC and NAc
have been reported, specifically transient sadness, anxiety and euphoria
(sometimes to the extent of hypomanic and manic symptoms). In most cases, the
acute mood changes appear to be transient. All hypomanic and manic episodes
dissolved after the field density was readjusted by changing the voltage and/or
the active contact (de Koning e.a. 2011).
The psychiatric condition and the potential development of hypomanic and/or
manic symptoms will be closely monitored by a psychiatrist, especially during
the first period of stimulation and after changing the stimulation settings.
Patients will receive instructions to report hypomanic and/or manic symptoms
immediately. In the case of hypomanic and/or manic symptoms, stimulation
settings will be adjusted. If necessary, patients can be admitted to the
Psychiatric Medical Unit of the AMC.

Patients with AN are predisposed to significant risk of multi-organ dysfunction
related to starvation and purging. This can have implications on mortality and
morbidity associated with anesthetic complications during DBS implantation
(Seller e.a. 2003). Therefore, a thorough pre-operative anesthetic assessment
and evaluation is required to assist the planning of safe peri-operative care.
Patients should be rehydrated adequately and any deranged electrolyte levels
should be corrected pre-operatively. There is an increased risk of
intra-operative hypothermia. Therefore measures should be taken to keep the
patient warm during surgery. Doses of most (anesthetic) drugs should be
adjusted for weight. Patients are particularly susceptible to nerve palsies due
to their cachexia and loss of cushioning subcutaneous tissue. Therefore they
must be placed carefully on the operating table. During the operation,
ECG-changes and potassium levels should be monitored carefully to minimize the
risk of arrhythmias (Seller e.a. 2003). To minimize the overall increased risks
associated with anesthesia the weight and somatic condition will be maximally
optimized prior to surgery.


In case of the hypothesized weight gain following successful treatment with
DBS, there is a risk of development of a refeeding syndrome (Khan e.a. 2010).
The refeeding syndrome is a potentially lethal complication of refeeding in
patients that are severely malnourished. Features of the refeeding syndrome
are: salt and water retention leading to oedema and cardiac failure;
hypokaliaemia; hypophosphataemia; rapid depletion of thiamine leading to
Wernicke*s encephalopathy and/or cardiomyopathy; hypomagnesaemia. Especially
rapid and excessive refeeding imposes a risk for development of the refeeding
syndrome. It is expected that weight increase following treatment with DBS will
be gradual rather than sudden and excessive. Other DBS studies, for example in
OCD and depression, showed that improvement of symptoms takes several months
(Denys e.a. 2009; Greenberg e.a. 2010; Lipsman e.a. 2013; Schlaepfer e.a.
2008). However, patients are advised to increase their food intake gradually
and under supervision of a dietary consultant. The somatic condition and the
potential development of a refeeding syndrome will be closely monitored by a
physician. Regular physical examinations and laboratory tests will be
conducted. If necessary, patients can be admitted to the Psychiatric Medical
Unit of the AMC.

Lipsman e.a. (2013) reported several adverse events in their pilot study on DBS
in AN, with one serious DBS-related adverse event (seizure during programming)
and the other serious adverse events being related to the underlying illness.
One patient in this study developed hypophospataemia and a refeeding delirium
(Lipsman e.a. 2013).

The fMRI assessment will be conducted in accordance with established guidelines
for MR imaging in DBS. In particular, care will be taken to minimize heat
production in the vicinity of the DBS electrodes. Therefore, MR imaging will be
performed on a 1.5 Tesla system rather than a 3 Tesla system. Moreover, we will
employ low Specific Absorption Rate (SAR) sequences and use MR paradigms known
to produce robust activations to limit scanning time (Carmichael e.a. 2007,
Bhidayasiri e.a. 2005, Georgi e.a. 2004).
As stated before, the subjects of this study are patients with very severe,
chronic, treatment refractory AN, associated with poor outcome and a high
mortality, for who there are no further treatment options. With this pilot
study, we aim to provide an optimal balance between risk and opportunity.