Keywords
neurosurgery - morbid obesity - deep brain stimulation (DBS) - nucleus accumbens -
hypothalamus
Introduction
Obesity is one of the civilization diseases, which afflicts westernized populations,
leading to several metabolic complications.[1] According to the World Health Organization (WHO), morbid obesity (MO) is defined
as a body mass index (BMI) amounting ≥40 kg/m2 or ≥35 kg/m2 with coexisting obesity-related health conditions for both women and men.[2]
[3] It is estimated that between 2005 and 2014 in the United States there were 7.7%
of adults meeting the criteria for MO.[4] Furthermore, since 1985 MO has been officially recognized as a chronic disease.[2]
People with obesity are at higher risk of developing other chronic diseases such as
hypertension, insulin resistance, diabetes, and cardiovascular diseases.[5] In addition, obesity is also associated with an elevated risk of carcinogenesis.[5] Obesity is a risk factor for breast, prostate, or colorectal cancer. Central fat
accumulation in children and adolescents is correlated with an unfavorable lipid profile
and blood lipoprotein concentrations (atherogenic dyslipidemia, hyperlipidemia), higher
blood pressure, atherosclerosis, and greater left ventricular mass.[6]
[7] Different factors may lead to the development of obesity, including genetic, environmental,
socioeconomic, and psychological factors.[4]
[8]
[9]
[10] The current treatment options include dieting, physical exercise, pharmacological
treatment, psychotherapy, and surgical treatment.[3]
[8]
[9]
[10] Surgical treatment is mostly covered by general and gastroenterological surgeons
who perform bariatric surgeries, which are considered the most effective type of treatment
for obesity.[11]
[12]
Deep brain stimulation (DBS) is a safe and proven treatment modality for patients
suffering from disabling movement disorders such as Parkinson's disease (PD), dystonia,
essential tremor (ET), and also more recently neuropsychiatric conditions such as
Tourette's syndrome (TS), major depressive disorder (MDD), obsessive-compulsive disorder
(OCD), anorexia nervosa (AN), or epilepsy.[13] DBS is also a new direction in the treatment of different appetite disorders and
MO.[2]
[3]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23] Three neural targets are considered for DBS in MO: lateral hypothalamus (LH), ventromedial
hypothalamus (VMH), and nucleus accumbens (NAc)[2]
[14]
[24] ([Fig. 1]).
Fig. 1 (A) The visualization of nucleus accumbens (NAc) in 1.5-T magnetic resonance imaging
(MRI) T1-weighted image in axial orientation. The nucleus accumbens is marked on the
image with white dots. NAc lies medial to the ventral capsule. (B) The ventromedial hypothalamus (VMH) presented on the axial 1.5-T MRI T2-weighted
image lies posterior to the optic nerve, anterior to the mammillary body, and inferior
to the anterior commissure. (C) The lateral hypothalamus (LH) is demarcated in 1.5-T MRI T2-weighted image in axial
orientation. The LH is located superoposterior to the optic nerve and chiasma and
inferior to the fornix. (D) The VMH and LH are marked on the sagittal image with white dots. The VMH lies medial and ventral to the LH. The arrows indicate the location of the
white dots.
LH is considered a feeding center. A lot of studies on animal models have shown that
lesions in the LH resulted in decreased food intake, weight loss, and accelerated metabolic rates.[15]
[22]
[25]
[26] Lesions of the VMH, which is known as the satiety center, have been shown to impact
the weight in obese animals.[3] NAc is an anatomical structure located in the ventral striatum and plays a major
role in a reward system, motivation, and action.[2] In the animal model studies, where the NAc was adopted as the stereotactic target,
a decrease in food intake, as well as body weight loss, was observed.[14]
[21]
[27]
The primary aim of the review was to investigate DBS outcomes in individuals with
MO based on published reports and evidence. Moreover, we have summarized the criteria
for implementing this treatment in severely obese patients. We have searched for all
the case reports connected with DBS for MO using the PubMed database. We included
magnetic resonance images of those structures targeted by DBS electrodes in MO.
Material and Methods
Using the PubMed search engine and passwords like MO and DBS, we found 23 studies,
including 9 studies on the use of DBS in the treatment of MO ([Tables 1] and [2]). So far, 16 participants have been subjected to the DBS procedure, of which 6 are
in case reports and 10 in case series. The most frequently chosen stereotactic targets
in the treatment of MO are the LH (50% of cases), the NAc (37.5% of cases), and the
VMH (12.5% of cases). The NAc is also a stereotactic target in other diseases, including
OCD, depression, TS, AN, and alcoholism.[23]
[28] The NAc was a stereotactic target in the treatment of six cases, despite many studies
on animal models. In more than half of all cases, DBS lead implantations caused weight
reduction and decrease in BMI. Even memory improvement was reported in a 2008 study.
There were no differences in side effects between women and men. Eight people had
side effects, including one successful suicide attempt.
Table 1
A list of published case reports raising the issue of deep brain stimulation for the
treatment of morbid obesity
|
Study
|
Age and sex
|
Main diagnosis
|
Target
|
Stimulation parameters
|
Follow-up (months)
|
Results
|
Side effects
|
|
Hamani et al[29]
|
50♂
|
MO
|
VMH (bilateral), stereotactic coordinates of the right electrode tip: 6 mm lateral,
11.7 mm inferior, and 10.5 mm anterior to the MCP; stereotactic coordinates of the
left electrode tip: 4.2 mm lateral, 11.3 mm inferior, and 11 mm anterior to the MCP;
no microelectrode recording; macrostimulation
|
Monopolar stimulation: 50 Hz, 210 µs, and 3–4 V
|
5 months
|
Decreased appetite, minimal long-term weight change (12 kg over 5 months), improved
memory;
during the last 4 months, the patient turned the stimulator off in the evenings
|
Warming sensation, flashes of light, and difficulties in falling asleep
|
|
Mantione et al[30]
|
47♀
|
OCD
MO
|
NAc (bilateral),
stereotactic coordinates of the electrode tip: 7 mm lateral, 4 mm inferior to the
ACPC line, and 3 mm anterior to the AC
|
185 Hz, 90 µs, and 3.5 V
|
24 months
|
Weight reduction from 39 to 25 kg/m2;reduction of obsessive-compulsive symptoms, anxiety, and depression
|
None
|
|
Wilent et al[31]
|
50♀
|
MO
|
VMH (bilateral),
stereotactic coordinates of the left electrode tip: 4.7 mm lateral, 3.8 mm inferior,
and 6 mm anterior to the MCP; stereotactic coordinates of the right electrode tip:
8.2 mm lateral, 3.8 mm inferior, and 8 mm anterior to the MCP; microelectrode recording
|
135 Hz, 60 µs, and 1–7 V
|
–
|
–
|
Panic attack
|
|
Harat et al[32]
|
19♀
|
MO
|
NAc (bilateral)
|
130 Hz, 208 µs, and 2–3.75 mA
|
14 months
|
Reduction in BMI from 52.9 to 46.2 kg/m2;weight reduction from 151.4 to 132 kg;
improvement of cognitive and psychomotor functions
|
No major adverse effects reported
|
|
Talakoub et al[33]
|
19♂
|
Obesity
Prader–Willi syndrome
|
LH (bilateral),
anatomically based target on MRI-CT images fusion; microelectrode recording; macrostimulation
|
8 Hz, 90 µs, and 3 V
|
–
|
Early feeling of fullness without effects on craving for food
|
None
|
|
Tronnier et al[34]
|
40♀
|
Depression
MO
|
NAc (bilateral),
stereotactic coordinates of the electrode tip: 7 mm lateral, 3 mm anterior to the
AC, and 4 mm inferior to the ACPC; microelectrode recording
|
130 Hz, 90 µs, and 3–4 V
|
14 months
|
2.85 kg/months weight reduction
|
Difficulties in falling asleep
|
Abbreviations: AC, anterior commissure; ACPC line, anterior commissure–posterior commissure
(intercommissural line); BMI, body mass index; MCP, midcommissural point; MO, morbid
obesity; NAc, nucleus accumbens; –, data not available; OCD, obsessive-compulsive
disorder; VMH, ventromedial hypothalamus.
Table 2
A list of published case series raising the issue of deep brain stimulation (DBS)
for the treatment of morbid obesity
|
Study
|
No. of patients, sex
|
Target
Targeting method
|
Stimulation parameters
|
Follow-up (months)
|
Results
|
Side effects
|
|
Whiting et al[35]
|
3 (2♀, 1♂)
|
LH (bilateral),
stereotactic coordinates: 6.5 mm lateral to the ACPC line, 3 mm inferior to the ACPC
line, and 4.5 mm posterior to the AC; microelectrode recording; macrostimulation
|
Monopolar or bipolar: 185 Hz, 90 µs, and 1–7 V (standard settings derived from movement
disorder DBS programming)
|
35
|
Weight reduction;
no change in cognitive functions
|
No major adverse effects reported
|
|
Franco et al[36]
|
4 (2♀, 2♂)
|
LH (bilateral),
stereotactic coordinates: 8.3 mm lateral, 7.3 mm inferior, and 5.8 mm anterior to
the MCP; no microelectrode recording; macrostimulation
|
Off (2 months)
40 Hz (1 month)
15-d washout
130 Hz (1 month)
|
Not found
|
No major effects on hormonal levels, blood workup, neuropsychological evaluation,
and sleep
|
2 patients developed mania symptoms, 2 developed infections, with 1 infection resulting
in the removal of hardware
|
|
Rezai et al[27]
|
3 (3♀)
|
NAc (bilateral),
targeting method not mentioned
|
Not reported (high-frequency)
|
36
|
Reduction of weight and desire to eat, binge eating behaviors, and depressed symptoms;
improvement in the quality of life and mood.
Two patients did not complete the trial. Following a review of the data from the first
3 subjects, the pilot study was discontinued due to lack of feasibility
|
One of the patients committed suicide after 27 mo into the study
|
Abbreviations: AC, anterior commissure; ACPC line, anterior commissure–posterior commissure
(intercommissural line); LH, lateral hypothalamus; MCP, midcommissural point; NAc,
nucleus accumbens.
Deep Brain Stimulation for Morbid Obesity (Case Reports)
Deep Brain Stimulation for Morbid Obesity (Case Reports)
Hamani et al implanted DBS electrodes bilaterally in the ventral hypothalamus in the
case of a 50-year-old man who suffered from MO (BMI: 55.1 kg/m2).[29] With the stimulation parameters set at 50 Hz, 3.0 to 4.0 V, and 210 microseconds,
the patient lost 12 kg over 5 months and reported reduced food cravings. In the case
of this patient, the hypothalamic stimulation modulated a limbic activity and resulted
in improvement of certain memory functions. In 2010, Mantione et al presented another
case report of a 47-year-old woman with OCD and coexisting obesity, who had DBS electrodes
bilaterally implanted in the NAc.[30] The stimulation resulted in BMI reduction from 39 to 25 kg/m2, and the OCD symptoms disappeared. Wilent et al reported the case of a 19-year-old
obese woman, who suffered from a panic attack after bilateral implantation in the
VMH.[31] Harat et al described the case of a 19-year-old woman with hypothalamic obesity
due to previous craniopharyngioma surgery. After 3 months of bilateral NAc stimulation,
weight reduction from 52.9 to 46.2 kg/m2 was observed.[32] Talakoub et al reported the case of a patient with Prader–Willi syndrome who underwent
bilateral implantation in the LH.[33] In this case, DBS resulted in the feeling of fullness without an effect on food
craving. Tronnier et al described the effect of bilateral NAc stimulation in a 47-year-old
obese woman with a history of gastric bypass surgery and drug-resistant depression.[34] The weight loss after bariatric surgery was 1.75 kg/month and accelerated to 2.85 kg/mo
after neurostimulation. The case reports have been presented and summarized in [Table 1].
Deep Brain Stimulation for Morbid Obesity (Case Series)
Deep Brain Stimulation for Morbid Obesity (Case Series)
In 2013, Whiting et al published a study in which three patients with intractable
obesity were implanted bilaterally with DBS electrodes in the LH.[35] Even though the patients lost weight, no significant weight reduction trends were
seen with stimulation parameters used in movement disorder patients. However, when
the monopolar DBS was implemented, a resting metabolic rate measured in a respiratory
chamber increased. Rezai et al performed a bilateral implantation into the NAc in
three patients with morbid, treatment-refractory obesity, and coexisting psychiatric
conditions.[27] Only one patient completed a 3-year trial with a reduction in BMI from 55.7 to 39.3 kg/m2. Two patients did not complete the study: one of them committed suicide and the other
one requested electrode explantation. The authors concluded that neuromodulation itself
was not responsible for these events. After a review of the data obtained from the
first three subjects, the research group decided to discontinue the study due to lack
of feasibility. Franco et al reported four case series of patients with Prader–Willi
syndrome.[36] After 6 months of bilateral implantation of DBS electrodes in the LH, there was
a mean 9.6% increase in weight and a 5.8% increase in BMI. The clinical features including
the number of patients enrolled, target with targeting method, stimulation parameters,
follow-up period, results, and side effects of the above-mentioned studies are presented
in [Table 2].
Discussion
Because of its rising prevalence, obesity has become a matter of great importance
in global health. When conservative treatments fail, surgery becomes a necessity.
The main goal of bariatric surgery is restriction of food intake or inducing of short
bowel syndrome.[11]
[12]
[14]
[15] Although bariatric surgeries are considered and have proven to be a highly effective
treatment modality, they bear a significant risk of adverse effects.[11]
[12] For example, laparoscopic Roux-en-Y gastric bypass that is considered a gold standard
bariatric operation is associated with 65% weight loss with over 85% of patients losing
and maintaining 50% of initial excess weight loss; however, the procedure is associated
with 10 to 15% long-term failure rate.[37] Also, this type of treatment might not be effective in some patients. This has forced
some investigators to search for new treatment possibilities. Since DBS has proven
to be highly effective in numerous movement disorders like PD and dystonia, and as
it is gaining popularity in the treatment of neuropsychiatric conditions, scientists
have attempted to apply this method in other indications as well.[17]
[23]
[28]
[38]
In the last decades, we have had a better insight into understanding the pathophysiology
of appetite disorders. Based on the current scientific reports in the field of obesity
and the research on animal and human models, there are three main stereotactic targets:
NAc, VMH, and LH.[2]
[14]
[24] The NAc is a part of the striatum lying just below the anterior limb of the internal
capsule, superolateral to the optic nerve, and anterior to the preoptic area.[39] The NAc consists of shell projecting mainly to the limbic system and core projecting
to the basal ganglia.[40] The NAc DBS high-frequency stimulation in animal model studies resulted in caloric
intake restriction and weight loss.[41] The VMH is a target lying posterior to the optic nerve, anterior to the mammillary
body, and inferior to the anterior commissure.[39] The results of animal model studies involving low-frequency stimulation of the VMH
showed reduction in body weight and fat, whereas high-frequency stimulation led to
increased food intake.[42]
[43] The LH is a small target placed inferior to the fornix and superoposterior to the
optic nerve and chiasm.[39] Animal model studies revealed that low-frequency stimulation of the LH resulted
in melanin-concentrating hormone and orexin stimulation, which induces food-seeking
behavior, whereas high-frequency stimulation of the LH resulted in weight loss.[44]
[45]
[46]
[47] Imaging studies, such as functional magnetic resonance imaging (fMRI), might be
useful to define the stereotactic target for MO.[48] Applying DBS in MO also requires a battery of neuropsychiatric tests.[14] For this reason, a multidisciplinary cooperation between clinicians, specialists
treating obesity, neurosurgeons, psychiatrists, and neuropsychologists is absolutely
needed.
The implementation of unequivocal inclusion and exclusion criteria for applying DBS
in MO patients is an important clinical step. In all of the proposed studies, the
main inclusion criterion is the diagnosis of MO in accordance with the WHO criteria.
Other criteria include age ≥18 years, chronicity of the illness, failure of bariatric
surgery, stable at present bodyweight for 6 months, and ability to give informed consent
to surgery.[15]
Patients between the ages of 18 and 60 years are typically referred for a DBS procedure.
The surgery is extremely demanding and may last from 3 to 6 hours. To overcome the
surgery-related stress, a patient must be in good physical condition. The exclusion
criteria are a treatable underlying cause of MO as well as an active neurologic disease
such as movement disorder. An active psychiatric disorder, excluding depression, is
another exclusion criterion. Patients with structural changes visible on MRI or a
history of brain surgery should be excluded from undergoing DBS surgery. Also, contraindications
for MRI examinations, such as a metal, pacemaker, or when the patient is unable to
fit in MRI, are the exclusion criteria for DBS. A lot of DBS studies associated with
mental illnesses emphasize the necessity of preservation of cognitive functions. Patients
should understand the consequences of the procedure to give informed written consent
for the procedure.[17]
[18]
[29]
[36]
[49] It is also associated with a better ability to control the patient's mental state.[21]
[49] Another exclusion criterion is dementia or an incorrect result in the Mini-Mental
State Examination (MMSE).[29]
[49] Moreover, the local ethics committee should review each case individually and decide
whether a MO patient is suitable for a DBS procedure.
The main advantage of DBS is reversibility and the possibility of applying different
stimulation parameters. However, some authors dispute this claim taking into account
the possibility of permanent morbidity and other complications related to the possible
risk of the procedure.[50] Despite promising results of preclinical trials addressing DBS in treating MO, the
clinical experience concerning human objects remains very limited.[51]
Conclusion
MO is a demanding condition. Since in some cases standardized treatment is ineffective,
new therapies should be implemented. DBS is a promising therapy that might be used
in patients suffering from MO. However, more studies incorporating more individuals
and with a longer follow-up are needed to obtain more reliable results concerning
its effectiveness and safety profile.
