Introduction

The prevalence rates of overweight and obesity are increasing rapidly in both
developed and developing countries. Previously, overweight and obesity were considered
primarily problems of developed countries. However, due to lifestyle changes and
urbanization, it is now apparent that developing countries are also faced with the same issues.
Policymakers in developing countries have not paid much attention to the problem of
excessive weight gain. Obesity contributes to a variety of serious chronic diseases, and thus
to a large health burden. Indonesia is a large and populous country and is one of the
economically fast growing nations of Asia, and has undergone rapid urbanization including a
move of traditional food systems towards a modern supply chain.
Recent surveys have shown that obesity rates are also increasing in Indonesia. Based
on the National Basic Health Research in 2007, the prevalence of overweight and obesity, as
determined by body mass index (BMI), were 8.8% and 10.3%, respectively. The cumulative
prevalence of overweight and obesity was higher in females than in males (23.8% versus
13.9%). Obesity was observed to be more prevalent in urban areas. Furthermore, central
obesity, as determined by waist circumference, was present in 18.8%, and was more
commonly observed in females (29% versus 7.7% in males) and in urban area dwellers
(23.6% versus 15.7% in rural areas).
Similarly, the Indonesian Family and Life Survey (IFLS) of the Rand Institute,
conducted in 1993, 1997, 2000 and 2007, showed that the mean BMI values among
Indonesian adults has notably increased Indonesian women had higher BMIs than men, and
the difference of BMIs between genders increased from 1993 onward. Average BMI levels
were higher in urban compared to rural areas. However, the rate of increase in BMI over time
among rural dwellers was higher compared to urban area residents. Data from the IFLS
represented 83% of Indonesian population; a few remote areas were not included in the
survey.
In 2006, performed an epidemiologic study in Jakarta, the capital city of Indonesia
(unpublished data). The survey included 1591 subjects aged 25 to 65 years, of which 41%
were male. The prevalence of obesity and central obesity were 52% and 53%, respectively. In
addition, the prevalence of obesity increased with age in both genders. There was a
decreasing trend noted after the age of 60.

Deep brain stimulation involves implanting a device called a neurostimulator, which

delivers tiny electrical signals to specific areas of the brain. DBS is routinely used to control
the symptoms of movement disorders, such as Parkinsons disease and dystonia.
In DBS, slender leads tipped by a row of electrical contacts deliver mild electric
pulses to the brain. The leads are connected to a compact, battery-operated pulse generator,
similar to a heart pacemaker.
The goal of electrical brain stimulation is to rebalance the brain's neural circuits by
influencing when nerves fire and neurotransmitter chemicals are released. According to
the National Institutes of Health, deep brain stimulation is a well-tolerated procedure that is
both individually programmable and reversible. However, potential risks include infection,
bleeding in the brain, and an allergic reaction to the device components.
Working with collaborators at Pennington Metabolic Center in Baton Rouge, La., Oh
and colleagues arranged for the trial patients to undergo detailed metabolic studies over the
course of three days.
The patients rested comfortably in enclosed metabolic chambers where their oxygen
consumption and carbon dioxide release were analyzed. Each patients normal resting
metabolism was measured and tested against a range of neurostimulation settings.
Based on the results, the researchers chose a DBS setting that would have the greatest
effect on raising each patients resting metabolic rate. The metabolic studies proved useful to
guide optimal settings (of neurostimulation).The scientists found no negative effects of DBS
on the patients' psychological or mental function.
Current management on obesity
Diets
The Dietary Guidelines for Americans (along with My Pyramid) provides one
example of a low-fat (LF) eating plan.1 The Dietary Guidelines are based on evidence that
eating a LF (20-35%) diet helps manage weight, promote health, and reduce the risk of
chronic disease. The guidelines include recommendations for foods to reduce (i.e.,
saturated and trans fat, cholesterol, sodium, added sugar, refined grains, alcohol) and foods
to increase (i.e., fruits, vegetables, whole grains, low-fat dairy and protein foods, oils) in

order to maximize the nutrient content and health promoting potential of the diet. Other
examples of a LF diet are the DASH diet and those recommended by the American Diabetes
Association2, American Heart Association3, and American Cancer Society4, as well as
commercial programs like Weight Watchers.
Efficacy, health effects, and sustainability
Low-fat diets are the best studied of all dietary approaches to weight loss. Three large,
multi-center, randomized studies (i.e., the PREMIER trial, Diabetes Prevention Program, and
the Finnish Diabetes Prevention study) have demonstrated that greater weight loss is achieved
in groups consuming LF diets compared to controls receiving standard lifestyle
recommendations.5Furthermore, they suggest that consumption of a low-fat, low calorie diet,
in the context of intensive group and/or individual counseling, has positive effects on
comorbid conditions as long as they are followed. A more detailed description has been
reported previously.
More recent studies have reported similar findings. The Look Ahead Trial 6 was a large
multicenter, randomized clinical trial that compared the effects of an intensive lifestyle
intervention (ILI) to diabetes support and education (DSE) on the incidence of major
cardiovascular disease (CVD) events in overweight or obese individuals with type 2 diabetes.
Participants in the ILI group were assigned a calorie restricted LF diet, received frequent
behavioral therapy, and extended contact. Those in the DSE group were given standard
instruction on 3 occasions each year for eating a healthy diet and engaging in physical
activity. Weight loss in the ILI group was significantly greater than the DSE group each year
over the course of four years, with maximal weight loss occurring at 1 year, Individuals in the
ILI group also displayed greater improvements in hemoglobin A1C (HbA1C), blood pressure,
high density lipoprotein (HDL), and triacylglycerides (TAG) over the course of the study.
Other studies prescribing LF diets with treatment phases ranging from 6 months to 12
months have reported weight losses of approximately 6-11 kg after 6 and 12 month 4-5 kg
after 24-36 months, and 4.7% initial body weight at 48 months .The Woman's Health Initiative
Dietary Modification trial showed that following a LF diet without instruction for calorie
restriction can help to maintain weight loss slightly better than following a diet higher in
fat.12Taken together, these findings suggest that a LF diet is an effective weight control
strategy in the short- and long-term as long as it is followed.

Weight Loss Outcomes of Studies 6 Months or Greater in Duration

Adherence to a calorie controlled diet appears to be one of the biggest barriers to the
long-term success of weight loss maintenance. LF eating is not immune to poor long-term
adherence. Researchers have investigated various strategies, from varying the percentage of
fat in the diet to matching diets with food preferences, in an attempt to promote better longterm dietary adherence. One study comparing weight loss and CVD risk factors in individuals
consuming calorie controlled 20% or 30% fat diets showed that although both diets produced
a similar amount of weight loss after 7 months, weight loss was maintained better and CVD
risk factors were reduced more after 14 months in those following the 30% fat diet. It appears
that intake was more restrictive in the 20% fat diet group, making it more difficult to follow
over the long-term and resulting in greater weight regain. A limited number of studies have
investigated the effects of matching treatment preferences with weight loss outcomes. A
recent study found that whether individuals were randomized to their preferred LF diet or not
(i.e., standard or lacto-ovo vegetarian), they lost similar amounts of weight after 6 months;
however, differences in weight regain patterns emerged after 6 months. Curiously, those who
were assigned their preferred diet began regaining weight sooner (i.e., 6 vs. 12 months) and
regained more weight (i.e., 4.5% vs. 2.1%) at 18 months than those who were not assigned to
their preferred diet. Similar findings were recently reported for both LF and low carbohydrate
diets.Borradaile et al found that the group assigned their preferred diet lost less weight (-7.7
kg) than the group who did not receive their preferred diet (-9.7 kg) or who did not report a
strong preference at baseline (-11.2 kg). 16 Given this seemingly counterintuitive finding, it
may be useful for future studies to elaborate on preference (e.g., is their preference based
on a preferred way of eating or on an alternative to their preferred way of eating).
Exercise
The following general description of fitness guidelines and exercise prescription
serves as a framework for a more detailed discussion of obesity treatment exercise
recommendations. Health-related physical fitness includes the following 3 components:
cardiorespiratory fitness, body composition, and muscular fitness.The ACSM and the Centers
for Disease Control and Prevention guidelines suggest 30 minutes or more of moderate
physical activity on most, and preferably all, days of the week.Fitness training follows the
fundamental physiologic principles of overload and specificity, where physiologic adaptation

requires a progressive increase in exercise stimuli specific to the muscles involved and the
type of exercise.
n exercise prescription defines the mode, intensity, duration, and frequency of
exercise activities. A broad fitness program that uses most major muscle groups transfers the
training effect to vocational and recreational activites.5 Components of a particular training
session include the warm-up, conditioning phase, and cooldown. The 5- to 20-minute warmup prepares muscles for more vigorous exercise and may reduce injuries. Stretching is
recommended following the warm-up and is thought to reduce muscular injury. The
conditioning phase involves a cardiorespiratory or resistance training session lasting 20 to 60
minutes. This is followed by a cooldown, which may attenuate postexercise hypotension,
allow better dissipation of body heat, remove lactic acid, mitigate the rise in potentially
arrhythmogenic catecholamines, and possibly reduce the risk of cardiac events during the
recovery period.
Cardiorespiratory conditioning uses large muscle groups in rhythmic dynamic
activity. Examples of this mode include running, jogging, cycling, swimming, walking, and
aerobic machines. Cardiorespiratory fitness is defined by aerobic capacity or by VO2max.
Training intensity is estimated based on calculations using percentages that depend on one's
overall level of fitness and stage of progression within an exercise program. Various methods
of determining VO2max and estimating the training zones are based on direct measurement or
estimations of the heart rate, as heart rate and oxygen consumption per unit time (V O2) are
linearly related.
Direct measurement of VO2max requires special equipment and expertise. Therefore,
heart rate estimations, although prone to inaccuracy, are more practical for routine use.
Recommended training ranges vary from 40% or 50% to 85% of oxygen uptake reserve
(VO2 reserve) or heart rate reserve or from 64% or 70% to 94% of maximum heart rate.5 The
VO2 reserve is the difference between VO2max and resting VO2, and the heart rate reserve is the
difference between maximum heart rate and resting heart rate. The lower end of these scales
represents threshold values for physiologic stimulation, and the higher rates represent adapted
training zones for accustomed individuals. Exercise intensity above the upper limit becomes
anaerobic, does not provide additional benefit, and may induce injury or performance
retrogression.

The duration of exercise sessions should be 20 to 60 minutes. Debate exists

concerning the value of performing exercise in shorter cumulative bouts throughout the day.
The frequency of cardiorespiratory exercise sessions should be 3 to 5 days per week.
Additional benefit derived by training beyond 6 days per week is minimal and is complicated
by higher injury rates. Progression is a concept that describes a participant's adaptation over
time, necessitating increased exercise volume stimulus, where volume is a function of
intensity, frequency, and duration. Progression consists of initial, improvement, and
maintenance stages. In general, intensity and duration are less in the initial stage, where one
becomes accustomed to exercising and develops orthopedic tolerance. The initial phase
occurs over the first 6 weeks or so of a new program. The improvement stage follows for the
next 4 to 8 months and includes a gradual increase in overall exercise stimulus. Increases in
duration or frequency should precede increases in intensity. Finally, a long-term maintenance
stage focuses on continued participation in enjoyable and varying exercises.
Resistance training is recommended as part of an overall fitness program, as such
training alone does little to increase VO2max, expends only moderate amounts of calories, and
marginally affects the resting metabolic rate.The benefits of resistance training include bone
density improvement and improvement in the performance of activities of daily living. Sets
of 8 to 12 repetitions, the last of which results in volitional fatigue, increase muscular
strength and endurance. A typical resistance training exercise prescription includes 8 to 10
separate exercises that involve major muscle groups of hips, thighs, legs, back, chest,
shoulders, arms, and abdomen. One set of each exercise is deemed adequate performed on 2
or 3 nonconsecutive days per week. The value of the traditional practice of multiple sets per
exercise has been disputed.5 Resistance training follows a phased progression similar to
cardiovascular fitness training, but the variable is increasing resistance.
Treatment
Medications
A variety of over-the-counter and prescription weight loss drugs are available. Some
people find these drugs help curb their appetites. Studies show that patients on drug therapy
lose around 10 percent of their excess weight, and that the weight loss plateaus after six to
eight months. As patients stop taking the medication, weight gain usually occurs.
Weight loss drugs, approved by the U.S. Food and Drug Administration (FDA) for treating
obesity, include:

Beta-methyl-phenylethylamine (Fastin) This is a stimulant that increases fat

metabolism.

Orlistat (Xenical) This drug works by blocking about 30 percent of dietary fat
from being absorbed. Alli is a lower-dose, over-the-counter formula of the same
medication.

Phentermine Phentermine, an appetite suppressant, has been available for many

years. It is half of the "fen-phen" combination that remains available for use. The use
of phentermine alone has not been associated with the adverse health effects of the
fenfluramine-phentermine combination.

Sibutramine (Meridia) This is an appetite suppressant approved for long-term

use.

Medications are an important part of the morbid obesity treatment process but weight-loss
drugs can have serious side effects. We recommend that you visit a certified health care
professional who can prescribe appropriate medications. Before insurance companies will
reimburse you for weight-loss surgery, you must follow a well-documented treatment plan
that typically includes medications.
Surgery
Many people ,who are morbidly obese and who have been unsuccessful in losing and
keeping off the weight, opt for bariatric or weight-loss surgery.
Bariatric surgery, which involves sealing off most of the stomach to reduce the quantity of
food you can consume, can be an effective means for morbidly obese people to lose weight
and maintain that weight loss.
To be considered for weight-loss surgery, you must meet at least one of the following
qualifications:

Be more than 100 pounds over your ideal, recommended body weight.

Have a body mass index (BMI) of 40 or higher (20 to 25 is considered a normal).

BMI is a number based on both your height and weight. Surgery may be considered
with a BMI as low as 35 if your doctor determines that there's a medical need for

weight reduction and surgery appears to be the only way to accomplish the targeted
weight loss.
To qualify for surgery, you must complete a medical and psychological pre-evaluation
process, and show how that you are committed to long-term, follow-up care after surgery.
Most surgeons require that you demonstrate serious motivation and a clear understanding of
the extensive dietary, exercise and medical guidelines that must be followed for the remainder
of your life.
The UCSF Bariatric Surgery Center has performed surgical weight loss procedures since
1996. Various procedures involve different risks and advantages. During your initial
consultation, your surgeon will discuss in detail the different options available to you, along
with their associated risks and advantages.
The most common bariatric surgeries are "restrictive" procedures that reduce the size of
the stomach and limit the calories you can consume.
Neurosurgery and weight modulation
Anatomy and animal studies
The rationale for a clinical application of VMH-DBS to treat morbid obesity and severe
eating disorders is based on an extensive literature demonstrating the regulation of food
intake and satiety by the hypothalamus, and the modulation of those functions by
hypothalamic electrical stimulation.
Consideration of a low frequency VMH-DBS clinical trial can be advanced upon
demonstration of its efficacy and safety in preclinical studies in which aspects of the clinical
procedures have been modeled. The primary goals of this research were to adapt human
neurosurgical methods and DBS instrumentation for use in a large animal obesity model and
then evaluate the effects of VMH-DBS on weight modulation and behavior. Our results
showed that in the Gttingen minipig under conditions of extra calorie intake, the continuous
delivery of low frequency (50 Hz) DBS in the ventral hypothalamus region was associated
with a lower weight gain compared to that in animals not receiving DBS.
Prior Electrical Stimulation Studies in Rodents
In the early 1960's , it was recognized that electrical stimulation in the range of 60 Hz of
the VMH region of the rat suppressed feeding in animals that were fasted for as long as 5

days. In later studies, VMH stimulation at 5060 Hz resulted in inhibition of feeding, reduced
food intake, and/or reduced weight gain. Increases in lipolysis were also observed which
were attributed to activation of sympathetic pathways to adipose tissues insofar as
sympathetic denervation impaired or abolished the electrical stimulation response. Increases
in metabolic rate and modulation of energy expenditure were also characterized for this 50
60 Hz range of electrical stimulation. Those results suggested a double effect of electrical
stimulation on energy balance. First, it favored a lipolytic effect by the utilization of body fat
stored in adipose tissue and that resulted in an anorexigenic effect as characterized by a
reduction in food ingestion as a de-novo energy source. Collectively, these studies have been
invaluable for defining regional effects of hypothalamic electrical stimulation, albeit with the
caveat that most studies were short term (days to weeks) and were conducted in non-obese
animals.
DBS Applications in the Hypothalamus
DBS represents the clinical counterpart of electrical stimulation as used in animal studies.
Generally, DBS applications in humans are classified bimodally by frequency range - either
high (100185 Hz) or low (<100 Hz). Within each mode, further options for amplitude (either
voltage or current) and pulse width then allow for a wide range of parameter settings
combinations. However, in the absence of a detailed theoretical framework for understanding
how those variables affect neuronal and glial tissues, the clinician usually uses combinations
that follow prior protocols that demonstrated positive clinical outcomes, and then they further
modify selected settings empirically to maximize efficacy and minimize adverse effects for
individual patients.
Molecular mechanisms underlying the therapeutic effects of DBS remain not welldefined. Initially, experimental evidence supported the theory that high-frequency DBS
paradoxically acts like a lesion, i.e., via a neuronal depolarization block. However, more
recent studies have shown that while high frequency DBS does inhibit somatic activity near
the DBS electrode, it can also increase regional output by directly activating axons of local
projection neurons. Additionally, surrounding neuropil can be stimulated to different extents
as the DBS intensity fades radially from the electrode placement. These secondary effects of
the high frequency DBS intensity may be analogous to those primarily produced by lowfrequency DBS which is hypothesized to activate neurons (cell bodies, axons or both) by
enhancing their firing and responsivity to other neural input.

Since the early 2000's, the posterior hypothalamus has been targeted with high frequency
DBS as treatment of cluster headaches, facial pain syndromes, and behavior disorders. For
example, low frequency (15 Hz) posterior hypothalamic DBS with a relatively low amplitude
and long pulse width (0.10.4 V, 450 s) was applied for treatment of drug-resistant
aggressiveness in a mentally retarded patient. In contrast, the hypothalamus as a novel target
for low frequency DBS in humans has been reported only recently in case reports. Relevant
to our preclinical study, hypothalamic DBS effecting changes in body weight in humans was
described for a single morbidly obese male. In this case report, weight loss of 6% body
weight over 5 mo without changes in diet or exercise habits was observed only with low
frequency DBS (50 Hz, 3.04.0 V, 210 s) in the VMH area. No such effects were observed
with high frequency (130 Hz) over 6 mo. When the low frequency VMH-DBS was turned
off, the subject regained the weight he had previously lost, suggesting reversibility of the
DBS effect. Another case report on the failure of DBS for weight control in a morbidly obese
individual mostly described an adverse effect associated with the procedure. Neither of these
case reports explicitly discussed their applied DBS parameters or their postulated effects in
terms of weight control.
Accurate targeting of DBS electrodes to deep structures of the brain, e.g., the
hypothalamus, is challenging since small initial trajectory errors are magnified as the depth of
insertion increases. Also, transiting across cerebral ventricle membranes enroute to
hypothalamus can cause distortion in the trajectory. We significantly obviated those issues
with the use of a guide tube to support the minielectrode. The guide tube was implanted with
a stainless steel stylet (removed after securing the guide tube) which passed through the
trajectory just proximal to the target without mechanical deformation. The electrode was then
passed through the guide tube to reach the intended target. Intraoperative fluoroscopy was
then used for target confirmation and to make 12 mm adjustments in trajectory depth and
final positioning (ventral) of the electrode in the target region.
Our prior experience with neurosurgical stereotactic methods, instrumentation and MR
imaging for implementing DBS in the human facilitated their adaptation to the minipig brain.
We achieved precise VMH targeting as evidenced by the DBS post-operative MR imaging
and post-mortem histology. No significant adverse behavioral effects were observed
following the DBS surgery or throughout the DBS stimulation period. The DBS IPG that was
subcutaneously implanted in the dorsolateral shoulder region allowed for accessible
programming in the conscious and unrestrained animal. Thus, the adaptation of DBS clinical

instrumentation (clinical IPG, and connector) could be coupled with an electrode scaled to
size for the minipig hypothalamus (electrode diameter: 0.64 mm/animal vs 1.5 mm/clinical).
However, the selection of the initial DBS parameter settings was not evidence-based since
the effects of systematic variations of low frequency VMH-DBS stimulation and pulse widths
over long periods of time (wks, mo) in any animal species had not been previously described.
Accordingly, we selected the stimulation frequency of 50 Hz, based on experimental
literature of VMH electrical stimulation showing that a majority of studies with 50 Hz (range:
10100 Hz) resulted in either a reduction of food intake or an increase in energy utilization.
We activated the most distal electrodes with a monopolar configuration to presumably affect
a larger VMH region. As our main read-outs on VMH-DBS efficacy were the amount of daily
food consumption and weekly weighing, we needed to maintain the same DBS settings for at
least 2 wks to determine any significant change. Since our initial DBS settings were without
apparent effect for 12 wks, we increased the amplitude to 1 mA and then observed a reduced
increase in weight (<1 kg) from the previous wk in 2 of 4 animals, suggestive of a DBS
effect. Insofar as all animals appeared to well-tolerate the VMH-DBS, we increased the
current to 1.5 mA in all animals which was then continued for the second mo of stimulation.
This resulted in a charge density of 76 C/cm2/phase. Although that value was higher than
the 30 C/cm2/phase limit recommended for clinical applications with the commercial
electrodes, it was within a no tissue damage-zone derived from multiple non-DBS electrical
stimulation and DBS clinical studies. In clinical applications, combinations of low frequency
(5060 Hz) and long pulse width (400507 s) will not likely be a safety issue concern
insofar as the larger surface area of clinically used DBS electrodes (0.06 cm2) yields a charge
density within the recommended safety zone.

The present study design with the read-out of weight change did not allow for accurate
assessments of alternating short periods of 12 wks with on- and off-DBS. However, it was
not our intention to induce significant weight fluctuations acutely with DBS since such short
term effects may not extrapolate to a safe, long term human application. The overall effect of
the VMH-DBS treatment for a 2 mo period of continuous stimulation did result in a
significantly lower weight gain of 10% relative to weight-matched DBS-off controls for
the same period of extra-calorie intake. We tentatively attribute this lower weight gain to an
increase in metabolic rate insofar as all animals ate their entire daily food ration within 3040

min of presentation throughout the 2 mo DBS period. This study was not designed to measure
changes in metabolic rate, but now having established an effective set of VMH-DBS
parameters, future studies employing indirect calorimetry to measure increases in metabolic
rate would provide confirmatory data. Further, the use of that method would be ideal for
conducting parameter sweeps of DBS settings that can be readily evaluated for their efficacy
and reversibility. A VMH DBS-induced increase in metabolic rate has some support from
prior experimental and clinical studies. In rodents, electrical stimulation in the hypothalamus
resulted in metabolic rate increases. In humans, a case report showed that a male subject lost
weight during VMH DBS without changing his eating habits or his physical activity,
suggestive of an increase in metabolic rate.
In conclusion, this study has demonstrated that clinical neurosurgical instrumentation and
methods can be applied to preclinical studies in a large animal model. We also demonstrated
that DBS leads and electrodes can be scaled down to appropriate size for use in the minipig
brain. The DBS that was targeted to the ventral hypothalamus of the Gottingen minipig
effected a reduction in weight gain under conditions of extra calorie intake. These results
show that DBS can provide CNS neuromodulation within the hypothalamus and provide
preclinical evidence in support for this DBS application as a potential strategy for the
treatment of humans with morbid obesity.
Human Studies of DBS in the Hypothalamus
Evidence from animal models and lesioning studies led to two studies in which the VMH
was targeted in 1 patient for obesity

with no effect on weight loss, though vivid

autobiographical memories were enhanced, presumably by forniceal activation. Confirming

the untoward effects of VMH stimulation, Wilent et al. exemplified the adverse psychogenic
manifestations associated with this region when panic-attacks were induced in a graded
manner with electrical stimulation of the VMH. These unwanted adverse effects have since
waned interest in targeting the VMH for obesity.
In our FDA-approved pilot study of 3 patients with refractory morbid obesity (all of
whom had failed gastric bypass), we were able to demonstrate increases in resting metabolic
rate in 2 of 3 patients using monopolar stimulation. Interestingly, traditional programming
parameters as used for DBS in movement disorders did not result in changes in metabolism.
Biochemical profiles of hormones involved in obesity including T4, T3, insulin growth factor
(IGF), leptin, AGRP, ghrelin, and NPY were all measured at baseline and after LHA-DBS

with no change following stimulation. The finding that there was no change in these
hormonal markers implies two possibilities: the fact that DBS may work as a modulator
independent of hormonal changes or the fact that long-term follow-up is needed to determine
whether changes do occur. Long-term programming at the RMR-optimized settings resulted
in a decreased urge to eat as well as increased subjective feelings of energy that resolved
when the stimulator was turned off, even in a blinded fashion. These findings suggest that
DBS for obesity may involve distinct neural networks that need further investigation to
determine optimal stimulation settings. Neuropsychological scales were also administered to
all 3 patients that measured binge eating, body image, and feelings of hunger. Binge eating
was reduced in one
patient, and importantly this same patient reported reduced feelings of hunger. The two
remaining patients while not showing any changes in binge eating behavior or feelings of
hunger did show improvements regarding body image. While the weight lost by our patients
was not significant, our pilot study was able to confirm the safety of LHA stimulation with
few adverse events, laying groundwork for future studies.
Nucleus Accumbens
The significant role of the nucleus accumbens in reward processing is undisputed. The
NAc has been targeted in both animal and human studies, with the latter focusing on
neuropsychiatric conditions such as MDD, OCD, and Tourettes as well as addiction. In
recent years, significant advances have shown that the NAc is made of two distinct regions:
the core and the shell that subserve specific functions. The shell of the accumbens receives
afferents from the ventral medial prefrontal cortex as well as the VTA, areas that have been
implicated in drug-seeking behavior, while the core is innervated predominantly by the
substantia nigra, involved with motor planning and execution . These differences in
functionality between the core and shell are recapitulated by their efferent projections, with
the former projecting to premotor and supplementary motor cortices and the latter to
subcortical motor areas, the LHA, and amygdala . In rodent models, it was found that a small
area in the rostrodorsal medial shell of the NAc by injection of opioid or endocannabinoid
agonist significantly increased both liking (orofacial reactions) and wanting for food
rewards. Surprising, however, was that opioid or endocannabinoid agonists into areas outside
this hotspot increased wanting for food without changing the absolute number of liking
orofacial reactions. This finding suggests that the dissociation between liking and

wanting may be applicable to humans. In parallel to drug addicts, obese individuals may
simply overeat not because they like food more, but simply crave it more than normal
individuals when exposed to palatable food or food-related cues. It also highlights the
importance of any future study targeting the NAc for obesity, as the goal is to modulate
craving without changing the hedonic experience of food.

Future
Optogenetics
Optogenetics refers to the integration of optics and genetics to achieve gain- or lossof-function of well-defined events within specific cells of living tissue. Optogenetics is
currently being utilized by numerous scientists to probe how the brain works and have
learned such information as which cells in the brains reward pathway become hijacked by
cocaine, as well as how deep brain stimulation relieves the symptoms of Parkinson Disease.
Obesity presents another area to focus the use of optogenetic techniques. Gradinaur et
al. stated that optogenetics, in principle, could be used to systematically probe specific
circuit elements with defined frequencies of true excitation or inhibition in freely behaving
parkinsonian rodents. Optogenetics has been used to study obsessive-compulsive behavior
in rats, a disorder which may be treated by DBS. In the study, a drop of water was dropped
onto the rodents noses after a tone was sounded due to the fact that oCD rats tend to overgroom.
Through the use of optogenetics, the MIT team found that these mutant animals fail
to keep the firing of so-called medium spiny neurons (MSNs) in check, because theyre
apparently deficient in fast-striking striatal interneurons (FSIs) and demonstrated that
normal inhibitory activity and normal grooming behavior could be restored almost
immediately. Optogenetics is also being used to discover the brains role in obesity. A recent
study in optogenetics has found that stimulation of pro-opiomelanocortin (PoMC) and agoutirelated peptide (AGRP) neurons acutely regulates feeding behavior in mice. It has been
found that the PoMC neurons play an important role in maintaining normal feeding behavior
and energy homeostasis. When the PoMC was activated by light, it resulted in a frequency-

dependent decrease in food intake, which required downstream melanocortin receptor activity
and light activation of AGRP neurons, and resulted in an acute, frequency-dependent increase
in food intake that was independent of melanocortin signaling.
The research team used this method to evaluate changes in regional brain glucose
metabolism in response to optogenetic stimulation of the NAc. Thus, as a robust research
technique with proven use in the study of neural disorders, optogenetics will likely become a
mainstay of obesity research. Understanding the mechanisms underlying disorders of obesity
is essential to developing targeted therapies, such as DBS.

Conclusions
With the large impact of obesity both on the health of individuals and the healthcare
system, novel therapies targeting underlying pathology must be developed and explored.
Current methods of obesity management can have several drawbacks.
Several investigations using neuromodulation and deep brain stimulation (DBS) have
yielded encouraging results, warranting further investigation the treatment of humans.
Currently, three human trials (Table 1) are ongoing and will likely represent the fullest
evidence on the role of DBS in the human treatment of obesity at the time of their respective
completions. In addition to DBS, other methods such as optogenetic may be employed in the
future as the ability to selectively modulate subpopulations of neurons.
With growing advances in uncovering the neural and homeostatic mechanisms
underlying disorders of obesity, novel treatments including neuromodulation and DBS will
hopefully emerge as effective tools in armamentarium against these disorders.
In the last several decades, the understanding of feeding physiology has grown
considerably more complex. But while the neural networks that govern feeding have become

clearer, treatment of pathological overeating that can lead to obesity and obesity-related
comorbidities has stalled. In addition, the surgical options (gastric bypass, banding) are
available to patients when conservative measures are not without adverse effects. The safety,
reliability, of

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