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Weight Loss Patent Abstract
Apparatus and methods for treating obesity using chronic cervical
vagal nerve stimulation (cVNS) of the left vagus trunk are disclosed.
Four men and ten women, average age 46 years (SD.+-.10) were treated
with output current typically 0.75 mA, pulse frequency 30 Hz and
width 250 or 500 .mu.s, and duty cycle of 30 s power per five minutes.
Mean intake weight was 91 kg (SD.+-.27, range 46 to 137 kg) with
body mass index (BMI) 43 kg/m.sup.2 (SD.+-.5, range 18 to 49 kg/mn.sup.2).
After 6-12 months, obese patients had marked weight loss while normal
weights were maintained. Decrease in BMI was consistently proportional
to initial BMI. Average weight loss at one year was 7 kg (SD.+-.3,
range -6 to +24) with mean drop in BMI of 2 kg/m.sup.2 (SD.+-.3,
range -2 to +8)k. All patients denied any major dieting or exercise.
Weight Loss Patent Claims
1. A method of treating obesity in a patient comprising chronic
cervical vagus nerve stimulation (cVNS) with an electrical signal
applied directly or indirectly to the vagus nerve in the neck of
the patient.
2. The method of claim 1 comprising unilateral stimulation of the
trunk of the left vagus nerve in the neck of the patient.
3. The method of claim 1, further comprising implanting subcutaneously
within the patient a signal generator operably coupled to one end
of an electrical lead that is operably coupled at the other end
to the vagus nerve for generating and applying said electrical signal
thereto.
4. The method of claim 3, wherein the signal generator is implanted
under the skin of the chest of the patient.
5. The method of claim 3, wherein the signal generator is implanted
under the skin of the neck of the patient.
6. The method of claim 3, wherein the signal generator is implanted
under the skin of the upper arm of the patient.
7. The method of claim 1, wherein the electrical signal has at
least one variable parameter selected from the group consisting
of current amplitude, pulse width, pulse frequency, and a duty cycle
of alternating intervals with power on and power off.
8. The method of claim 1, wherein the electrical signal is applied
for a substantially continuous period of at least six months.
9. The method of claim 8, wherein the electrical signal is applied
for a substantially continuous period of greater than two years.
amplitude between about 0.5 mA to about 1.5 mA, a stimulation frequency
between about 10 Hz and 100 Hz, a pulse width in the range of 100
microseconds to 1000 microseconds (.mu.s), and a duty cycle of intervals
with power on for about 10 s to about 100 s and power off for the
remainder of each 3 minute to 10 minute period of treatment.
11. The method of claim 10, wherein said electrical signal comprises
an output current of about 0.75 mA, a stimulation frequency of about
30 Hz, a pulse width of either about 250 microseconds or about 500
microseconds (.mu.s), and a duty cycle intervals with power on for
about 30 s and power off for the remainder of each 5 minute period
of treatment.
12. The method of claim 1, wherein said patient has a body mass
index (BMI) greater than 25.
13. The method of claim 12, wherein said patient has a BMI greater
than 30.
14. The method of claim 13, wherein said patient has a BMI greater
than 40.
15. A method of treating obesity in a patient, said method comprising:
implanting subcutaneously within the patient a device comprising
an electrical signal generator, and at least one electrical lead
having at least one proximal electrical connector and one distal
nerve electrode; operably connecting a proximal electrical connector
of the electrical lead to the signal generator, operably coupling
a distal nerve electrode of the electrical lead to the trunk of
the left vagus nerve in the neck of the patient, and activating
the signal generator to chronically stimulate the vagus nerve with
an electrical signal for a period of at least six months, wherein
group consisting of current amplitude, pulse width, pulse frequency,
and a duty cycle of alternating intervals with power on and power
off, said device further comprises at least two predetermined programs
for controlling at least one parameter of said electrical signal
according to a programmed regimen that cannot be altered while said
device is implanted in the patient; and said signal generator is
activated by an externally activated control system that selectively
activates each of said at least two predetermined programs; whereby
said apparatus provides vagus nerve stimulation which is controllable
by said externally activated control system.
16. The method of claim 15, wherein said externally activated control
system is selected from the group consisting of a magnetically activated
control system, a mechanically activated control system that responds
to tapping on the skin near said device, and an acoustically activated
control system that responds to an audio or supersonic signal.
17. The method of claim 15, wherein each of said at least two predetermined
programs to control parameters of said electrical signal produces
an electrical signal that has an output current amplitude between
about 0.5 mA to about 1.5 mA, a stimulation frequency between about
10 Hz and 100 Hz, a pulse width in the range of 100 microseconds
to 1000 microseconds (.mu.s), and a duty cycle of intervals with
power on for about 10 s to about 100 s and power off for the remainder
of each 3 minute to 10 minute period of treatment. predetermined
programs to control parameters of said electrical signal produces
an electrical signal that comprises an output current amplitude
of about 0.75 mA, a stimulation frequency of about 30 Hz, a pulse
width of either about 250 microseconds or about 500 microseconds
(.mu.s), and a duty cycle of intervals with power on for about 30
s and power off for the remainder of each 5 minute period of treatment.
20. Apparatus for treating obesity in a patient, said apparatus
comprising: a device suitable for implanting subcutaneously in the
patient and at least one implantable electrical lead, said device
comprising an electrical signal generator, said electrical lead
having at least one proximal connector for operably connecting said
electrical lead to said signal generator and at least one distal
nerve electrode for operably coupling said electrical lead to a
trunk of the vagus nerve in the neck of the patient; said signal
generator comprising a power source suitable to chronically stimulate
said trunk of the vagus nerve with an electrical signal while implanted
for a period of at least one year, said electrical signal having
at least one variable parameter selected from the group consisting
of current amplitude, pulse width, pulse frequency, and a duty cycle
of alternating intervals with power on and power off, said device
further comprising at least two predetermined programs for controlling
at least one parameter of said electrical signal according to a
programmed regimen that cannot be altered while said device is implanted
in the patient; said signal generator being activated by an externally
activated control system that selectively activates each of said
at least two predetermined programs; controllable by said externally
activated control system.
21. The apparatus of claim 20, wherein said external control system
is selected from the group consisting of a magnetically activated
control system, a mechanically activated control system that is
adapted to be activated in response to tapping on the skin near
said device, and an activation system responsive to an audio or
supersonic signal generated by an external control component.
22. The apparatus of claim 21, wherein each of said at least two
predetermined programs to control parameters of said electrical
signal produces an electrical signal that has an output current
amplitude between about 0.5 mA to about 1.5 mA, a stimulation frequency
between about 10 Hz and 100 Hz, a pulse width in the range of 100
microseconds to 1000 microseconds (.mu.s), and a duty cycle of intervals
with power on for about 10 s to about 100 s and power off for the
remainder of each 3 minute to 10 minute period of treatment.
24. The apparatus of claim 23, wherein at least one of said at
least two predetermined programs to control parameters of said electrical
signal produces an electrical signal that has an output current
amplitude of about 0.75 mA, a stimulation frequency of about 30
Hz, a pulse width of either about 250 microseconds or about 500
microseconds (.mu.s), and a duty cycle of intervals with power on
for about 30 s and power off for the remainder of each 5 minute
period of treatment.
Weight Loss Patent Description
[0001] This application claims the benefit of U.S. Provisional Patent
Application No. 60/439,824 filed Jan. 14, 2003, the entirety of
which is hereby incorporated herein by reference for all purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to a novel method for inducing
weight loss in a patient by stimulating the vagus nerve in the patient's
neck.
BACKGROUND OF THE INVENTION
[0003] Obesity is a major public health concern afflicting 300
million people worldwide. Serious and common complications from
obesity include hypertension, diabetes, cardiovascular disease,
dyslipidernia, osteoartbritis, sleep apnea, etc. Standard treatments
include diet, exercise, behavioral therapy, and medications. Most
patients do not succeed at maintaining normal weight. In some with
disabling and life-threatening obesity, gastric surgery provides
a last resort, despite invasiveness, potential for serious complications,
and cost. More effective and novel approaches to the treatment of
obesity are needed. One largely untapped focus is the brain itself.
[0004] In animal studies, stimulation of the vagus nerve in the
abdomen of healthy male rabbits, by electrical pacing during a month,
reduces food intake and body mass. Sobocki. J., et al., Microchip
vagal pacing reduces food intake and body mass. Hepatogastroenterology
48:1783-1787 (2001). Stimulation of the human vagus nerve to treat
eating disorders also has been described. See, for instance, U.S.
Pat. No. 6,609,025 ("the '025 patent") to Barrett et al.,
assigned to Cyberonics, Inc., and patents discussed therein. [0005]
U.S. Pat. No. 5,263,480 to J. Wernicke et al. ["the '480 patent,"
which issued on application Ser. No. 07/926,915, filed Aug. 7, 1992,
which was a continuation of application Ser. No. 07/649,618 of the
same inventors filed Feb. 1, 1991, now U.S. Pat. No. 5,188,104],
assigned to the same assignee as [Barrett et al.], discloses treatment
for eating disorders including obesity and compulsive overeating
disorder by selectively applying modulating electrical signals to
the patient's vagus nerve, preferably using an implanted neurostimulator.
Modulating signals may be used to stimulate vagal activity to increase
the flow of neural impulses up the nerve, or to inhibit vagal activity
to block neural impulses from moving up the nerve, toward the brain,
for producing excitatory or inhibitory neurotransmitter release.
Barrett et al. in the '025 patent further characterize the teachings
of the '480 patent as follows: [0006] Both of these cases of modulating
the electrical activity of the vagus nerve have been termed vagus
nerve stimulation, or VNS. The '480 patent theorized that VNS could
be used for appetite suppression by causing the patient to experience
satiety, a sensation of `fullness` of the stomach which would result
in decreased food consumption and consequent weight reduction. For
example, the stimulus generator of the neurostimulator is implanted
in a convenient location in the patient's body, attached to an electrical
lead having a nerve electrode implanted on the vagus nerve or branch
thereof in the esophageal region slightly above the stomach. If
the patient's food consumption over a given period exceeded a predetermined
threshold level, detected and measured for example by sensing electrodes
implanted at or near the esophagus, the stimulus generator is triggered
to apply VNS and thereby normal waking hours except in periods of
prescribed mealtimes, or is applied as a result of patient intervention
by manual activation of the stimulus generator using external magnet
control.
[0007] Barrett et al. in the '025 patent also characterize the
disclosure of U.S. patent application Ser. No. 09/346,396 ("the
'396 application," filed Jul. 1, 1999 (now U.S. Pat. No. 6,587,719
to Barrett et al., also assigned to Cyberonics, Inc.), as follows:
[0008] The aforementioned '396 application discloses a method of
treating patients for obesity by bilateral stimulation of the patient's
vagus nerve (i.e., bilateral VNS) in which a stimulating electrical
signal is applied to one or both branches of the vagus. The parameters
of the signal are predetermined to induce weight loss of the patient.
The signal is preferably a pulse signal applied at a set duty cycle
(i.e., its on and off times) intermittently to both vagi. In any
event, VNS is applied at a supra-diaphragmatic position (i.e., above
the diaphragm) in the ventral cavity. The electrical pulse stimuli
are set at a current magnitude below the retching level of the patient
(e.g., not exceeding about 6 milliamperes (mA), to avoid patient
nausea) in alternating periods of continuous application and no
application. Pulse width is set at or below 500 microseconds (.mu.s),
and pulse repetition frequency at about 20-30 Hz. The on/off duty
cycle (i.e., first period/second period of the alternating periods)
is programmed to a ratio of about 1:1.8. The neurostimulator, which
may be a single device or a pair of devices, is implanted and electrically
coupled to lead(s) having nerve electrodes implanted on the right
and left branches of the vagus. [0009] [i].sub.n dog tests conducted
by the applicants herein, the dietary pattern included twice-a-day
feedings of approximately 400 grams of solid food with one scoop
of soft meat product added to make the food more edible. During
the surgical procedure, a threshold referred to herein as the retching
threshold was documented while the animal was under anesthesia,
based on the threshold value of the stimulus output current of the
device at which the animal exhibited a retching or emetic response.
The amount of current was adjusted to determine this threshold.
Other parameters were left fixed at a frequency of 30 Hertz (Hz),
a pulse width of 500 milliseconds (ms), and an on/off cycle of one
minute on and 1.8 minutes off.
[0010] Barrett et al. in the '025 patent disclose yet another variation
of treatment of obesity by vagus nerve stimulation, using bilateral
sub-diaphragmatic stimulation, which the '025 patent characterizes
as follows: [0011] According to the present invention, a method
of treating patients for obesity comprises unilateral or bilateral
stimulation of the left and right vagi at a sub-diaphragmatic position
(i.e., below the diaphragm) in the ventral cavity, rather than at
a supra-diaphragmatic position as taught by the '396 application.
The stimulating electrical signal is preferably applied to the vagus
two to three inches below the diaphragm, and may be applied either
synchronously or asynchronously to both the right and left branches,
preferably in the form of a series of pulses applied intermittently
to both branches according to a predetermined on/off duty cycle.
The intermittent application is preferably chronic, rather than
acute. However, continuous application or acute application by bilateral
stimulation of the right and left vagi or unilateral contemplated.
[0012] The sub-diaphragmatic application of VNS may have an enhanced
effect in inducing satiety in the patient, being in closer proximity
to the stomach itself. Certainly, in the case of neurostimulator
device implantation superficially in the abdominal region of the
patient, the sub-diaphragmatic application has an advantage of enabling
shorter leads for the nerve electrode(s). Additionally, application
of the neurostimulator may be more easily accomplished with this
approach as opposed to a supra-diaphragmatic approach which requires
accessing the vagi in the chest cavity.
[0013] Accordingly, as taught, for instance, by Barrett et al.
in the '025 patent, above, implantation of the devices used to provide
the electrical pulses to the vagus nerve in abdomen, or supradiaphragmatically
or sub-diaphragmatically, typically requires an invasive implantation
procedure exposing the patient to risks associated with such invasive
procedures. Thus, methods of inducing weight loss in a patient that
do not require such invasive surgical implantation procedures are
desired.
[0014] In addition, none of the patents discussed by Barrett et
al. in the '025 patent, nor the '025 patent itself, discloses any
clinical results of testing the disclosed methods on human subjects.
Greene et al., Perspectives on the metabolic management of epilepsy
through dietary reduction of glucose and elevation of ketone bodies,
J. Neurochem. 86:529-537 (2003), discloses (at p. 533) that vagal
nerve stimulation is a novel therapy that significantly reduces
seizure frequency in patients with refractory seizures and asserts
that "(the vagus nerve is also known to affect eating behavior
and vagal nerve stimulation has been used to treat morbid obesity
(Roslin and Kurian 2001)", where the full citation for the
disclosure of "Roslin and Kurian 2001" is given as "Roslin
M. and Kurian M. (2001) The use of electrical "Roslin M"
is presumably Mitchell S. Roslin, one of the inventors of the '025
patent.
[0015] The above cited publication by Roslin and Kurian (Epilepsy
Behav. 2, S11-S16, 2001) teaches that [0016] [o]besity is actually
defined as having excess adiposity or fat tissue. Since it is more
practical to measure height and weight rather than amount of fat,
determination of level of obesity is generated using these numbers.
The most accurate numerical assessment is obtained by determining
the body mass index (BMI). This number is derived by dividing weight
in kilograms (or pounds) by height in meters squared (or feet).
A BMI of more than 40 is considered morbidly obese. As an example,
an individual who is 5 feet 10 inches tall (177.8 cm) and weighs
280 pounds (127 kg) has a body mass index of 40. A patient with
a BMI of 25 to 30 is considered overweight; 30 to 35 corresponds
to stage I obesity, 35 to 40 to stage II obesity, and >40 to
stage m or morbid obesity.
[0017] Roslin and Kurian further disclose the basis for their approach
toward developing a method of treating obesity using VNS, as follows:
[0018] The combination of the anatomic relationship of the vagus
nerve to the GI tract and the above physiologic experiments provided
the rationale for the investigation of electrical stimulation of
the vagus nerve for obesity and development of a preclinical animal
experimental program. Despite this appealing theory, one major factor
needed to be considered prior to beginning investigation. During
the numerous years of clinical experience with vagus nerve stimulation
(VNS) for epilepsy, no weight loss was reported, other than a few
anecdotal reports. Thus several modifications were necessary. Because
we would be best to be in closer proximity to the gastroesophageal
junction. Such positioning would avoid stimulation of fibers that
join the trunk from the heart and lungs and, we speculated, have
a greater likelihood of stimulating our target fibers. Additionally,
positioning away from the neck and the recurrent laryngeal nerve
would allow the delivery of higher levels of current that could
be necessary to stimulate these unmyelinated fibers. Finally, because
the right and left trunks have different distributions in the abdomen
and the contribution of both could be essential, we chose to investigate
bilateral stimulation of the vagus nerve.
[0019] Following a preclinical study which Roslin and Kurian considered
to study suggest that the use of bilateral VNS is effective in changing
eating behavior, with a corresponding weight loss in a canine animal
model, the authors describe the initiation of a human "pilot"
program, as follows: [0020] The results of the canine study and
the known safety of VNS in humans served as the basis for initiating
a phase I study. Enrollment began during the summer of 2000, and
clinical implantation has started. Thirty patients will be enrolled,
all of whom will have their generators activated. To control for
placebo, 60% of the patients will have their NCP systems activated
2 weeks after surgery, and those of the other 40% will be activated
14 weeks after surgery. Initial implantation has been performed
with an open technique to ensure proper lead placement. Laparoscopic
and thoracoscopic techniques will be used in future implants. Because
obesity is a chronic disease, long-term data are mandatory before
results can be analyzed. Preliminary data may be available late
in 2001. experience with vagus nerve stimulation (VNS) for epilepsy,
the disclosure of Roslin and Kurian contemplates a need to stimulate
the small unmyelinated C fibers of the nerve and, hence, that VNS
stimulation for treating obesity would best be in closer proximity
to the gastroesophageal junction, thereby avoiding stimulation of
fibers that join the trunk from the heart and lungs and allowing
the delivery of higher levels of current that could be necessary
to stimulate these unmyelinated fibers. Finally, because the right
and left trunks have different distributions in the abdomen and
the contribution of both could be essential, these authors chose
to investigate bilateral stimulation of the vagus nerve in an animal
model and thereafter in human clinical testing.
[0021] U.S. Pat. No. 6,611,715 ("the '715 patent") to
Boveja, issued Aug. 26, 2003, discloses apparatus and methods for
neuromodulation therapy for obesity and compulsive eating disorders
using an implantable lead-receiver and an external stimulator. According
to Boveja in the '715 patent: [0022] [a]system and method of neuromodulation
adjunct (add-on) therapy for obesity and compulsive eating disorders,
comprises an implantable lead-receiver and an external stimulator.
Neuromodulation is performed using pulsed electrical stimulation.
The external stimulator contains a power source, controlling circuitry,
a primary coil, and predetermined programs which control the different
levels of therapy. The primary coil of the external stimulator inductively
transfers electrical signals to the lead-receiver, which is also
in electrical contact with the left vagus nerve. The external stimulator
emits electrical pulses to stimulate the vagus nerve according to
a predetermined program. In a second mode of operation, an operator
may manually override the predetermined sequence of stimulation.
The protected. The external stimulator may also be equipped with
a telecommunications module to control the predetermined programs
remotely. Further according to Boveja in the '715 patent: [0023]
Apparatus and method for neuromodulation, in the current application
has several advantages over the prior art implantable pulse generator.
The external stimulator described here can be manufactured at a
fraction of the cost of an implantable pulse generator. The therapy
can be freely applied with [sic, without] consideration of battery
depletion. Surgical replacement of pulse generator is avoided. The
programming is much simpler, and can be adjusted by the patient
within certain limits for patient comfort. And, the implanted hardware
is significantly smaller.
[0024] U.S. Pat. No. 6,449,512 ("the '512 patent") to
Boveia, issued Sep. 10, 2002, discloses apparatus and methods for
treatment of urological disorders using a "programmerless"
implantable pulse generator system, which is characterized as follows:
[0025] System and method of neuromodulation therapy for urinary
incontinence disorders comprises a lead to selectively stimulate
the sacral plexus and an implantable pulse generator for providing
the appropriate pulses. The implantable pulse generator having prepackaged/predetermined
programs stored in the memory of the pulse generator, and means
for accessing these with an external magnet. The pulse generator
adapted to selectively activate predetermined programs with the
external magnet, thereby eliminating the need for an external programmer.
The elimination of the external programmer resulting in significant
cost reduction with essentially the same functionality. vagus nerve
stimulation, Neurology 59:463-464 (2002) reported on weight loss
in patients who underwent VNS implantation for treatment of epilepsy
for up to two years, as follows: [0026] Of the 27 patients for who
complete data were available, 17 had lost weight. Weight in the
remaining patients fluctuated, without a specific pattern toward
weight gain. [0027] Eight patients (25%) (four men, age range 18-41)
had significant weight loss of more than 5% of body weight, and
of these, five lost more than 10% of body weight. Two patients lost
more than 5% of the weight in the first 6 months, four at 1 year,
and six in 2 year. More than 10% of weight loss was seen in one
patient after 6 months, in two patients after 1 year, and in three
patients after 2 years of VNS (figure [captioned "Percentage
of weight loss vs months of follow-up for each patient found with
this characteristic side effect."]). In none of our patients
was VNS discontinued or the generator removed due to weight loss.
Burneo et al. concluded that, [0028] "[a]lthough weight loss
may be multifactorial, its occurrence in our patients undergoing
VNS implantation appears causally related. This may be due to decreased
appetite, resulting in changes in eating behaviors, or to gastrointestinal
side effects, such as dyspepsia, previously reported as a side effect
of VNS [citations omitted]. Even though this was not a control-case
study, patients and physicians should be aware of weight loss as
an associated phenomenon of VNS stimulation." Accordingly,
the report of Burneo et al. does not disclose whether the patients
who lost weight in this epilepsy study were obese or of normal weight
and does not teach or suggest should be aware of weight loss as
an associated phenomenon [or "characteristic side effect"]
of VNS stimulation."
[0029] It is known that, in the human body the innervation of the
right and left vagus nerves is different. The innervation of the
right vagus nerve is such that stimulating it results in profound
bradycardia (slowing of the heart rate). The left vagus nerve has
some innervation to the heart, but mostly innervates the visceral
organs such as the gastrointestinal tract. It is further known that
stimulation of the left vagus nerve does not cause substantial slowing
of the heart rate or cause any other significant deleterious side
effects.
SUMMARY OF THE INVENTION
[0030] The present invention is based in part on the surprising
observation by the inventors that chronic cervical vagus nerve stimulation
(cVNS) of the left vagal trunk for extended periods of time, under
conditions similar to those used for treatment of epilepsy, effected
a consistent and reliable reduction of weight, as described herein
below. Weight loss occurred gradually over one year and some of
the most obese patients continued to lose weight thereafter. The
amount of weight loss was proportional to the initial severity of
the obesity.
[0031] Accordingly, the present invention relates to methods of
inducing weight loss in patients through the stimulation of the
vagus nerve in the patient's neck. In one embodiment an obese patient
is treated with chronic vagus nerve stimulation in the neck until
the patient achieves and maintains an amount of weight loss appropriate
for such patient. In one embodiment, a neurostimulator (preferably
but not necessarily implantable) is employed to deliver electrical
impulses to the vagus nerve either unilaterally to one branch or
bilaterally to both branches of the vagus nerve simultaneously or
alternately. In some embodiments, the method of the invention is
used to treat obesity in patients, without regard to whether the
obesity is related to a compulsive eating disorder. obesity in a
patient comprising chronic cervical vagus nerve stimulation (cVNS)
with an electrical signal applied directly or indirectly to the
vagus nerve in the neck of the patient. In some embodiments this
method comprises unilateral stimulation of the trunk of the left
vagus nerve in the neck of the patient Some embodiments of this
method further comprise implanting subcutaneously within the patient
a signal generator operably coupled to one end of an electrical
lead that is operably coupled at the other end to the vagus nerve
for generating and applying the electrical signal to the vagus nerve.
Advantageously, the signal generator used in the invention method
is implanted under the skin of the chest of the patient but also
may be implanted under the skin of the neck or the upper arm of
the patient.
[0032] In this method, the electrical signal may be applied for
a substantially continuous period of at least six months and, preferably,
the electrical signal is applied for a substantially continuous
period of greater than two years. Further, the electrical signal
may have at least one variable parameter selected from the group
consisting of current amplitude, pulse width, pulse frequency, and
a duty cycle of alternating intervals with power on and power off.
In particular embodiments, the electrical signal may have an output
current amplitude between about 0.5 mA to about 1.5 mA, a stimulation
frequency between about 10 Hz and 100 Hz, a pulse width in the range
of 100 microseconds to 1000 microseconds (.mu.s), and a duty cycle
of intervals with power on for about 10 s to about 100 s and power
off for the remainder of each 3 minute to 10 minute period of treatment.
Advantageously, the electrical signal has an output current amplitude
of about 0.75 mA, a stimulation frequency of about 30 Hz, a pulse
width of either about 250 microseconds or about 500 microseconds
(.mu.s), and a duty cycle intervals with power on for about 30 s
and power off for the remainder of each 5 minute period of treatment.
[0033] index, BMI) proportional to the weight (BMI) of the patient
at the beginning of treatment The method also generally produces
weight loss only in obese patients. Advantageously, therefore, the
method is helpful for a patient having a body mass index (BMI) greater
than 25, greater than 30, or even greater than 40. As noted above,
a patient with a BMI of 25 to 30 is considered overweight; 30 to
35 corresponds to stage I obesity, 35 to 40 to stage II obesity,
and over 40, to stage III or morbid obesity.
[0034] In another aspect the invention provides a method of treating
obesity in a patient which comprises implanting subcutaneously within
the patient a device comprising an electrical signal generator and
at least one electrical lead having at least one proximal electrical
connector and one distal nerve electrode. This method further comprises
operably connecting a proximal electrical connector of the electrical
lead to the signal generator, either before or after implanting
the signal generator or the lead, and operably coupling a distal
nerve electrode of the electrical lead to the trunk of the left
vagus nerve in the neck of the patient. The method then involves
activating the signal generator to chronically stimulate the vagus
nerve with an electrical signal, advantageously for a period of
at least one year.
[0035] This method of the invention utilizes an implantable pulse
generator system similar to that described in U.S. Pat. No. 6,449,512
Boveja for treatment of urological disorders, which has been called
a "programmerless" pulse generator system. This implantable
pulse generator comprises prepackaged/predetermined programs stored
in a memory component of the pulse generator, and an external control
system for accessing these with an external control element, such
as a magnet. In particular, the electrical signal used in the present
invention method typically has at least one variable parameter selected
from the group consisting of current amplitude, pulse width, pulse
frequency, and a duty cycle of alternating intervals with power
on and power off. The device also further comprises at least two
predetermined programs for that cannot be altered while the device
is implanted in the patient. Further, the signal generator is activated
by an externally activated control system that selectively activates
each of the predetermined programs, whereby the implanted device
provides vagus nerve stimulation which is controllable by the externally
activated control system.
[0036] In various embodiments the externally activated control
system of the invention may be a magnetically activated control
system, a mechanically activated control system that responds to
tapping on the skin near the device, or an acoustically activated
control system that responds to an audio or supersonic signal. Examples
of systems suitable for use as externally activated control systems
in the present invention are disclosed, for instance, in U.S. Pat.
No. 5,722,998 to Prutchi et al., which discloses an implantable
medical device with a sensor to detect the presence of a magnet
in order to command the device to enter a predetermined mode of
operation, and U.S. Pat. No. 5,304,206 to Baker, Jr. et al., which
discloses other suitable external activation techniques for an implantable
medical device.
[0037] Advantageously, in the method using by an externally activated
control system that selectively activates each of the predetermined
programs, such programs control parameters of the electrical signal
such that the output current amplitude is between about 0.5 mA to
about 1.5 mA, stimulation frequency is between about 10 Hz and 100
Hz, pulse width is in the range of 100 microseconds to 1000 microseconds
(.mu.s), and the duty cycle has intervals with power on for about
10 s to about 100 s and power off for the remainder of each 3 minute
to 10 minute period of treatment. In particular, advantageously
at least one of the predetermined programs to control parameters
of the electrical signal produces an electrical signal having an
output current of about 0.75 mA, a stimulation frequency of about
30 Hz, a pulse width of either about 250 microseconds or about 500
microseconds (.mu.s), and a duty cycle of intervals treatment.
[0038] Another aspect of the present invention relates to apparatus
for treating obesity in a patient, comprising a device suitable
for implanting subcutaneously in the patient and at least one implantable
electrical lead. The device comprises an electrical signal generator,
and the electrical lead has at least one proximal connector for
operably coupling the electrical lead to the signal generator and
at least one distal nerve electrode for operably connecting the
electrical lead to a trunk of the vagus nerve in the neck of the
patient. Advantageously, the signal generator comprises a power
source suitable for chronically stimulating the trunk of the vagus
nerve with an electrical signal while implanted for a period of
at least one year, more preferably for at least two years, or three
years or longer.
[0039] In this apparatus, the electrical signal produced by the
signal generator of the invention device has at least one variable
parameter selected from current amplitude, pulse width, pulse frequency,
and a duty cycle of alternating intervals with power on and power
off, and the device further comprises a memory component containing
at least two predetermined programs for controlling at least one
parameter of the electrical signal according to a programmed regimen.
For reasons of simplicity and attendant economy, the implantable
device is designed without any capability for altering the electrical
signal parameter regimen specified in each predetermined program
while the device is implanted in the patient. However, the signal
generator is designed to be activated by an externally activated
control system that selectively activates each of the predetermined
programs, thereby allowing the apparatus to provide chronic cervical
vagus nerve stimulation which is controllable by the externally
activated control system, such as a magnetically activated control
system, a mechanically activated control system, or an activation
system responsive to an audio or supersonic signal. Typically, the
predetermined programs controlling the electrical signal between
about 10 Hz and 100 Hz, a pulse width in the range of 100 microseconds
to 1000 microseconds (.mu.s), and a duty cycle of intervals with
power on for about 10 s to about 100 s and power off for the remainder
of each 3 minute to 10 minute period of treatment.
[0040] Various other features, objects and advantages of the invention
will be made apparent from the following description taken together
with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] FIG. 1 is a simplified block diagram of an implantable neurostimulator
electronics package (stimulus generator) for use (with appropriate
parameter settings and ranges) in treating patients to induce weight
loss according to the present invention (adapted from FIG. 1 of
U.S. Pat. No. 5,299,569 to Wernicke et al., the disclosure of which
is hereby incorporated herein by reference in its entirety);
[0042] FIG. 2 is a simplified fragmentary illustration of one embodiment
of the stimulus generator and lead/electrode system of the neurostimulator
implanted in the patient's body (adapted from FIG. 2 of U.S. Pat.
No. 5,299,569 to Wernicke et al.);
[0043] FIG. 3 is a detailed fragmentary illustration of the nerve
electrode as implanted on the vagal nerve in the neck of the patient
for modulating vagal activity (adapted from FIG. 3 of U.S. Pat.
No. 5,299,569 to Wernicke et al.);
[0044] FIG. 4 is a simplified block diagram of an implantable neurostimulator
electronics package (stimulus generator) for use (with appropriate
parameter settings and ranges) in treating patients to induce weight
loss according to the present invention (adapted from FIG. 1 of
U.S. Pat. No. 5,330,513 to Wernicke et al., the disclosure of which
is hereby incorporated herein by reference in its entirety), which
is simpler than the stimulus generator in FIG. 1, above, because
it has no signal analysis circuit which is not needed for embodiments
in which no sensory input signal is monitored;
[0045] stimulus generator and lead/electrode system of the neurostimulator
implanted in the patient's body (adapted from FIG. 2 of U.S. Pat.
No. 5,330,513 to Wernicke et al.), showing implantation and wiring
of the stimulus generator in FIG. 4, above, to stimulate the left
vagus nerve only, with no sensory input leads;
[0046] FIG. 6 shows the relationship between a patient's BMI after
one year of vagus nerve stimulation and the patient's BMI at the
beginning of the study. Patients whose positron emission tomographic
(PET) scans were determined are highlighted with hexagons.
[0047] FIG. 7 shows weights taken for each patient as a function
of time after initiation of the VNS study, up to 500 days.
DETAILED DESCRIPTION OF THE INVENTION
[0048] Referring now to the drawings, a block diagram of the basic
components of the stimulus generator of a neurostimulator and their
interrelationship is illustrated in FIG. 1, and further details
of location of an implantable version of the device and the associated
lead/electrode system are shown in FIGS. 2 and 3. A generally suitable
form of neurostimulator for use in the apparatus of the present
invention is disclosed in U.S. patent application Ser. No. 07/434,985,
now U.S. Pat. No. 5,154,172, issued Oct. 13, 1992, to Anthony J.
Varrichio et al., titled "Current Source with Programmable
Overhead Voltage" (referred to herein as the '985 application").
The specification of the '985 application is incorporated herein
in its entirety by reference.
[0049] The neurostimulator useful with the method of the invention
utilizes a conventional microprocessor and other standard electrical
and electronic components, and in the case of an implanted device,
communicates with a programmer and/or monitor located external to
the patient's body by asynchronous serial communication for controlling
or indicating states of the device. Passwords, handshakes and parity
checks may be employed for data integrity. battery operated device
and especially so where the device is implanted for medical treatment
of a disorder, and means for providing various safety functions
such as preventing accidental reset of the device.
[0050] The stimulus generator 10 (FIG. 1) is preferably adapted
to be implantable in the patient's body, in a pocket formed by the
surgeon just below the skin in the chest as shown in FIG. 2. Although
a primarily external neurostimulator may alternatively be employed.
The neurostimulator also includes implantable stimulating electrodes
(described below) together with a lead system 22 for applying the
output signal of the stimulus generator to the patient's vagus nerve.
Components external to the patient's body may include a programming
wand for telemetry of parameter changes to a stimulus generator
so signals from the generator may be monitored, and a computer and
associated software for adjustment of parameters and control of
communication between the generator, the programming wand and the
computer. Such external components of the system are not shown in
the drawings. The device of the invention may include an internet
transmitting/receiving device that will allow parameters and monitoring
information to be transmitted through the internet to/from a remote
site.
[0051] In conjunction with its microprocessor-based logic and control
circuitry, the stimulus generator 10 or other implanted or external
circuitry may include detection circuitry for sensing an event indicative
of an abnormality to trigger automatic delivery of the stimulating
signal. For example, surface or depth electrodes may be implanted
to sense specific characteristics of the patient's EEG for triggering
the therapy. However, this involves complex and delicate electrode/lead
implantation procedures as well as the requirement of circuitry
for spectral analysis and/or programmable spectral or pattern recognition.
Preferably, therefore, the treatment is applied continuously, periodically
or intermittently or in accordance with the patient's circadian
rhythm.
FIG. 1, for use in treating patients to induce weight loss according
to the present invention without a signal analysis circuit which
is not needed for embodiments in which no sensory input signal is
monitored.
[0052] As shown in FIG. 1 and FIG. 4, stimulus generator 10 includes
a battery (or set of batteries) 12, which may be of any reliable
long-lasting type conventionally employed for powering implantable
medical electronic devices (such as batteries employed in implantable
cardiac pacemakers or defibrillators). In the preferred embodiment
of the stimulus generator, the battery is a single lithium thionyl
chloride cell. The terminals of the cell 12 are connected to the
input side of a voltage regulator 13. The regulator smoothes the
battery output to produce a clean, steady output voltage, and provides
enhancement thereof such as voltage multiplication or division if
necessary for a specific application.
[0053] Regulator 13 supplies power to logic and control section
15, which includes a microprocessor and controls the programmable
functions of the device. Among these programmable functions are
output current, output signal frequency, voltage, output signal
pulse width, output signal on-time, output signal off-time, daily
treatment time for continuous or periodic modulation of vagal activity,
and output signal-start delay time. The device may use either one
of these programmable functions independently or for a particular
patient, a combination of parameters may be used. Such programmability
allows the output signal to be selectively crafted for application
to the stimulating electrode set (FIGS. 2 and 3) to obtain the desired
modulation of vagal activity for treatment and control of the weight
loss. Timing signals for the logic and control functions of the
generator are provided by a crystal oscillator 16. A magnetically-actuated
reed switch 14 may be incorporated in the electronics package to
provide the generator with manual activation capability (by use
of an external magnet, not shown, placed immediately adjacent to
the package or its implant site).
[0054] medical treatment of a disorder. To that end, a power down
circuit (identified as 18 in a similar stimulator in FIG. 1 of U.S.
Pat. No. 5,304,206 to Baker et al., the disclosure of which is hereby
incorporated herein by reference in its entirety) may be electrically
connected to reed switch 14 and logic/control circuit 15 and timed
by the clock pulses from the crystal oscillator 16 to reduce power
to the microprocessor of section 15 and/or to the oscillator to
a point at which the device is essentially in a sleep state but
sufficiently alert to be awakened on command. The power down mode
or sleep state may be initiated automatically within a timed interval
after the device has been activated to generate its programmed stimulating
output signal. Alternatively, the device may stay in a reduced power
state until the microprocessor is awakened by manual activation
of the device by the patient.
[0055] Referring to instant FIG. 1 herein, built-in antenna 17
enables communication between the implanted stimulus generator and
the external electronics (including both programming and monitoring
devices) to permit the device to receive programming signals for
parameter changes, and to transmit telemetry information, from and
to the programming wand. Once the system is programmed, it operates
continuously at the programmed settings until they are reprogrammed
(by trained, certified, personnel) by means of the external computer
and the programming wand.
[0056] Logic and control section 15 of the stimulus generator 10
controls an output circuit or section 19, which generates the programmed
signal levels appropriate to the disorder being treated. The output
section and its programmed output signal are coupled (directly,
capacitively, or inductively) to an electrical connector 20 on the
housing 21 of the generator and to lead assembly 22 connected to
the stimulating electrodes (FIGS. 2 and 3).
[0057] Housing 21 in which stimulus generator 10 is encased is
hermetically sealed and composed of a material such as titanium,
which is biologically compatible with the fluids and neurostimulator
are available in the '985 application.
[0058] FIG. 2 illustrates one location where the generator 10 may
be implanted, in case 21 with connector 20, in the patient's chest
in a cavity formed by the implanting surgeon just below the skin,
much as a pacemaker pulse generator would be implanted. As discussed
elsewhere, the location of the generator may vary with each patient
and may be placed in on a patient's arm, under the skin in the neck
area either proximal or distal to the site where the stimulating
electrodes are attached to the vagus nerve. For some patients, wireless
transmissions of stimulating signals replace the implantable generator.
A stimulating nerve electrode set 25 (FIG. 3) is conductively connected
to the distal end of insulated electrically conductive lead assembly
22, which is attached at its proximal end to connector 20. Electrode
set 25 is a bipolar stimulating electrode, preferably of the type
described in U.S. Pat. No. 4,573,481 issued Mar. 4, 1986 to Bullara,
the teachings of which are herein incorporated by reference in their
entirety. The electrode assembly is surgically implanted on the
vagus nerve 27 in the patient's neck. The two electrodes 25-1 and
25-2 are wrapped about the vagus nerve, and the assembly is secured
to the nerve by a spiral anchoring tether 28 desirably as disclosed
in U.S. Pat. No. 4,979,511 issued Dec. 25, 1990 to Reese S. Terry.
Jr., the teachings of which are herein incorporated by reference
in their entirety. Lead(s) 22 is secured, while retaining the ability
to flex with movement of the chest and neck, by a suture connection
30 to nearby tissue.
[0059] The open helical design of electrode assembly 25 (described
in detail in the above-cited Bullara patent), which is self-sizing
and flexible, minimizes mechanical trauma to the nerve and allows
body fluid interchange with the nerve. The electrode assembly conforms
to the shape of the nerve, providing a low stimulation threshold
by allowing a larger stimulation contact area. Structurally, the
electrode assembly comprises two ribbons of platinum first two spiral
loops 25-1 and 25-2 of a three-loop helical assembly, and the two
lead wires are respectively welded to the conductive ribbon electrodes.
The remainder of each loop is composed of silicone rubber, and the
third loop acts as the tether 28 for the electrode assembly. The
inner diameter of the helical bipolar electrode assembly may typically
be approximately two millimeters (mm), and an individual spiral
is about seven mm long (measured along the axis of the nerve).
[0060] Eye movement sensing electrodes 33 may be implanted at or
near the outer periphery of each eye socket in a suitable location
to sense muscle movement or actual eye movement, as shown in FIG.
2, and electrically connected to leads 34 implanted via a catheter
or other suitable means (not shown) and extending along the jawline
through the neck and chest tissue to the sense signal analysis circuit
23 of stimulus generator 10. Alternatively, or additionally, EEG
sense electrodes 36 may be implanted in spaced apart relation through
the skull, and connected to leads 37 implanted and extending along
the scalp and temple and then along the same path and in the same
manner as described above for the eye movement electrode leads.
These or other types of sensing electrodes would only be required
for alternative embodiments of the invention, since the preferred
embodiment utilizes a continuous, periodic or intermittent stimulus
signal applied to the vagus nerve (each of which constitutes a form
of continual application of the signal).
[0061] The stimulus generator may be programmed with an IBM/Unix/Linux-compatible
personal computer (not shown) using suitable software based on the
description herein, and a programming wand (not shown). The wand
and software permit noninvasive communication with the generator
after the latter is implanted. The wand is preferably powered by
internal batteries, and provided with a "power on" light
to indicate sufficient power for is occurring between the wand and
the generator.
[0062] The device parameters may be varied to provide the optimal
nerve stimulation for each individual patient. In one embodiment,
patients typically received 0.75 mA and pulse width of either 250
microsecond (.mu.s) or 500 microsecond (.mu.s) (Example 1). The
method of the invention comprises providing chronic pre-programmed
vagal stimulation to a patient in the neck either unilaterally or
bilaterally. Desirably, the patient is treated for a six to twelve
month period or longer. The amount of weight loss obtained using
the method of the invention will vary between patients, with the
heaviest patients showing the greatest weight loss. There is no
known limit to the period of treatment that can be safely and effectively
applied to an obese patient, while those with normal weight will
maintain their weight if treated according to the present invention
methods.
[0063] The present inventors appear to be the first to recognize
that the above treatment method, which is similar to methods used
to treat epilepsy for several years, provides a method to lose weight
without invading the abdomen or thorax. The invention shows that
rather than a side-effect [which Burneo et al., supra, considered
unpredictable and hence necessary to include in warnings to patients
and physicians considering VNS for treatment of epilepsy], cervical
VNS induces weight loss reliably based upon the initial weight of
the person. The method shows that proper selection of patients (i.e.,
BMI>30) and timing (6 months-one year) are critical for weight
loss. The device used for VNS, unlike current devices, need not
have any sensing capabilities; therefore, cost reductions are possible.
Placement in the neck should allow simple attachment to the vagus
nerve and should require only local anesthesia and surgical outpatient,
same-day procedures. The invention is [in part] a method to induce
weight loss and maintain normal weight in the obese without changing
lifestyle or diet.
[0064] pulse generator system similar to that described in U.S.
Pat. No. 6,449,512 ("the '512 patent", the disclosure
of which is hereby incorporated herein by reference in its entirety)
to Boveia, for treatment of urological disorders. The implantable
pulse generator for use in the present invention comprises prepackaged/predetermined
programs stored in the memory of the pulse generator, and means
for accessing these with an external control element, such as a
magnet. For instance, U.S. Pat. No. 5,722,998 to Prutchi et al.
(the disclosure of which is hereby incorporated herein by reference
in its entirety) discloses an implantable medical device that includes
a giant magnetoresistance ratio (GMR) sensor to detect the presence
of a magnet in order to command the device to enter a predetermined
mode of operation. Alternatively, U.S. Pat. No. 5,304,206 to Baker,
Jr. et al. (the disclosure of which is hereby incorporated herein
by reference in its entirety) discloses activation techniques for
an implantable medical device, including an activation means which
is responsive to a patient-initiated signal to activate, or in some
instances to deactivate, the stimulus generator. According to one
aspect of the invention, the neurostimulator is adapted to be activated
to the "on" state in response to tapping by the patient
on the skin overlying the implant site. Alternative manual activation
is also enhanced by incorporating a pushbutton which is readily
depressed for electrical actuation of the implanted device, using
a miniaturized generator in the bracelet to transmit an audio or
supersonic signal for detection by circuitry within the implanted
neurostimulator.
[0065] In any case, the programmerless implantable pulse generator
is adapted to selectively activate predetermined programs with the
external control system, thereby eliminating the need for an external
programming device, resulting in significant cost reduction with
essentially the same functionality as an externally programmable
stimulus generator. For instance, the '512 patent" to Boveja,
for treatment of urological disorders, teaches a device in which
the number of predetermined programs can be 100, but for patient
convenience, less predetermined programs, arranged in such a way
that the aggressiveness of the therapy increases from program #1
to Program #9.
[0066] In one aspect, therefore, the present invention, provides
an apparatus for neuromodulation of a vagus nerve, comprising: a)
an implantable lead having at least one electrode adapted to be
in contact with a cervical vagus nerve and connected to a programmerless
pulse generator which comprises circuitry, a power source, and at
least two predetermined programs to control electrical signals;
b) means to control the at least two predetermined programs by an
external control system, whereby the implantable pulse generator
provides neuromodulation therapy which is controllable by an external
control system. The external control system is selected from the
group consisting of a magnetically activated control system, a mechanically
sensitive activation system that is adapted to be activated to the
"on" state in response to tapping by the patient on the
skin overlying the implant site, and an activation system responsive
to an audio or supersonic signal generated by an external control
device. The electrical signals controlled by the apparatus comprise
at least one variable component selected from the group consisting
of the current amplitude, pulse width, frequency, on-time and off-time,
and the at least two predetermined programs control the variable
component of those electrical signals. Device parameters controlled
by the programs include: the output current which is ramped up gradually
(e.g., in 0.23 mA increments) to one of several final values between
about 0.5 to about 1.5 mA (typically, 0.75 mA) depending on patient
tolerance; stimulation frequency, typically 20 or 30 Hz but optionally
another value in the range of 10-100 Hz; pulse width in the range
of 100 to 1000 microseconds (.mu.s), typically either 250 .mu.s
or 500 .mu.s; and device (duty) cycle on for a substantially shorter
time than off, for instance 10 to 100 s on out of each 3 to 10 minute
period, preferably 30 s on in every five minutes of signal application.
For patient comfort is ramped up and ramped down, instead of providing
abrupt delivery and cessation of electrical pulses.
[0067] In another aspect the invention provides a method wherein
the vagus nerve signal stimulus is applied at a portion of the nervous
system remote from the vagus nerve such as at or near the esophageal
wall, for indirect stimulation of the vagus nerve in the vicinity
of the cervical location. Here, at least one signal generator is
implanted together with one or more electrodes subsequently operatively
coupled to the generator via lead(s) for generating and applying
the electrical signal internally to a portion of the patient's nervous
system other than the vagus nerve, to provide indirect stimulation
of the vagus nerve in the vicinity of the desired location. Alternatively,
the electrical signal stimulus may be applied non-invasively to
a portion of the patient's nervous system other than the vagus nerve
per se, for indirect stimulation of the vagus nerve at a cervical
location. For instance, U.S. Pat. App. No. 2002/0183237 by Puskas,
published Dec. 5, 2002 (the entire disclosure of which is hereby
incorporated herein by reference), discloses methods for indirectly
stimulating a vagus nerve of a patient which includes the steps
of positioning one or more electrodes in the vicinity of the vagus
nerve and then actuating the electrode(s) to create an electrical
field for stimulating the vagus nerve. Disclosed embodiments include
positioning one or more electrodes in the esophagus, trachea, or
jugular vein, on the neck of the patient, and combinations thereof.
[0068] Functional brain imaging (PET) scans performed on patients
receiving chronic vagus nerve stimulation and exhibiting weight
loss show that various regions of the brain are involved. The brain
regions that were affected included the midbrain (Substantia Nigra
or SN/Ventral tegmental area or VTA) and the ventromedial prefrontal
cortex (VMPFC). Example. It will be apparent to those skilled in
the art that many changes can be made in the embodiments described
in the Examples without departing from the scope of the present
invention. Thus, the scope of the present invention should not be
limited to the embodiments described in this application, but only
by the embodiments described by the language of the claims and the
equivalents of those embodiments.
EXAMPLE 1
[0069] Fourteen patients were treated with chronic vagus nerve
stimulation. Four men and ten women, with an average age of 46 years
(SD.+-.10) were treated. All but two (Hispanic and Middle Eastern)
were Euro-Americans. The mean weight on intake was 91 kg (SD.+-.27,
range 46 to 137 kg) with a body mass index (BMI) of 43 kg/m.sup.2
(SD.+-.5, range 18 to 49 kg/mn.sup.2). The average weight loss at
one year was 7 kg (SD.+-.3, range -6 to +24) with a mean drop in
BMI at one year of 2 kg/m.sup.2 (SD.+-.3, range -2 to +8)k. All
patients denied making any major attempts to diet or exercise during
the study. Medication changes of all patients were minimized during
the study.
[0070] The neurostimulator device described above was implanted
under the skin of the chest, and connected in the neck to the trunk
of the left vagus nerve. Default device parameters were used except
for the output current was from about 0.5 to 1.5 mA (most patients
received 0.75 mA) and the pulse width was either 250 .mu.s or 500
.mu.s. The device cycled on for 30 s every five minutes. After chronic
vagus nerve stimulation for a six to twelve month period, several
patients characterized as obese at the beginning of the treatment
had marked weight loss, while those with normal weight maintained
their weight. The heaviest patient initially weighed 137 kg (BMI
49 kg/m.sup.2) and after one year of vagus nerve stimulation in
accordance with the method of the invention the patient weighed
114 kg (BMI 40 kg/n.sup.2), a decrease of 24 kg. FIG. 6 shows that
the decrease in BMI of individual patients was consistently equivalently,
the loss of weight was proportional to the initial weight. This
linear relationship accounted for two-thirds of the variance (r.sup.2=64%).
[0071] FIG. 7 shows weights taken for each patient as a function
of time after initiation of the VNS study, up to 500 days. Each
line represents a single patient. Straight lines connect pairs of
points for an individual; missing data were interpolated. This plot
shows the change in weight (or, because height does not change in
this time scale, BMI) as a function of the number of days since
implantation of the device (for patients in the treatment arm, the
VNS device was turned ON about two weeks after implanting; for those
in the control arm, the device was turned ON at the end of the trial
(i.e., 120 days). The figure demonstrates several points: (1) There
is no significant change in weight overall during the first interval
of 120 days. In PET scans taken at this time, the final (at one
year) pattern of deactivation from the PET scans was not visualized.
(2) The first indication for weight loss at 180 days coincides with
the earliest changes in brain metabolic activity at regions templated
to the final results. (3) For those over 200 lbs initially, there
is a clear and consistent decrease in weight. Given the variance
in the data for those under 200 lbs, it is difficult to support
statistical models not indicating a causal relationship, such as
a hypothesis that the three heaviest patients are outliers or represent
some sort of phenomenon such as regression to the mean (where obese
patients would decrease in weight while those whose weights were
less would increase in weight). (4) In some cases there is data
extending beyond 400 days, suggestive of further decreases in weight
in the morbidly obese, whereas those under 200 lbs do not show further
weight loss.
[0072] The patients in this study were enrolled in a trial testing
the efficacy of cVNS for severe clinical depression unresponsive
to conventional treatments. The change in weight during cVNS was
not significantly related to changes in the level of depression
during respond to the depression treatment. In fact, the most obese
patient, who lost the most weight, was more depressed after the
trial (Hamilton depression score went from 37 to 49). No patient
intentionally altered activity or implemented diets. Anecdotally,
the obese patients felt that their appetite had normalized during
treatment. Of note, weight loss as a potential outcome of cVNS therapy
was unknown at the time of the trial and was not listed in the informed
consent. No patient reported spontaneously weight loss; none considered
that the weight loss was related to cVNS therapy. cVNS therapy was
tolerated well; only one patient requested removal of the device
because of lack of efficacy for her depression.
[0073] Thus, among the patients in this study, this data provides
evidence that chronic vagus nerve stimulation applied to the nerve
in the patient's neck affected a consistent and reliable reduction
of weight. Weight loss occurred gradually over one year and some
of the most obese patients continued to lose weight thereafter.
The amount of weight loss was proportional to the initial severity
of the obesity.
[0074] For Positron Emission Tomography (PET), patients fasted
at least eight hours. Two hours before scanning, the cVNS device
was turned off with the magnet to avoid imaging the direct effects
of electrical stimulation. An ECAT EXACT camera (Siemens, Knoxyille,
Tenn.) was operated in 2-D mode with septae extended. The instrument's
field of view was 15 cm, covering the whole brain. A transmission
scan was collected for attenuation correction. Patients received
.sup.18F-fluorodeoxyglucose (5 mCi/70 kg up to 10 mCi maximum) intravenously
and rested quietly during uptake with eyes closed and ears unplugged
in a quiet, darkened room. A static emission scan was obtained containing
approximately .about.15 million counts. Data were corrected for
electronic deadtime and randoms. A previous quantitative study with
arterial catheters of the cerebral metabolic rate for glucose in
subjects with normal weight versus patients with severe obesity
(but without diabetes) did not find whole-brain or Cognitive Neurology,
London, GB). Global whole-brain normalization was adjusted proportionately.
A linear, random effects model was selected to test the contrast
(post-cVNS[one year] minus pre-cVNS). Coordinates of activation
foci (x,y,z) in mm are referenced to the bicommissural planes (atlas
of Talairach and Tournoux, 198816). Magnitudes of activation are
reported in terms of Z-scores (mean/SD).
[0075] Identification of changes in regional brain activity induced
by chronic cVNS may help clarify mechanisms and suggest new therapeutic
pathways to weight reduction. Here, we report the neuroimaging results
from the seven subjects (denoted by hexagons in FIG. 6) who were
overweight (BMI>26 kg/m2) and who gave written informed consent
for PET scanning. Not all of these patients provided data at three
months and six months, while all seven provided data at one year.
The interval data will not be presented, but at six months, the
PET data appeared consistent with, but less robust, than that at
one year.
[0076] Table 1 shows the negative and positive changes in brain
metabolism identified in the difference image: [post-cVNS(one year)
minus pre-cVNS] with a conservative threshold Z-score=4.5. Although
we report local maxima and minima, the pattern of change in medial
prefrontal cortical metabolism appeared broad, rather than clearly-resolvable,
separate activation foci; perhaps consistent with widespread neuromodulation
across brain regions. Brain metabolism was reduced after treatment
in several structures: medial prefrontal cortex (Brodmann area,
BA, 9 with extension into polar and ventromedial prefrontal cortex
(VMPFC); ventral tegmentum (VTA)/substantia nigra (SN) at [x,y,z]=[12,-20,-8];
and hypothalamus at [x,y,z]=[0,-14,-2]; see FIG. 2. Brain metabolism
was increased after cVNS treatment in the inferior cerebellum, inferior
parietal cortex (BA 40) and fusiform gyrus (BA 37).
[0077] cVNS (one year) minus pre-cVNS]. TABLE-US-00001 Post-cVNS
minus Pre-cVNS Coordinates Region BA Side x y z Z-value Decreases
in metabolism Medial Frontal Gyrus 9 Left -6 54 30 -5.4 Middle Frontal
Gyrus 6 Right 40 14 52 -4.6 VTA/SN Right 12 -20 -8 -4.5 Hypothalamus
Midline 0 -16 -2 -4.5 Increases in metabolism Inferior Cerebellum
Left -16 -56 -50 5.3 Fusiform Gyrus 37 Right 38 -46 -16 4.8 Inf.
Parietal Lobe 40 Left -44 -28 24 4.7
[0078] The major target of the vagus nerve is the nucleus of the
solitary tract. This nucleus was not visualized here, probably because
of its small size with respect to the resolution of PET. The vagus
indirectly innervates many brainstem nuclei including those in the
VTA/SN and hypothalamus. The SN (A9) has dopamine neurons innervating
the neostriatum, while the VTA (A10) has dopamine neurons innervating
prefrontal and paralimbic cortices (VMPFC, cingulate, and entorhinal
regions) and associated structures (nucleus accumbens, amygdala,
etc.). PET can not resolve VTA from SN, but based on the observed
pattern of changes in brain activity, VTA is the more likely target
of cVNS.
[0079] We cannot dissect unambiguously which components of the
involved neural network might relate to weight loss versus mood
disorder. The network is not typical of drug treatment of depression;
however, such studies do not focus on severe, chronic, treatment-resistant
depression. These two phenomena (i.e., weight loss and antidepressant
action) appear independent since there was no significant correlation
between depression scores and BMI. The central role of the hypothalamus
in weight control adds support to this network's cVNS studies of
obese patients without depression will be necessary to definitively
isolate the effects of weight alone.
[0080] In conclusion, chronic cVNS offers potential as a new treatment
for severe obesity. Patients with near-normal BMI get little weight
loss; morbidly obese patients show the greatest weight loss. The
brain correlates of treatment with chronic cVNS in these patients
is a network of deactivated structures including VTA/SN, hypothalamus,
and VMPFC. Much of this network overlaps with the circuitry of reward
processing and dopamine neurotransmission. These results identify
an urgent need for a full-fledged, controlled, clinical trial of
cVNS for the treatment of severe obesity alone. Despite some invasiveness,
cVNS appears justifiable in such a trial given potential benefits
versus the known morbidity and mortality of persistent severe obesity
in children, adolescents, and adults.
[0081] The present invention may be embodied in other specific
forms without departing from the essential attributes thereof. Therefore,
the illustrated embodiments should be considered in all respects
as illustrative and not restrictive, reference being made to the
appended claims rather than to the foregoing description to indicate
the scope of the invention. |