Note: Descriptions are shown in the official language in which they were submitted.
CA 02466024 2004-04-30
METHOD OF TREATING MOOD DISORDERS AND/OR ANXIETY
DISORDERS BY BRAIN STIMULATION
TECHNICAL FIELD
This invention relates to neuronal tissue stimulation for treating anxiety
disorders
and/or mood disorders, and more particularly to modulating neuronal tissue at
a
predetermined stimulation site in brain tissue.
BACKGROUND OF THE INVENTION
Recent estimates indicate that more than 19 million Americans over the age of
18
years experience a depressive illness each year. The American Psychiatric
Association
recognizes several types of clinical depression, including Mild Depression
(Dysthymia),
Major Depression, and Bipolar Disorder (Manic-Depression). Major Depression is
defined
by a constellation of chronic symptoms that include sleep problems, appetite
problems,
anhedonia or lack of energy, feelings of worthlessness or hopelessness,
difficulty
concentrating, and suicidal thoughts. Approximately 9.2 million Americans
suffer from
Major Depression, and approximately 15 percent of all people who suffer from
Major
Depression take their own lives. Bipolar Disorder involves major depressive
episodes
alternating with high-energy periods of rash behavior, poor judgment, and
grand
delusions. An estimated one percent of the American population experiences
Bipolar
Disorder annually.
Significant advances in the treatment of depression have been made in the past
decade. Since the introduction of selective serotonin reuptake inhibitors
(SSRIs), e.g.,
Prozac~, many patients have been effectively treated with anti-depressant
medication.
New medications to treat depression are introduced almost every year, and
research in this
area is ongoing. However, an estimated 10 to 30 percent of depressed patients
taking an
anti-depressant are partially or totally resistant to the treatment. Those who
suffer from
treatment-resistant depression have almost no alternatives. Thus, there is a
need to
develop alternative treatments for these patients.
The use of electrical stimulation for treating neurological disease, including
such
disorders as movement disorders including Parkinson's disease, essential
tremor, dystonia,
and chronic pain, has been widely discussed in the literature. It has been
recognized that
electrical stimulation holds significant advantages over lesioning since
lesioning destroys
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CA 02466024 2004-04-30
the nervous system tissue. In many instances, the preferred effect is to
modulate neuronal
activity. Electrical stimulation permits such modulation of the target neural
structures and,
equally importantly, does not require the destruction of nervous tissue. Such
electrical
stimulation procedures include electroconvulsive therapy (ECT), repetitive
transcranial
(rTMS) magnetic stimulation and vagal nerve stimulation (VNS).
Efforts have been made to treat psychiatric disorders with peripheral/cranial
nerve
stimulation. Recently, partial benefits with vagus nerve stimulation i:n
patients with
depression have been described in U.S. Pat. No. 5,299,569. .Another example of
electrical
stimulation to treat depression is described in U.S. Pat. No. 5,470,846, Which
discloses the
use of transcranial pulsed magnetic fields to treat depression. Yet further,
U.S. Pat. No.
5,263,480 describes that stimulation of the vagus nerve may control depression
and
compulsive eating disorders and U.S. Pat. No. 5,540,734 teaches stimulation of
the
trigeminal or glossopharyngeal nerves for psychiatric illness, such as
depression.
Deep brain stimulation (DBS) has been applied to the treatment of central pain
syndromes and movement disorders, and it is currently being explored as a
therapy for
epilepsy. For instance, U.S. Pat. No. 6, 016,449 and U.S. Pat. No. 6,176,242
disclose a
system for the electrical stimulation of areas in the brain for the treatment
of certain
neurological diseases such as epilepsy, migraine headaches and Parkinson's
disease.
Various electrical stimulation and/or drug infusion devices have been proposed
for
treating neurological disorders. Some devices stimulate through the skin, such
as
electrodes placed on the scalp. Other devices require significant surgical
procedures for
placement of electrodes, catheters, leads, and/or processing units. These
devices may also
require an external apparatus that needs to be strapped or otherwise affixed
to the skin.
However, despite the aforesaid available treatments, there are patients with
mood
and/or anxiety disorders that remain treatment refractory and chronically
disabled. For
these severely ill and disabled patients, novel therapies are required.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to stimulation techniques (e.g., electrical
and/or
chemical) described in aforesaid U.S. Pat No. 6,176,242, but applied to novel
areas of the
brawn not considered in the prior art to play a role in depression. In certain
embodiments,
the invention uses electrical stimulation andlor one or more pharmaceuticals
to treat
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CA 02466024 2004-04-30
i~ F.-
affective disorders, such as mood andlor anxiety disorders. According to one
embodiment
of the invention, the stimulation modulates areas of the brain that exhibit
altered activity in
patients relative to psychiatrically normal control subjects, thereby treating
or preventing
affective disorders, for example depression and/or anxiety disorders. Such
stimulation is
likely to be produced by electrical stimulation, an excitatory
neurotransmitter agonist(s)
(e.g., norepinephrine), an inhibitory neurotransmitter antagonist(s), and/or a
medication
that increases the level of an excitatory neurotransmitter (e.g., flouxetine
(Prozac~),
trazodone).
Certain embodiments of the present invention involve a method and a
therapeutic
system having a surgically implanted device in communication with a
predetermined site.
The device is operated to stimulate the predetermined site thereby treating
the mood
and/or anxiety disorder. The device can include a probe, for example,
electrode assembly
(e.g., electrical stimulation lead), pharmaceutical-delivery assembly (e.g.,
catheters) or
combinations of these. The proximal end of the probe is coupled to an
electrical signal
source, pharmaceutical delivery pump, or both which, in turn, is operated to
stimulate the
predetermined treatment site.
Another embodiment of the present invention comprises a method of treating the
mood and/or anxiety disorder comprising the steps of: surgically implanting an
electrical
stimulation lead having a proximal end and a stimulation portion, wherein
after
implantation the stimulation portion is in communication with a predetermined
site;
coupling the proximal end of the lead to a signal generator; and generating an
electrical
signal with the signal generator to modulate the predetermined site thereby
treating the
mood and/or anxiety disorder. The mood disorder is selected from the group
consisting of
major depressive disorder, bipolar disorder, and dysthymic disorder. The
anxiety disorder
is selected from the group consisting of panic disorder, posttraumatic stress
disorder,
obsessive-compulsive disorder and phobic disorder.
In further embodiments, the method can comprise the steps o~ surgically
implanting a catheter having a proximal end coupled to a pump and a discharge
portion for
infusing a dosage of a pharmaceutical, wherein after implantation the
discharge portion of
the catheter is in communication with the predetermined stimulation site; and
operating
the pump to discharge the pharmaceutical through the discharge portion of the
catheter
into the stimulation site thereby treating the mood and/or anxiety disorder.
The
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CA 02466024 2004-04-30
pharmaceutical is selected from the group consisting of inhibitory
neurotransmitter
agonist, an excitatory neurotransmitter antagonist, an agent that increases
the level of an
inhibitory neurotransmitter, an agent that decrease the level of an excitatory
neurotransmitter, and a local anesthetic agent. It is envisioned that chemical
stimulation or
pharmaceutical infusion can be preformed independently of electrical
stimulation and/or in
combination with electrical stimulation.
It is envisioned that the predetermined site can be the hypothalamus. Thus,
any
site that is in communication with the hypothalamus is within the scope of the
present
invention. Other sites can also be stimulated, for example, but not limited to
the inferior
thalamic peduncles (IPT) and/or the thalamic reticular nuclei.
Stimulation of the hypothalamus and/or myelinated and/or non-myelinated
pathways that are associated with the hypothalamus can result in an
alleviation or
modulation of the mood and/or anxiety disorder. Modulating the hypothalamus
via
electrical and/or chemical stimulation (i.e., pharmaceutical) can result in
increasing,
decreasing, masking, altering, overriding or restoring neuronal activity
resulting in
treatment of the mood and/or anxiety disorder.
In further embodiments, stimulation of the inferior thalamic; peduncle the
surrounding or adj acent white matter tracts leading to or from the inferior
thalamic
peduncle or white matter tracts that are contiguous with the inferior thalamic
peduncle
results in an alleviation or modulation of the mood and/or anxiety disorder.
Modulating
the inferior thalamic peduncle via electrical and/or chemical stimulation (i.
e.,
pharmaceutical) can result in increasing, decreasing, masking, altering,
overnding or
restoring neuronal activity resulting in treatment of the mood and/or anxiety
disorder.
Yet further, stimulation of thalamic reticular nucleus and/or myelinated
and/or
non-myelinated pathways that are associated with the thalamic reticular
nucleus can result
in an alleviation or modulation of the mood and/or anxiety disorder.
Modulating the
thalamic reticular nucleus via electrical and/or chemical stimulation (i.e.,
pharmaceutical)
can result in increasing, decreasing, masking, altering, overriding or
restoring neuronal
activity resulting in treatment of the mood and/or anxiety disorder.
Another embodiment of the present invention is a method of treating a mood
and/or anxiety disorder comprising the steps of: surgically implanting an
electrical
stimulation lead having a proximal end and a stimulation portion, wherein
after
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CA 02466024 2004-04-30
implantation the stimulation portion is in communication with a first
predetermined site
selected from the group consisting of hypothalamus, inferior thalamic peduncle
and
thalamic reticular nucleus; surgically implanting a catheter having a proximal
end coupled
to a pump and a discharge portion for infusing a dosage of a pharmaceutical,
wherein after
implantation the discharge portion of the catheter is in communication with a
second
predetermined stimulation site selected from the group consisting of
hypothalamus,
inferior thalamic peduncle and thalamic reticular nucleus; and coupling the
proximal end
of the lead to a signal generator; generating an electrical signal with the
signal generator to
modulate the predetermined site; and operating the pump to discharge the
pharmaceutical
through the discharge portion of the catheter into the predetermined site
thereby treating
the mood and/or anxiety disorder.
Other embodiments of the present invention include a system for txeating
subjects
with mood and/or anxiety disorders. The therapeutic system comprises an
electrical
stimulation lead that is implanted into the subject's brain, the lead
comprises at least one
electrode that is in communication with the hypothalamus, inferior thalamic
peduncle, or
thalamic reticular nucleus and delivers electrical signals to hypothalamus,
inferior
thalamic peduncle, or thalamic reticular nucleus in response to received
signals; and a
signal generator that generates signals for transmission to the electrodes of
the lead
resulting in delivery of electrical signals to the predetermined site thereby
treating the
mood and/or anxiety disorder. The electrical stimulation lead may comprise one
electrode
or a plurality of electrodes in or around the target area. Still further, the
signal generator is
implanted in the subject's body.
Another example of a therapeutic system is a catheter having a proximal end
coupled to a pump and a discharge portion for infusing a dosage of a
pharmaceutical,
wherein after implantation the discharge portion of the catheter is in
communication with a
predetermined stimulation site; and a pump to discharge the pharmaceutical
through the
discharge portion of the catheter into the predetermined stimulation site
thereby treating
the mood and/or anxiety disorder.
In a specific embodiment, the catheter of the therapeutic system can be a
combination catheter and lead. Thus, the system also comprises a signal
generator that
generates signals for transmission to the electrodes of the Lead resulting in
delivery of
CA 02466024 2004-04-30
3
electrical signals to the predetermined site thereby treating the mood and/or
anxiety
disorder.
The foregoing has outlined rather broadly the features and technical
advantages of
the present invention in order that the detailed description of the invention
that follows
may be better understood. Additional features and advantages of the invention
will be
described hereinafter which form the subject of the claims of the invention.
It should be
appreciated that the conception and specific embodiment disclosed may be
readily utilized
as a basis for modifying or designing other structures for carrying out the
same purposes
of the present invention. It should also be realized that such equivalent
constructions do
not depart from the invention as set forth in the appended claims. The novel
features
which are believed to be characteristic of the invention, both as to its
organization and
method of operation, together with further objects and advantages will be
better
understood from the following description when considered in connection with
the
accompanying figures. It is to be expressly understood, however, that each of
the figures is
provided for the purpose of illustration and description only and is not
intended as a
definition of the limits of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
For a more complete understanding of the present invention, reference is now
made to the following descriptions taken in conjunction with the accompanying
drawings.
FIGS, IA and 1B illustrate example electrical stimulation systems.
FIGS. 2A-2D illustrate example electrical stimulation leads that may be used
in the
present invention.
FIGS. 3A and 3B illustrate the placement of the electrodes. FIG. 3A shows
axial
and frontal MRI sections showing the 8 contact electrodes' placement in both
sides. FIG.
3B shows the area within the squares is analyzed anatomically on the
horizontal (Hv -0.5)
and frontal sections (Fa 7.5) of the Schaltenbrand and Wahren atlas.
Abbreviations: Cma
= anterior commisure, Fx = farnix, Hpth = hypothalamus, Put = putamen, Pl =
Lateral
pallidus, Pm = medial pallidus, Cpip = posterior branch internal capsule, Zi =
zona incerta,
Tmth = mammillo-thalamic tract, Raprl = Prelemniscal radiations, Pu =
pulvinar, Cd=
caudate nucleus, Cpig = gems of internal capsule, Pd th if = inferior thalamic
peduncle
(ITP in this paper), Rtpo= nucleus reticularis polaris, Vm= nucleus ventralis
hipothalami,
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An Pd = ansa lenticularis, B = Meynert's basal nucleus and II = optic tract,
R= right
electrode, L= left electrode (28).
FIGS. 4A and 4B show an MRI and plotting of electrodes for chronic stimulation
(3389 DBS by Medtronic) indicating the place for stimulation. As in FIG. 3B,
the
abbreviations are the same.
FIGS. SA and SB show scalp distribution of the electro-cortical responses
elicited
by acute low frequency (6/sec) and high frequency (60/sec) stimulation of the
left nucleus
reticularis thalami (L Rtpo) and the left inferior thalamic peduncle (ITP).
Conventional
EEG recording from right and left frontopolar (FP2, FPl), frontal (F4, F3),
central (C4,
C3), parietal (P4, P3), occipital (02, Ol), frontotemporal (F8, F7) finally
anterior temporal
(T4, T3) and posterior temporal (T6, TS) scalp regions referred to ipsilateral
ears (A2,
A1). FIG. SA shows surface negative recruiting - like responses produced by
6/sec
unilateral supra-threshold stimulation of Rtpo and ITP predominant at the
bilateral fronto-
polar regions. FIG. SB shows surface negative DC shifts and desynchronization
produced
by 60 /sec unilateral supra-threshold stimulation of Rtpo and ITP with similar
distribution
to that of the recruiting responses.
FIGS. 6A and 6B show the results of the Self Rating Depression Scale (ZDS) and
the Depression Scale of Beck (BDI} and Hamilton (HAM-D). FIG. 6A shows ZDS.
FIG.
6B shows: HAM-D and BDI. The arrows indicate electrode insertion. Double blind
trial
is indicated by the bar in the bottom of the figure. The horizontal line
indicates the limit of
normal values.
FIGS. 7A-7D shows neuropsychological testing after ITP-DBS. FIG. 7A shows
the results for Wisconsin Card Sorting Test. FIG. 7B shows the results for
Finger Tapping
Test. FIGS. 7C-7D shows the results for auditory verbal learning (Rey Test,
FIG. 7C) and
Corsi Block Tapping Test (non-verbal memory, FIG. 7D). The horizontal lines
indicate
limit of normal values. The bax in the bottom of the graphics indicates double
blind trial.
Arrows show the effect of electrodes insertion.
DETAILED DESCRIPTION OF THE INVENTION
It is readily apparent to one skilled in the axt that various embodiments and
modifications can be made to the invention disclosed in this Application
without departing
from the scope and spirit of the invention.
7
CA 02466024 2004-04-30
f a
I. Definitions
As used herein, the use of the word "a" or "an" when used in conjunction with
the
term "comprising" in the claims and/or the specification may mean "one," but
it is also
consistent with the meaning of "one or more," "at least one," and "one or more
than one."
Still further, the terms "having", "including", "containing" and "comprising"
are
interchangeable and one of skill in the art is cognizant that these terms are
open ended
terms.
As used herein the term "affective disorders" refers to a group of disorders
that are
commonly associated with co-morbidity of depression and anxiety symptoms.
As used herein the term "anxiety" refers to an uncomfortable and unjustified
sense
of apprehension that may be diffuse and unfocused and is often accompanied by
physiological symptoms.
As used herein the term "anxiety disorder" refers to or connotes significant
distress
and dysfunction due to feelings of apprehension, guilt, fear, etc. Anxiety
disorders
include, but are not limited to panic disorders, posttraumatic stress
disorder, obsessive-
compulsive disorder and phobic disorders.
As used herein the term "depression" refers to a morbid sadness, dejection, or
melancholy.
As used herein, the term "hypothalamus" refers to the defined area of
hypothalamus as known by one of skill in the art, as well as the myelinated
and/or non-
myelinated pathways leading to and from the hypothalamus and myelinated and/or
non-
myelinated pathways that are associated, surround, adjacent andlor are
contiguous with the
hypothalamus.
As used herein, the term "inferior thalamic peduncle" or "ITP" refers to the
defined area of inferior thalamic peduncle as known by one of skill in the
art, as well as
the surrounding or adjacent white matter tracts leading to and from inferior
thalamic
peduncle and/or white matter tracts that are contiguous with inferior thalamic
peduncle.
The surrounding or adj acent white matter can include up to approximately a 1
cm radius of
inferior thalamic peduncle.
As used herein, the term "in communication" refers to the stimulation lead
and/or
catheter being adjacent, in the general vicinity, in close proximity, or
directly next to or
directly on the predetermined stimulation site. Thus, one of skill in the art
understands
8
CA 02466024 2004-04-30
that the lead and/or catheter is "in communication" with the predetermined
site of the
brain if the stimulation results in a modulation of neuronal activity. Still
further, "in
communication" with brain tissue encompasses surrounding or adjacent
myelinated and/or
non-myelinated tissue or fibers leading to and from the brain tissue and/or
myelinated
and/or non-myelinated tissue or fibers that are contiguous with the brain
tissue.
As used herein the term "limbic system" encompasses the amygdala, hippocampus,
septum, cingulate gyros, cingulate cortex, hypothalamus, epithalamus, anterior
thalamus,
mammillary bodies, and fornix. The limbic system has connections throughout
the brain,
more particularly with the primary sensory cortices, including the
rhinencephalon fox
smell, the autonomic nervous system via the hypothalamus, and memory areas.
Alterations in mood, emotion, and thought.
As used herein the teen "mania" or "manic" refers to a disordered mental state
of
extreme excitement.
As used herein the term "mood" refers to an internal emotional state of a
person.
As used herein the term "mood disorder" is typically characterized by
pervasive,
prolonged, and disabling exaggerations of mood and affect that are associated
with
behavioral, physiologic, cognitive, neurochemical and psychomotor
dysfunctions. The
major mood disorders include, but are not limited to major depressive disorder
(also
known as unipolar disorder), bipolar disorder (also known as manic depressive
illness or
bipolar depression), dysthymic disorder. Other mood disorders may include, but
are not
limited to major depressive disorder, psychotic; major depressive disorder,
melancholic;
major depressive disorder, seasonal pattern; postpartum depression; brief
recurrent
depression; late luteal phase dysphoric disorder (premenstrual dysphoria); and
cyclothymic disorder.
As used herein the term "modulate" refers to the ability to regulate
positively or
negatively neuronal activity. Thus, the term modulate can be used to refer to
an increase,
decrease, masking, altering, overnding or restoring neuronal activity.
Modulation of
neuronal activity affects psychological and/or psychiatric activity of a
subject.
As used herein, the term "neuronal" refers to a neuron which is a morphologic
and
functional unit of the brain, spinal column, and peripheral nerves.
As used herein, the term "obsessive-compulsive disorder" refers to an anxiety
disorder in which an individual has developed rituals and/or compulsions that
are
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CA 02466024 2004-04-30
ti
performed to ward off an unwanted occurrence or to fulfill an obsession. One
of the
characteristics of this disorder is recurrent obsessions, i.e., persistent,
intrusive thoughts
and/or urges that are troublesome to the subject. Compulsions can be defined
as repetitive
behaviors performed in response to an obsession.
As used herein, the term "pharmaceutical" refers to a chemical or agent that
is used
as a drug. Thus, the term pharmaceutical and drug are interchangeable.
As used herein, the term "stimulate" or "stimulation" refers to electrical
and/or
chemical modulation of predetermined sites in the brain.
As used herein, the term "thalamic reticular nucleus" refers to the defined
area of
thalamic reticular nucleus as known by one of skill in the art, as well as the
myelinated
and/or non-myelinated pathways leading to and from the thalamic reticular
nucleus and
myelinated and/or non-myelinated pathways that are associated, surround,
adjacent and/or
are contiguous with the thalamic reticular nucleus.
As used herein, the term "treating" and "treatment" refers to modulating
certain
areas of the brain so that the subject has an improvement in the disease, for
example,
beneficial or desired clinical results. For purposes of this invention,
beneficial or desired
clinical results include, but are not limited to, alleviation of symptoms,
diminishment of
extent of disease, stabilized (i.e., not worsening) state of disease, delay or
slowing of
disease progression, amelioration or palliation of the disease state, and
remission (whether
partial or total), whether detectable or undetectable. One of skill in the art
realizes that a
treatment may improve the disease condition, but may not be a complete cure
for the
disease.
II. Electrical Stimulation Devices
FIGS. lA and 1B illustrate example electrical stimulation systems 10 used to
provide deep brain stimulation. Stimulation system 10 generates and applies a
stimulus to
a target area of the brain or is in communication with the target area of the
brain, for
example, a target area of the hypothalamus and/or the inferior thalamic
peduncle (ITP),
and/or the thalamic reticular nucleus. For the purposes of this application,
the
hypothalamus includes all the gray matter nuclei that are associated with the
hypothalamus, as well as the any myelinated and/or non-myelinated pathways
(i.e.,
afferent andlor efferent) associated with or is contiguous with the
hypothalamus. Yet
further, for the purposes of this application, ITP includes the defined area
and/or fibers of
CA 02466024 2004-04-30
the ITP, as well as the surrounding or adjacent white matter tracts leading to
and from ITP
and/or white matter tracts that are contiguous with ITP. Still further, for
the purposes of
this application, the thalamic reticular nucleus includes all the gray matter
nuclei that are
associated with the thalamic reticular nucleus, as well as any myelinated
and/or non-
myelinated pathways (i. e., afferent and/or efferent) associated with or
contiguous with the
thalamic reticular nucleus.
In general terms, stimulation system 10 includes an implantable electrical
stimulation source 12 and an implantable electrical stimulation lead 14 for
applying the
stimulation signal to the target brain tissue. In operation, both of these
primary
components are implanted in the person's body. Stimulation source 12 is
coupled to a
connecting portion 16 of electrical stimulation lead 14. Stimulation source 12
controls the
electrical signals transmitted to electrodes 18 located on a stimulating
portion 20 of
electrical stimulation lead 14, located adjacent the target brain tissue,
according to suitable
signal parameters (e.g., duration, intensity, frequency, etc.). A doctor, the
patient, or
another user of stimulation source 12 may directly or indirectly input signal
parameters for
controlling the nature of the electrical stimulation provided.
In one embodiment, as shown in FIG. 1 A, stimulation source 12 includes an
implantable pulse generator (IPG). One of skill in the art is aware that any
commercially
available implantable pulse generator can be used in the present invention, as
well as a
modified version of any commercially available pulse generator. Thus, one of
skill in the
are would be able to modify an IPG to achieve the desired results. An
exemplary IPG is
one that is manufactured by Advanced Neuromodulation Systems, Inc., such as
the
Genesis~ System, part numbers 3604, 3608, 3609, and 3644. Another example of
an IPG
is shown in FIGURE 1B, which shows stimulation source 12 including an
implantable
wireless receiver. An example of a wireless receiver may be one manufactured
by
Advanced Neuromodulation Systems, Inc., such as the Renew~ System, part
numbers
3408 and 3416. The wireless receiver is capable of receiving wireless signals
from a
wireless transmitter 22 located external to the person's body. The wireless
signals are
represented in FIG. 1 B by wireless link symbol 24. A doctor, the patient, or
another user
of stimulation source 12 may use a controller 26 located external to the
person's body to
provide control signals for operation of stimulation source 12. Controller 26
provides the
control signals to wireless transmitter 22, wireless transmitter 22 transmits
the control
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CA 02466024 2004-04-30
signals and power to the wireless receiver of stimulation source 12, and
stimulation source
12 uses the control signals to vary the signal parameters of electrical
signals transmitted
through electrical stimulation lead 14 to the stimulation site. An example
wireless
transmitter 122 may be one manufactured by Advanced Neuromodulation Systems,
Inc.,
such as the Renew~ System, part numbers 3508 and 3516.
FIGS. 2A-2D illustrate example electrical stimulation leads 14 that may be
used to
provide electrical stimulation to an area of the brain. As described above,
each of the one
or more leads 14 incorporated in stimulation system 10 includes one or more
electrodes 18
adapted to be positioned near the target brain tissue and used to deliver
electrical
stimulation energy to the target brain tissue in response to electrical
signals received from
stimulation source 12. A percutaneous lead 14, such as example leads shown in
FIGS.
2A-2D, includes one or more circumferential electrodes 18 spaced apart from
one another
along the length of lead 14. Circumferential electrodes 18 emit electrical
stimulation
energy generally radially in all directions.
IILImplantation of Electrical Stimulation Devices
In certain embodiments, for example, patients who are to have an electrical
stimulation lead or electrode implanted into the brain, generally, first have
a stereotactic
head frame, such as the Leksell, CRW, or Compass, mounted to the
patient°s skull by fixed
screws. However, frameless techniques may also be used. Subsequent to the
mounting of
the frame, the patient typically undergoes a series of magnetic resonance
imaging sessions,
during which a series of two dimensional slice images of the patient's brain
are built up
into a quasi- three dimensional map in virtual space. This map is then
correlated to the
three dimensional stereotactic frame of reference in the real surgical field.
In order to
align these two coordinate frames, both the instruments and the patient must
be situated in
correspondence to the virtual map. The current way to do this is to rigidly
mount the head
frame to the surgical table. Subsequently, a series of reference points are
established to
relative aspects of the frame and patient's skull, so that either a person or
a computer
software system can adjust and calculate the correlation between the real
world of the
patient°s head and the virtual space model of the patient MRI scans.
The surgeon is able to
target any region within the stereotactic space of the brain with precision
(e.g., within 1
mm). Initial anatomical target localization is achieved either directly using
the MRI
images, or indirectly using interactive anatomical atlas programs that map the
atlas image
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CA 02466024 2004-04-30
onto the stereotactic image of the brain. As is described in greater detail
elsewhere in this
application, the anatomical targets may be stimulated directly or affected
through
stimulation in another region of the brain.
Based upon the coordinates, the electrical stimulation lead 14 can be
positioned in
the brain. Typically, an insertion cannula for electrical stimulation lead 14
is inserted
through the burr hole into the brain, but a cannula is not required. For
example, a hollow
needle may provide the cannula. The cannula and electrical stimulation lead 14
may be
inserted together or lead 14 may be inserted through the cannula after the
cannula has been
inserted.
Once electrical stimulation lead 14 has been positioned in the brain, lead 14
is
uncoupled from any stereotactic equipment present, and the cannula and
stereotactic
equipment are removed. Where stereotactic equipment is used, the cannula may
be
removed before, during, or after removal of the stereotactic equipment.
Connecting
portion 16 of electrical stimulation lead 14 is laid substantially flat along
the skull. Where
appropriate, any burr hole cover seated in the burr hole may be used to secure
electrical
stimulation lead 14 in position and possibly to help prevent leakage from the
burr hole and
entry of contaminants into the burr hole. Example burr hole covers that may be
appropriate in certain embodiments are illustrated and described in co-pending
U.S.
Application Nos. 60!528,604 and 60/528,689, both filed December 11, 2003 and
entitled
"Electrical Stimulation System and Associated Apparatus for Securing an
Electrical
Stimulation Lead in Position in a Person's Brain", both of which are
incorporated herein in
their entirety.
Once electrical stimulation lead 14 has been inserted and secured, connecting
portion 16 of lead 14 extends from the lead insertion site to the implant site
at which
stimulation source 12 is implanted. The implant site is typically a
subcutaneous pocket
formed to receive and house stimulation source 12. The implant site is usually
positioned
a distance away from the insertion site, such as near the chest, below the
clavicle or
alternatively near the buttocks or another place in the torso area. Once all
appropriate
components of stimulation system 10 are implanted, these components may be
subject to
mechanical forces and movement in response to movement of the person's body. A
doctor, the patient, or another user of stimulation source 12 may directly or
indirectly
input signal parameters for controlling the nature of the electrical
stimulation provided.
13
CA 02466024 2004-04-30
Although example steps are illustrated and described, the present invention
contemplates two or more steps taking place substantially simultaneously or in
a different
order. In addition, the present invention contemplates using methods with
additional
steps, fewer steps, or different steps, so long as the steps remain
appropriate for implanting
an example stimulation system 10 into a person for electrical stimulation of
the person's
brain.
IV. Infusion pumps
In further embodiments, it may be desirable to use a drug delivery system
independent of or in combination with the DBS. Drug delivery may be used
independent
of or in combination with a lead/electrode to provide electrical stimulation
and chemical
stimulation. When used, the drug delivery catheter is implanted such that the
proximal
end of the catheter is coupled to a pump and a discharge portion for infusing
a dosage of a
pharmaceutical or drug. Implantation of the catheter can be achieved by
combining data
from a number of sources including CT, MRI or conventional and/or magnetic
resonance
angiography into the stereotactic targeting model. Thus, implantation of the
catheter can
be achieved using similar techniques as discussed above for implantation of
electrical
leads, which is incorporated herein. The distal portion of the catheter can
have multiple
orifices to maximize delivery of the pharmaceutical while minimizing
mechanical
occlusion. The proximal portion of the catheter can be connected directly to a
pump or via
a metal, plastic, or other hollow connector, to an extending catheter.
Any type of infusion pump can be used in the present invention. For example,
"active pumping" devices or so-called peristaltic pumps are described in U.S.
Pat. Nos.
4,692,147, 5,840,069, and 6,036,459, which are incorporated herein by
reference in their
entirety. Peristaltic pumps are used to provide a metered amount of a drug in
response to
an electronic pulse generated by control circuitry associated within the
device. An
example of a commercially available peristaltic pump is SynchroMed~
implantable pump
from Medtronic, Inc., Minneapolis, Minn.
Other pumps that may be used in the present invention include accumulator-type
pumps, for example certain external infusion pumps from Minimed, Inc.,
Northridge,
Calif. and Infusaid~ implantable pump from Strato/Infusaid, Inc., Norwood,
Mass.
Passive pumping mechanisms can be used to release an agent in a constant flow
or
intermittently or in a bolus release. Passive type pumps include, for example,
but are not
14
CA 02466024 2004-04-30
c
limited to gas-driven pumps described in U.S. Pat. Nos. 3,731,681 and
3,951,147; and
drive-spring diaphragm pumps described in U.S. Pat. Nos. 4,772,263, 6,666,845,
6,620,151 all of which are incorporated by reference in their entirety. Pumps
of this type
are commercially available, for example, Model 3000~ from Arrow International,
Reading, Penn. and IsoMed~ from Medtronic, Inc., Minneapolis, Minn.; AccuRx~
pump
from Advanced Neuromodulation Systems, Inc., Plano, TX.
In certain embodiments, the catheter can be in the form of a lead catheter
combination, similar to the ones described in U.S. Patent 6,176,242 and U.S.
Pat. No.
5,423,877, which are incorporated herein by reference in their entirety.
V. Treatment of an Affective Disorder
Initially there is an impetus to treat psychiatric disorders with direct
modulation of
activity in that portion of the brain causing the pathological behavior. In
this regard there
have been a large number of anatomical studies that have helped to identify
the neural
structures and their precise connections which are implicated in psychiatric
activity/disorders. These are the structures that are functioning abnormally
and
manifesting in psychiatric/behavioral/addiction disorders. Numerous anatomical
studies
from autopsies, animal studies, and imaging such as computerized tomography
(CT)
scans, and magnetic resonance imaging (MRI) scans have demonstrated the role
of these
structures and their connections in psychiatric activity/disorders. In
addition to these
anatomical studies, a number of physiological techniques and diagnostic tools
are used to
determine the physiological aberrations underlying these disorders. This
includes electrical
methods such as electroencephalography (EEG), magnetoencephalography (MEG), as
well as metabolic and blood flow studies such as functional magnetic resonance
imaging
(fMRI), and positron emission tomography (PET). The combination of the
anatomical and
physiological studies have provided increased insight into our understanding
of the
structures which are involved in the normal functioning or activity of the
brain and the
abnormal functioning manifesting in psychiatric, behavioral and addiction
disorders.
Accordingly, the present invention relates to modulation of neuronal activity
to
affect psychological or psychiatric activity. The present invention finds
particular
application in the modulation of neuronal function or processing to effect a
functional
outcome. The modulation of neuronal function is particularly useful with
regard to the
prevention, treatment, or amelioration of psychiatric, psychological,
conscious state,
CA 02466024 2004-04-30
behavioral, mood, and thought activity (unless otherwise indicated these will
be
collectively referred to herein as "psychological activity" or "psychiatric
activity°'). When
referring to a pathological or undesirable condition associated with the
activity, reference
may be made to "psychiatric disorder" or "psychological disorder" instead of
psychiatric
or psychological activity. Although the activity to be modulated usually
manifests itself in
the form of a disorder such as a mood disorder (e.g., major depressive
disorder, bipolar
disorder, and dysthymic disorder) or an anxiety disorder (e.g., panic
disorder,
posttraumatic stress disorder, obsessive-compulsive disorder and phobic
disorder), one
skilled in the art appreciates that the invention may also find application in
conjunction
with enhancing or diminishing any neurological or psychiatric function, not
just an
abnormality or disorder. Psychiatric activity that may be modulated can
include, but not
be limited to, normal functions such as alertness, conscious state, drive,
fear, anger,
anxiety, repetitive behavior, impulses, urges, obsessions, euphoria, sadness,
and the fight
or flight response.
The present invention finds particular utility in its application to human
psychological or psychiatric activity/disorder. One skilled in the art
appreciates that the
present invention is applicable to other animals which exhibit behavior that
is modulated
by the brain. This may include, for example, primates, canines, felines,
horses, elephants,
dolphins, etc. Utilizing the various embodiments of the present invention, one
skilled in
the art may be able to modulate the functional outcome of the brain to achieve
a desirable
result.
One technique that offers the ability to affect neuronal function is the
delivery of
electrical and/or chemical stimulation for neuromodulation directly to target
tissues via an
implanted device having a probe. The probe can be stimulation lead or
electrode assembly
or drug-delivery catheter. The electrode assembly may be one electrode,
multiple
electrodes, or an array of electrodes in or around the target area. The
proximal end of the
probe is coupled to system to operate the device to stimulate the target site.
Thus, the
probe is coupled to an electrical signal source, pharmaceutical delivery pump,
or both
which, in turn, is operated to stimulate the predetermined treatment site.
Thus, certain embodiments of the present invention involve a method of
treating a
mood and/or anxiety disorder comprising the steps of: surgically implanting an
electrical
stimulation lead having a proximal end and a stimulation portion, wherein
after
16
CA 02466024 2004-04-30
implantation the stimulation portion is in communication with a predetermined
site;
coupling the proximal end of the lead to a signal generator; and generating an
electrical
signal with the signal generator to modulate the predetermined site thereby
treating the
mood and/or anxiety disorder.
The therapeutic system or deep brain system of the present invention is
surgically
implanted as described in the above sections. One of skill in the art is
cognizant that a
variety of electrodes or electrical stimulation leads may be utilized in the
present
invention. It is desirable to use an electrode or lead that contacts or
conforms to the target
site for optimal delivery of electrical stimulation. One such example, is a
single mufti
contact electrode with eight contacts separated by 2 1/2 mrn each contract
would have a
span of approximately 2 mm. Another example is an electrode with two 1 cm
contacts
with a 2 mm intervening gap. Yet further, another example of an electrode that
can be
used in the present invention is a 2 or 3 branched electrode/catheter to cover
the
predetermined site or target site. Each one of these three pronged
catheters/electrodes
have four contacts 1-2 mm contacts with a center to center separation of 2 of
2.5 mm and a
span of 1.5 mm. Similar designs with catheters to infuse drugs with single
outlet pore at
the extremities of these types of catheters or along their shaft may also be
designed and
used in the present invention.
In certain embodiments, the predetermined site or target area is the
hypothalamus.
The hypothalamus consists of gray matter nuclei that surrounds the anterior
end of the
third ventricle. The hypothalamus is grouped into three levels that are also
grouped into
three medial to lateral zones, i.e., (front to back) chiasmatic (i.e.,
suprachiasmatic,
paraventricular, anterior, supraoptic, and lateral and medial preoptic
nuclei), tuberal (i. e.,
dorsomedial, ventromedial, arcuate, and tuberal nuclei), and posterior (medial
and lateral
mamillary and posteriour nuclei). The hypothalamus integrates internal and
external
stimuli that is received via afferent pathways and relays or projects output
via efferent
pathways. Exemplary afferent pathways to the hypothalamus, include, but are
not limited
to input from the brain stem via dorsal longitudinal fasciculus, medial
forebrain bundle,
and mamillary peduncle; inputs from the thalamus via the inferior thalamic
peduncle,
input from the hippocampus via the fornix, inputs from the amygdala via the
stria
terminalis, input from the cerebral cortex via the medial forebrain bundle,
and direct input
from the eyes and olfactory bulb. Exemplary efferent pathways to the
hypothalamus,
17
CA 02466024 2004-04-30
include, but are not limited to output from the septal area and nuclei via the
medial
forebrain bundle; output from the anterior nucleus of the thalamus via the
mamillothalamic tract; output from the mediodorsal nucleus of the thalamus via
the
inferior thalamic peduncle; output from the amygdaloid complex via the stria
terminalis
and the ventral amygdalopetal pathway; output from the brainstem nuclei and
spinal cord
via the dorsal longitudinal fasciculsus; output from the adenohypophysis via
the
tuberohypophyseal tract and hypophyseal portal system; and output from the
neurohypophysis via the supraopticohypophyseal tract. Thus, one skill in the
art is
cognizant that the scope of the present invention includes all the associated
gray matter
nuclei of the hypothalamus, as well as any afferent and/or efferent
projections, which
would include any myelinated and/or non-myelinated projections of the
hypothalamus.
Stimulation of the hypothalamus and/or any myelinated and/or non-myelinated
proj ections
of the hypothalamus can result in changes that alleviate or improve the mood
and/or
anxiety disorder of the subject. It is contemplated that modulating the
hypothalamus
and/or myelinated and/or non-myelinated projections of the hypothalamus via
electrical
and/or chemical stimulation can result in increasing, decreasing, masking,
altering,
overriding or restoring neuronal activity resulting in treatment of the mood
and/or anxiety
disorder. It is envisioned that a possible mechanism by which stimulation of
the
hypothalamus may affect a mood and/or anxiety disorder may be via modulation
of the
neuroendocrine axis. It is envisioned that stimulating the hypothalamus and/or
any
myelinated and/or non-myelinated projections of the hypothalamus may influence
the
neuxoendocrine axis thereby affecting mood and/or anxiety disorders. A
neuroendocrine
disturbance that has been shown to be associated with depression is a
hypersecrection of
cortisol from the adrenal cortex in response to excessive or hypersecrection
of
adrenocorticotropin CATCH) from the pituitary. The hypersecrection of ATCH is
in
response to an excessive or hypersecrection of corticotropin-releasing hormone
(CTRH)
from the hypothalamus. Thus, it is envisioned that stimulating the
hypothalamus or
related projections may modulate the hypersecretion of cortisol or any other
neuroendocrine disturbance. Another possible mechanism by which stimulation of
the
hypothalamus may affect a mood and/or anxiety disorder may be via modulation
of the
hypothalamic-limbic circuits, for example, but not limited to the circuit of
Papez (Goetz,
18
CA 02466024 2004-04-30
Textbook of Clinical Neurology, 2"d ed., pp. 64-65 2003 and Brodal, p. 672,
Neuroanatomy 3ra ed., both which are incorporated by reference).
In further embodiments, the predetermined site or target area is the inferior
thalamic peduncle (ITP). Stimulation of ITP and/or the surrounding or adjacent
white
matter tracts leading to or from the ITP or white matter tracts that are
contiguous with ITP
results in changes that alleviate or improve the mood and/or anxiety disorder
of the
subject. It is contemplated that modulating ITP and/or surrounding or adjacent
or
contiguous white matter tracts leading to or from the ITP via electrical
and/or chemical
stimulation can result in increasing, decreasing, masking, altering,
overriding or restoring
neuronal activity resulting in treatment of the mood and/or anxiety disorder.
It is
envisioned that the mechanism by which stimulation of the ITP may affect a
mood and/or
anxiety disorder is via influencing the cortex and/or the brainstem. ITP
consists of white
matter tracts leading to and from the cortex and brain stem. Thus, stimulation
of the ITP
may affect the cortex and/or the brainstem thereby affecting the mood and/or
anxiety
disorders.
Yet further, the predetermined site or target area is the thalamic reticular
nucleus.
Thalamic reticular nucleus is classified as one of the diffuse-projection
nuclei of the
thalamus, which have widespread connections in the cerebral cortex and
thalamus. More
specifically, the reticular nucleus caps the entire lateral aspect of the
thalamus and is
separated from the lateral nucleic my the external medullary lamina. The
nuclei or cells of
the reticular nucleus receives input (also referred to as afferent pathways)
from the
cerebral cortex, other thalamic nuclei, and brainstem, and then projects
information (also
referred to as efferent pathways) back to the thalamic nuclei. Thus,
stimulation of the
thalamic reticular nucleus and/or any myelinated and/or non-myelinated
projections of the
thalamic reticular nucleus can result in changes that alleviate or improve the
mood and/or
anxiety disorder of the subject. It is contemplated that modulating the
thalamic reticular
nucleus and/or myelinated and/or non-rnyelinated projections of the
hypothalamus via
electrical and/or chemical stimulation can result in increasing, decreasing,
masking,
altering, overriding or restoring neuronal activity resulting in treatment of
the mood and/or
anxiety disorder. It is envisioned that the mechanism by which stimulation of
the thalamic
reticular nucleus may affect a mood and/or anxiety disorder is via influencing
other
thalamic nuclei. The reticular nucleus is the only thalamic nucleus that does
not have
19
CA 02466024 2004-04-30
projections to the cortex, and the only thalamic nucleus that has inhibitory
output. Thus,
stimulation of the thalamic reticular nucleus may affect at least one other
thalamic nuclei
thereby affecting the mood and/or anxiety disorders.
Using the therapeutic stimulation system of the present invention, the
predetermined site or target area is stimulated in an effective amount or
effective treatment
regimen to decrease, reduce, modulate or abrogate the mood and/or anxiety
disorder.
Thus, a subject is administered a therapeutically effective stimulation so
that the subject
has an improvement in the parameters relating to the affective disorder
including
subjective measures such as, for example, neurological examinations and
neuropsychological tests (e.g., Minnesota Multiphasic Personality Inventory,
Beck
Depression Inventory, Hamilton Rating Scale for Depression, or Yale-Brown
Obsessive
Compulsive score (Y-BOCS)), motor examination, and cranial nerve examination,
and
objective measures including use of additional psychiatric medications, such
as anti-
depressants, or other alterations in blood flow or metabolism in the brain.
The
improvement is any observable or measurable improvement. Thus, one of skill in
the art
realizes that a treatment may improve the patient condition, but may not be a
complete
cure of the disease.
Treatment regimens may vary as well, and often depend on the health and age of
the patient. Obviously, certain types of disease will require more aggressive
treatment,
while at the same time, certain patients cannot tolerate more taxing regimens.
The
clinician will be best suited to make such decisions based on the known
subject's history.
According to one embodiment of the present invention, the target site is
stimulated
using stimulation parameters such as, pulse width of about 1 to about 500
microseconds,
more preferable, about 1 to about 90 microseconds; frequency of about 1 to
about 300 Hz,
more preferably, about 100 to about 185 Hz; and voltage of about 0.5 to about
10 volts,
more preferably about 1 to about 10 volts. It is known in the art that the
range for the
stimulation parameters may be greater or smaller depending on the particular
patient needs
and can be determined by the physician. Other parameters that can be
considered may
include the type of stimulation for example, but not limited to acute
stimulation, subacute
stimulation, and/or chronic stimulation.
It is envisioned that stimulation of the hypothalamus and/or any myelinated
and/or
non-myelinated projections of the hypothalamus and/or the ITP and/or the
adjacent,
CA 02466024 2004-04-30
surrounding or contiguous white matter tracts of the ITP modulates, andlor the
thalamic
reticular nucleus and/or any myelinated and/or non-myelinated projections of
the thalamic
reticular nucleus, or other targets in the limbic-cortical circuit or pathway
thereby
improving any dysfunctional limbic-cortical circuits resulting in an
improvement or
alleviation or providing remission of depression and/or anxiety in the treated
subjects.
Other such improvements can be sensations of calm, tranquility, peacefulness,
increased
energy and alertness, improved mood, and improvement in motor speed and in
spontaneity
of speech, decreases in anxiety, decreases in repetitive behavior, impulses,
obsessions, etc.
For purposes of this invention, beneficial or desired clinical results
include, but are
not limited to, alleviation of symptoms, diminishment of extent of disease,
stabilized (i.e.,
not worsening) state of disease, delay or slowing of disease progression,
amelioration or
palliation of the disease state, and remission (whether partial or total),
whether objective or
subjective.
VI. Combination Treatment
In order to increase the effectiveness of the electrical stimulation method of
the
present invention, it rnay be desirable to combine electrical stimulation with
chemical
stimulation to treat the mood and/or anxiety disease.
In one preferred alternative, an implantable signal generator and electrical
stimulating lead and an implantable pump and catheters) are used to deliver
electrical
stimulation and/or one or more stimulating drugs to the above mentioned areas
as a
treatment for mood and/or anxiety disorders.
Herein, stimulating drugs comprise medications, anesthetic agents, synthetic
or
natural peptides or hormones, neurotransmitters, cytokines and other
intracellular and
intercellular chemical signals and messengers, and the like. In addition,
certain
neurotransmitters, hormones, and other drugs are excitatory for some tissues,
yet are
inhibitory to other tissues. Therefore, where, herein, a drug is referred to
as an "excitatory"
drug, this means that the drug is acting in an excitatory manner, although it
may act in an
inhibitory manner in other circumstances and/or locations. Similarly, where an
"inhibitory" drug is mentioned, this drug is acting in an inhibitory manner,
although in
other circumstances and/or locations, it may be an "excitatory" drug. In
addition,
stimulation of an area herein includes stimulation of cell bodies and axons in
the area.
21
CA 02466024 2004-04-30
Similarly, excitatory neurotransmitter agonists (e.g., norepinephrine,
epinephrine,
glutamate, acetylcholine, serotonin, dopamine), agonists thereof, and agents
that act to
increase levels of an excitatory neurotransmitters) (e.g., edrophonium;
Mestinon;
trazodone; SSRIs (e.g., flouxetine, paroxetine, sertraline, citalopram and
fluvoxamine);
tricyclic antidepressants (e.g., imipramine, amitriptyline, doxepin,
desipramine,
trimipramine and nortriptyline), monoarnine oxidase inhibitors (e.g.,
phenelzine,
tranylcypromine, isocarboxasid)), generally have an excitatory effect on
neural tissue,
while inhibitory neurotransmitters (e.g., dopamine, glycine, and gamma-
aminobutyric acid
(GABA)), agonists thereof, and agents that act to increase levels of an
inhibitory
neurotransmitters) generally have an inhibitory effect (e.g., benzodiasepine
(e.g.,
chlordiazepoxide, clonazepam, diazepam, lorazepam, oxazepam, prazepam
alprazolam);
flurazepam, temazepam, or triazolam). (Dopamine acts as an excitatory
neurotransmitter
in some locations and circumstances, and as an inhibitory neurotransmitter in
other
locations and circumstances.) However, antagonists of inhibitory
neurotransmitters (e.g.,
bicuculline) and agents that act to decrease levels of an inhibitory
neurotransmitters) have
been demonstrated to excite neural tissue, leading to increased neural
activity. Similarly,
excitatory neurotransmitter antagonists (e.g., prazosin, and metoprolol) and
agents that
decrease levels of excitatory neurotransmitters may inhibit neural activity.
Yet further,
lithium salts and anesthetics (e.g., lidocane) may also be used in combination
with
electrical stimulation.
VII. Examples
The following examples are included to demonstrate preferred embodiments of
the
invention. It should be appreciated by those of skill in the art that the
techniques disclosed
in the examples which follow represent techniques discovered by the inventor
to function
well in the practice of the invention, and thus can be considered to
constitute preferred
modes for its practice. However, those of skill in the art should, in light of
the present
disclosure, appreciate that many changes can be made in the specific
embodiments which
are disclosed and still obtain a like or similar result without departing from
the spirit and
scope of the invention.
22
CA 02466024 2004-04-30
Example 1
Patient Selection for Treatment of Depression
A 49 years old female with history of recurrent depression for 23 years and a
5
years episode of major depression fulfilling DSM IV criteria (depressed mood,
anhedonia,
late night insomnia, increased appetite, hopeless attitude and suicidal ideas)
was presented.
Symptoms were resistant to medication and electroconvulsive therapy. Hamilton,
Beck and Zung scales detected high scores for depression. Neuropsychological
abnormalities in memory and praxias were also documented.
Example 2
Surgical Procedure
Under local anesthesia, a stereotactic frame was first placed on the patient's
head,
followed by acquisition of an MRI (Magnetic Resonance Imaging) scan to
localize the
target region. The patient was then taken to the operating room where, under
local
anesthesia, burr holes were placed behind the hairline. Two coronal burr-holes
were
drilled at 15 mm from the midline in each side plus a plastic ring and skull
cap (by
Medtronic) to hold the electrodes. Guided by TC and MRI the electrodes were
directed to
coordinates lateral (X) = 5.0 mm at each side of the midline, AP (Y) = 4.0 mm
posterior to
anterior commisure (AC), and depth (Z) over passed by 10 mm the anterior
commisure to
posterior commisure level (AC - PC). The electrodes trajectories were oblique
with a 10°
inclination in the frontal plane and 20° inclination in the sagittal
plane. Temporary eight
contacts electrodes were plotted on correspondent frontal sections of the
Schaltenbrand
and Wahren atlas (Schaltenbrand and Wahren, 1977) (FIG. 3). The electrodes
were left
externalized for recording and temporary stimulation.
23
CA 02466024 2004-04-30
Example 3
Acute Stimulation of a Depressed Patient
After surgery electrical stimulation (ES) of different pair of contacts of the
electrodes was carned out using the ES parameters (130 Hz, 0.45 ms) intended
for
subacute and chronic stimulation increasing the voltage from 1.0 to 10.0 V to
detect
adverse reactions. Searching for recruiting responses was performed by bipolar
stimulation
of different pair of contacts at 6 Hz, 1.0 ms and increasing from 0.5 to 4.0
mA while
recording scalp EEG in conventional 10-20 montage referred to the ears (A 1-A
2).
Regional DC shifts searched at 60 Hz, 1.0 ms and intensities from 1.0 to 4.0 m
A (Velasco
et al., 1996).
Table I summarizes the effects of low (6Hz) and high (60 Hz) stimulation.
Other
parameters were 1.0 ms pulse duration, increasing pulse amplitude in steps of
0.5 mA,
increasing from 0.5 to 4.0 mA. Stimulation was always unilateral and bipolar
between two
adjacent contacts of the electrode, that according to our MRI and stereotactic
plotting the
following structures: 1 - 2 nucleus ventromedialis hipotalami (Vm), 3 - 4
fornix (Fx), 5 -6
pedunculus thalami inferior (Pd. Th. If) and 7 - 8 nucleus reticularis Polaris
(Rtpo) (FIG.
1). While all low frequency stimulation in different pair of contacts elicited
RR like
potentials and most high frequency stimulation elicited negative DC shifts,
the distribution
of the cortical responses were different. In Vm, RR were bilateral central and
temporal,
while DC shifts could not be elicited because at 1.5 mA in right side and 2.0
mA in left
side the patient reported and intense sensation of fear that precluded further
stimulation.
At Fx, RR were recorded in all regions of the ipsilateral EEG and DC shifts
were fronto-
central ipsilateral. ITP (Pd. Th. If) and Rtpo stimulation at low and high
frequencies
evoked similar cortical responses prominent at fronto-polar leads in both
sides (FIG. 5).
Except for the fear sensation reported when stimulating at high frequency the
Vm no other
objective or subjective reaction were induced up to 4.0 mA.
24
CA 02466024 2004-04-30
a
Table 1. Acute Electrical Stimulation
PULSE
CONTACTS FREQUENCY AMPLITUDE RESPONSE
(mA)
Right Left
6 for RR 2.5 2.5 Bilarteral central
1-2 (VmH) and temporal
60 for DC shift 1.5 2.0 Intense fear and anxiety
6 for RR 4.0 4.0 Ipsilateral Generalized
4 (Fx)
3
- 60 for DC shift 2.0 2.5 Ipsilateral fronto
central
6 for RR 3.0 2.5 Bilateral fronto polar
5-6 (ITP) 60 for DC shift 4.0 1.5 Bilateral fronto polar
60 for RR 2.5 1.5 Bilateral fronto polar
7-9 (Rtpo) 60 for DC shift 4.0 3.5 ~ Bilateral fronto
~ polar
Example 4
Subacute Stimulation of a Depressed Patient
Stimulation was always bipolar between two adjacent contacts. This stimulation
circumscribed the electrical current on a specific target. The most efficient
contacts t. e.,
the ones that induced the best clinical response in acute stimulation test at
the lowest
threshold and were not accompanied by adverse reactions, were selected for a
30 days trial
of continuous stimulation. The patient remained hospitalized during that
period and EEG
recordings, depression scales and neuropsychological evaluations were repeated
every
week. At the end of this period, the patient was taken back to the operating
room, and
under general anesthesia the stereotactic frame was repositioned, the 8
contact electrodes
were removed and tetrapolar electrodes (DBS 3389) with intercontact distance
of 1.5 mm
were aimed to the site where most efficient stimulation was obtained. The
electrodes were
internalized and connected through extension cables to a dual LPG (Kinetra by
Medtronic)
(FIG. 4).
The initial improvement in depression scales described above was further
increased by bilateral continuous stimulation through contacts 5-6 (ITP). HAM-
D
decreased one month later, to 4, BDI to 11 and ZDS to 35. From the
neuropsychological
evaluation visual attention, visuo-constructive perception and verbal fluency
were normal
in the BL and remained so. All abnormal neuropsychological findings in BL were
improved at one month post stimulation: Abstraction that was mildly impaired
(Wisconsin
Card Sorting Test) in BL (6 categories, 60 correct, 45 errors) improved
substantially (6
CA 02466024 2004-04-30
categories, 60 correct and 20 errors). Manual praxias were severely affected
mainly on
right hand and improved in both sides mainly on the right. Hemispheric
dominance
(Finger Tapping Test) affected mainly on the right side with scores of 2.87
tap / s on the
right and 3.67 tap I s on the left became better for right hand (5.63 tap I s
and 5.28 tap I s
in right and left respectively). Mild verbal memory deficit (Rey Test) (7
trials to learn 10
words m 8 min l Os time became 5 trials in 4 min 51 s). Finally, non verbal
memory (Corsi
Block Tapping Test) shown moderate deficit (21 trials = 8 correct + 13 errors
in 6 min
54s) became light memory problem (18 trials = 12 correct + 6 errors in 4 min
18s).
Example S
Chronic Stimulation of a Depressed Patient
The patient was discharged from the hospital and bipolar stimulation between
contacts 0 (positive) and 1 (negative) in both sides, setting the parameters
at 130 Hz 0.45
ms and 2.0 and 2.5 V amplitude in the left and right sides, respectively. All
ATD
medication was discontinued and appointments for monthly follow-up were
scheduled. In
each visit, the patient had a psychiatric and neuropsychological evaluations
through the
same scales used in BL and a repeated EEG. Every month recording of RR induced
by
stimulation through the IPG at 6 Hz, 0.45 ms and 6.0 to 8.0 V, were performed
for
monitoring the integrity of the stimulation systems as well as the efficiency
of stimulation
(Velasco et al., 1998). At month 8, the patient entered a double blind
protocol with
srirnulation off for 2 months.
The patient has remained without ATD with reduction in all depression scales
scores and improvement in the verbal and non verbal memory and abstraction
test that
became normal by month 8 (FIG. 6 and FIG. 7). At this time a double blind
protocol
started with patient and examiners (psychiatrist and neuropsychologist)
unaware of the
stimulator being turned off and only one monitor handling the code. The double
blind test
was valid because the patient had not objective or subjective sensation when
stimulation
was on. During double- blind period the patient remained in complete remission
of
depression (HAM-D below 7 points). Patient has returned to home work and her
relatives
describe her as the active and pleasant person she used to be many years
before.
26
CA 02466024 2004-04-30
Example 6
Treatment of Obsessive-Compulsive Disorder
A 21 years old male with a 15 year history of obsessive-compulsive disorder
characterized by agoraphobia and compulsive writing of his symptoms and
resistant to
pharmacological and cognitive therapy with a score of 37 in Yale-Brown
Obsessive
Compulsive score (Y-BOCS) underwent the surgery protocol as described in
Example 2.
Prior to surgery a complete neurophyschological evaluation was performed.
Electrodes (DBS 3389 by Medtronic) were sterotactica,lly implanted in ITP (x =
5.0 mm, z
= AC-PC level, y = 5.0 mm behind) and their correct position confirmed by MRI
and
electrophysiologically by the evoked recruiting responses. ES parameters were
130 Hz,
with a pulse width of 0.45 ms and a voltage from 2.5 to 4.5 volt, bipolar and
continuous.
Psychiatric and neuropsychological evaluations were repeated every 3 months.
On the Y-BOCS scale score, the patient decreased 20 points and has remained so
for 9 months (dropped from 37 to 17), with an improvement in WCST performance
from 2
to 6 categories and number of errors decreased from 11 to 34.
REFERENCES
All patents and publications mentioned in the specifications are indicative of
the
levels of those skilled in the art to which the invention pertains. All
patents and
publications are herein incorporated by reference to the same extent as if
each individual
publication was specifically and individually indicated to be incorporated by
reference.
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Ebmeier et al., Br J Psychiatry, 170:77-81, 1997.
Galynker et al., J Nucl Med., 39:608-12, 1998.
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CA 02466024 2004-04-30
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Although the present invention and its advantages have been described in
detail, it
should be understood that various changes, substitutions and alterations can
be made
herein without departing from the invention as defined by the appended claims.
Moreover, the scope of the present application is not intended to be limited
to the
particular embodiments of the process, machine, manufacture, composition of
matter,
means, methods and steps described in the specification. As one will readily
appreciate
from the disclosure, processes, machines, manufacture, compositions of matter,
means,
methods, or steps, presently existing or later to be developed that perform
substantially the
same function or achieve substantially the same result as the corresponding
embodiments
described herein may be utilized. Accordingly, the appended claims are
intended to
include within their scope such processes, machines, manufacture, compositions
of matter,
means, methods, or steps.
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