U.S. patent application number 12/028699 was filed with the patent office on 2008-05-29 for responsive therapy for psychiatric disorders.
This patent application is currently assigned to NEUROPACE, INC.. Invention is credited to Martha Morrell.
Application Number | 20080125831 12/028699 |
Document ID | / |
Family ID | 36035145 |
Filed Date | 2008-05-29 |
United States Patent
Application |
20080125831 |
Kind Code |
A1 |
Morrell; Martha |
May 29, 2008 |
Responsive Therapy for Psychiatric Disorders
Abstract
A medical device is capable of delivering a form of stimulation
(e.g., electrical stimulation) to a region of the cingulate cortex
of the human brain to treat a neurological event, condition or
disorder, especially an event, condition, or disorder that is
psychiatric in nature, such as depression, bipolar disorder,
anxiety and obsessive-compulsive disorders, post-traumatic stress
disorder, addiction, schizophrenia, and autism and other
developmental disorders. The device additionally or alternatively
may be capable of detecting a biological marker or changes in a
biological marker corresponding to the neurological event,
condition or disorder. Methods of using the device are also
disclosed.
Inventors: |
Morrell; Martha; (Portola
Valley, CA) |
Correspondence
Address: |
NEUROPACE, INC.
1375 SHOREBIRD WAY
MOUNTAIN VIEW
CA
94043
US
|
Assignee: |
NEUROPACE, INC.
Mountain View
CA
|
Family ID: |
36035145 |
Appl. No.: |
12/028699 |
Filed: |
February 8, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10941759 |
Sep 14, 2004 |
7353065 |
|
|
12028699 |
|
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Current U.S.
Class: |
607/45 |
Current CPC
Class: |
A61N 1/36082 20130101;
A61N 1/0539 20130101; A61N 1/36071 20130101; A61N 1/0531
20130101 |
Class at
Publication: |
607/45 |
International
Class: |
A61N 1/05 20060101
A61N001/05 |
Claims
1. A method for modulating the cingulate cortex of a patient's
brain comprising: implanting in the patient's body an electrode
array comprising a plurality of electrodes so that the plurality of
electrodes are either disposed within or against substantially the
entire length of the cingulate cortex; associating the electrode
array with a stimulation source; delivering stimulation from the
stimulation source through at least one of the electrodes in the
electrode array.
2. The method of claim 1, wherein delivering stimulation comprises
delivering electrical stimulation.
3. The method of claim 1, wherein delivering stimulation comprises
delivering at least one dose of a drug.
4. The method of claim 1, further including implanting the
stimulation source in the patient's body.
5. The method of claim 1, further comprising triggering the
delivery of stimulation with a signal corresponding to a command
initiated by the patient.
6. The method of claim 1, wherein delivering stimulation comprises
causing a temperature change at or in the vicinity of the at least
one of the electrodes.
7. The method of claim 6, further comprising: implanting at least
one sensor in the patient's body; detecting at least one biological
marker with the at least one sensor.
8. The method of claim 7, wherein the biological marker is a
biological marker from the group consisting of electrical activity,
concentration of inhibitory or excitatory neurochemicals,
concentration of proteins or other gene products, temperature, and
metabolic rate.
9. The method of claim 7, wherein detecting the at least one
biological marker further comprises monitoring the at least one
biological marker over a predetermined period of time.
10. The method of claim 9, wherein delivering stimulation further
comprises delivering stimulation based on predefined changes in the
detected and monitored at least one biological marker.
11. The method of claim 9, wherein monitoring the at least one
biological marker over a predetermined period of time further
includes continuously monitoring the at least one biological
marker.
12. A device for modulating the function of the cingulate cortex of
a patient's brain comprising: an electrode array comprising a
plurality of electrodes designed for and intended to be deployed so
that the electrodes can be used to deliver stimulation to
substantially any area of the cingulate cortex; a stimulation
source associated with the electrode array for delivering a form of
stimulation through at least one of the electrodes in the electrode
array; a programmable selector circuit for selecting one or more of
the electrodes in the electrode array through which stimulation can
be delivered.
13. The device of claim 13, further including at least one sensor
for detecting at least one biological marker from the patient.
14. The device of claim 14, further including a monitoring circuit
for monitoring information sensed by the at least one sensor for a
programmable period of time.
15. The device of claim 13, wherein the stimulation source is a
signal generator for generating electrical stimulation.
16. The device of claim 13, wherein the biological marker is a
biological marker from the group consisting of electrical activity,
concentration of inhibitory or excitatory neurochemicals,
concentration of proteins or other gene products, temperature, and
metabolic rate.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. Ser. No. 10/941,759, filed
Sep. 14, 2004. U.S. Ser. No. 10/941,759 is hereby incorporated by
reference herein in the entirety.
FIELD OF THE INVENTION
[0002] The invention relates to systems and methods for treating
brain disorders, and more particularly to treating neuropsychiatric
disorders and related diseases with automatically delivered
therapies.
BACKGROUND OF THE INVENTION
[0003] Severe affective and behavioral psychiatric disorders affect
5 to 10 million adults in the United States and are the leading
cause of disability in North America and Europe. Men and women of
all ages and races are at risk for mental illness and for the
associated morbidity and societal cost. Although
psychopharmacological therapy provides at least partial relief for
between 70 to 90% of persons suffering from major depression,
bipolar disorder (BPD), obsessive-compulsive disorder (OCD) and
panic and other severe anxiety disorders; others are not helped or
experience unacceptable medication related side effects. Those
experiencing schizophrenia, episodic behavioral disorders,
post-traumatic stress disorder (PTSD), addictions, and the
behavioral and social disorders associated with autism and
pervasive developmental disorders are less often helped by
pharmacotherapy or psychotherapy. The economic cost of untreated
mental illness is more than 100 billion dollars each year in the
United States.
[0004] Accordingly, new treatments are clearly needed for those
whose symptoms persist and for those not tolerating therapy, as
well as to relieve the societal burden created by untreated and
undertreated mental illness.
[0005] Major depression is a serious and persistent medical illness
affecting 9.9 million American adults, or approximately 5 percent
of the adult population in a given year. Among all medical
illnesses, major depression is the leading cause of disability in
the U.S. and many other developed countries. About three-fourths of
those who experience a first episode of depression will have at
least one other episode in their lives and some individuals have
several episodes in the course of a year. If untreated, episodes
commonly last anywhere from six months to a year. Left untreated,
depression can lead to suicide.
[0006] Treatment typically includes medications, psychotherapy, and
electroconvulsive therapy (ECT) used singly or in combination.
Although mild to moderate depression can often be treated
successfully with medications or psychotherapy used alone, severe
depression usually requires a combination of psychotherapy and
medication. ECT is highly effective for treatment resistant or
treatment intolerant severe depression and to relieve symptoms such
as psychosis or thoughts of suicide. However, ECT often requires
repeated therapies and can cause persistent and troubling memory
disturbances.
[0007] Bipolar disorder is another other common major psychiatric
disorders that may be treatment resistant. Bipolar disorder is a
chronic disorder that affects 2.3 million adult Americans. Bipolar
disorder is characterized by episodes of mania and depression that
can last from days to months. Persons with bipolar disorder usually
require lifelong treatment, and recovery between episodes is often
poor. Generally, those who suffer from bipolar disorder have
symptoms of both mania and depression (sometimes at the same time).
Medications are available to treat depression or mania and provide
mood stabilization. However, most persons with bipolar disorder
require multiple medications to achieve symptom relief. Thus,
persons with bipolar disease are at risk for medication related
side effects that prompt some to discontinue therapy. Others who
are compliant with therapy do not achieve complete symptom
relief.
[0008] Obsessive-Compulsive Disorder (OCD) affects 2 to 3% of the
population as confirmed in the U.S. and international
epidemiological studies, and is two to three times more common than
schizophrenia and bipolar disorder. Obsessions and compulsive
behaviors can cause suffering and severe restrictions on life
activities. Response to treatment varies from person to person.
Most people treated with effective medications find their symptoms
reduced by about 40 percent to 50 percent. Although such symptom
relief is welcome, freedom from symptoms is rarely achieved and
only a small number of people are fortunate to go into total
remission. Only one fifth of patients achieve full remission within
one decade of the onset of the illness and two-thirds continue to
experience symptoms despite treatment with selective serotonin
reuptake inhibitor drugs (SSRIs) and the use of behavior
therapy.
[0009] Some persons with chronic, treatment resistant mental
illness have turned to surgical therapies. Frontal lobotomy was
championed in the late 1930s to the 1970s. Although effective in
some cases, the surgery was crude, not standardized and involved
destruction of a large region of the frontal lobe. The procedure
was largely abandoned because of unacceptable surgical
complications and because of ethical violations in its application.
A few centers continued to offer surgical therapy to the most
devastated patients. The National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research (1977)
indicated that more than half of 400 surgeries performed annually
between 1971 and 1973 for psychiatric indications were efficacious,
and there is reason to believe efficacy has improved since
then.
[0010] Recently, neurosurgeons have developed more precise surgical
procedures to treat psychiatric disorders, including depression
and, more commonly, obsessive-compulsive disorder. The majority of
these procedures involve targeted ablative procedures. In these
refractory patients, stereotactic surgical interventions performed
include subcaudate tractotomy, limbic leucotomy, capsulotomy, and
cingulotomy. Cingulotomy is the most commonly performed procedure.
Twenty-five to 30% of patients treated with cingulotomy experience
improvement at more than 2 years follow-up. However, these
procedures are associated with risks including changes in
personality and development of epilepsy. Other adverse effects
include frontal lobe deficit in as many as 30% with fatigue,
emotional blunting, emotional incontinence, indifference, low
initiative, disinhibition and impaired judgment. These procedures
carry the risk that the lesion will be malpositioned, which may
require repeated surgery to extend the size of the lesion. Thus,
concerns about safety and the irreversibility of surgical
procedures remain.
[0011] Due to the limited response to lesion-based surgery and
concerns about adverse effects, some investigators have turned to
electrical stimulation therapy. Building on the experience from
essential tremor and Parkinson's Disease, investigators have
utilized commercially available deep brain stimulators implanted in
the anterior internal capsule bilaterally and have reported
symptomatic improvement in OCD. However, because of the stimulation
requirements for clinical response (4 to 10.5V, impedance 700 ohms,
pulse width 210 microseconds, 100 Hz frequency) the stimulator
battery requires replacement every 5 to 12 months, limiting patient
acceptance for this therapy.
[0012] The neuroanatomical base for many psychiatric disorders is
better understood because of advances in functional neuroimaging,
such as Positron Emission Tomography (PET), Magnetic Resonance
Imaging (MRI), Functional MRI (fMRI), and Magnetoencephalography
(MEG). In addition, clinical observations after destructive brain
lesions identify regions subserving specific aspects of behavior
and affect. The cingulate cortex is a large structure around the
rostrum of the corpus callosum that has extensive projections with
the amygdala, periaqueductal grey, ventral striatum, orbitofrontal
and anterior insular cortices. This structure and its
interconnections are intimately involved in mood and behavior.
Dysfunction of the cingulate and disruption of its connections has
been implicated in a number of psychiatric disorders. As noted
above, cingulotomy is the most common psychosurgery procedure for
major depression and obsessive-compulsive disorder. This procedure
is effective for many but carries considerable risk for
post-surgical changes in personality and motivation, and for
post-operative epilepsy.
[0013] The size and complexity of the cingulate cortex poses a
challenge in targeting the region responsible for specific
psychiatric and behavioral disorders. The cingulate is divided
functionally into regions concerned with affect and cognition.
Affect is mediated in cingulate regions 25, 33 and rostral area 24
that are extensively interconnected to the amygdala and
periaqueductal grey, as well as autonomic brainstem nuclei. The
cognitive division resides in caudal areas 24' and 32', and in
cingulate motor areas in the cingulate sulcus and nociceptive
cortex. Individuals with disturbances to the cingulate cortex, such
as those with cingulate onset epilepsy, often display sociopathic
behavior. Elevated anterior cingulate activity may contribute to
tics, obsessive-compulsive behaviors and aberrant social behavior.
Reduced cingulate activity can contribute to schizophrenia,
behavioral disorders such as akinetic mutism, diminished
self-awareness and depression, motor neglect and impaired
initiation of movement, reduced pain response and abnormal social
behavior.
[0014] There is a need for a responsive implantable system capable
of ameliorating the symptoms of, and in some cases the underlying
causes of, various psychiatric disorders.
SUMMARY OF THE INVENTION
[0015] Modulation of the function of the cingulate cortex can
alleviate symptoms associated with psychiatric disorders believed
to arise because of functional or structural abnormalities of this
structure. Research indicates that a number of psychiatric disease
are mediated through the cingulate cortex, including major
depression, obsessive compulsive disorder, panic and anxiety
disorders, explosive behavior disorder, post-traumatic stress
disorder, substance addiction and schizophrenia. Dysfunction of the
cingulate cortex is also implicated in the social disability
associated with autism and pervasive developmental disorders.
[0016] In systems, devices and methods according to the present
invention, therapy for the psychiatric diseases set forth above is
provided by means of a device that is able to provide responsive
and programmed electrical stimulation to the cingulate cortex and
other relevant portions of the brain and peripheral nervous
system.
[0017] In an embodiment of the invention, a device is implanted in
the cranium and attached to leads with electrodes at the distal end
of each lead. The electrodes are placed within or against the
entire length of cingulate cortex, whether in the form of a depth
electrode or a subdural electrode. A single electrode or multiple
electrodes may be implanted.
[0018] The device has a sensing function that responds to changes
in a biological marker. Such biological markers could be changes in
electrical activity, changes in concentration of inhibitory or
excitatory neurochemicals, changes in proteins or other gene
products, or changes in temperature or markers of metabolic rate.
Sensing electrodes are placed over the cingulate cortex or at a
distance.
[0019] Responsive therapy is provided at some location within the
cingulate cortex. Such therapy may include a depolarizing
electrical stimulation, drug delivery or changes in temperature. In
addition, therapy delivery can be programmed by the physician in
response to the patient's symptoms. The device also includes the
capability for therapy to be triggered by the patient.
[0020] Such a device system could provide benefit for those
individuals with treatment resistant psychiatric illness and for
those who experience drug-related side effects that limit quality
of life. In addition, a device therapy as described above can be
anticipated to have a more favorable safety profile than cortical
resection or cortical lesion, and will be modifiable across
individuals and over time and is reversible if the desired effects
are not achieved.
[0021] The precise region of the cingulate cortex over which
therapy is optimally applied may differ from individual to
individual and by the psychiatric or behavioral disorder. The
proposed electrode array affords wide coverage of the cingulate.
Also, the electrodes over which therapy is applied can be adjusted
according to the patient's short and long-term response.
[0022] The device provides continuous monitoring of
electrocorticographic signals. This capability can identify
disturbances in brain electrical activity over the cingulate gyrus,
which is a region that cannot be adequately monitored by scalp EEG
due to its distance from the recording electrodes and the
significant filtering effect of skull and scalp. This is an
especially important capability of the system because psychiatric
disorders are likely to be accompanied by dynamic electrographic
disturbances. This device will also enable continuous monitoring of
other biological markers that may reveal signals of disease and
disease symptoms. Identifying these biological markers will
contribute to knowledge regarding the underlying pathophysiology of
these diseases and will provide information that may open new
avenues for targeted therapy.
[0023] Direct cortical stimulation of the cingulate cortex using a
device according to the invention provides advantages over
resective and lesion-based surgery and over deep-brain stimulation.
Targeted cortical stimulation (as opposed to the high amount of
energy required to achieve symptom relief from stimulation of
anterior capsule electrodes) promises longer battery life. As
described above, an exemplary device utilizes two leads of four
electrodes each. Using either depth or subdural leads (or a
combination of the two), electrodes can be applied over much of the
cingulate cortex bilaterally. Optimal stimulation electrodes can be
configured over time as a patient's symptoms are observed.
Stimulation may be quite focal, using adjacent electrodes as anode
and cathode, or can be applied to both left and right cingulate
cortices simultaneously by utilizing all eight electrodes referred
to the can of the device.
[0024] Another advantage of the implantable neurostimulator system
is the capacity to apply modifiable stimulation settings. In an
embodiment of the invention, pulse widths can be set between 40 and
1000 microseconds, pulse frequency may range between 1 and 333 Hz,
and current can be adjusted between 0.5 and 12 milliamps. This
ensures that patients receive the optimal pulse settings without
adverse effects. It is reasonable to assume that individual
patients will differ in terms of the optimal stimulus settings. A
practitioner of ordinary skill would be able to make adjustments to
these parameters based on clinical observations.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] These and other objects, features, and advantages of the
invention will become apparent from the detailed description below
and the accompanying drawings, in which:
[0026] FIG. 1 is a drawing of a neurostimulator device according to
the invention in communication with an exemplary brain hemisphere
including the cingulate gyrus;
[0027] FIG. 2 is a schematic illustration of a patient's head
showing the placement of an implantable neurostimulator according
to an embodiment of the invention;
[0028] FIG. 3 is a schematic illustration of a patient's cranium
showing the implantable neurostimulator of FIG. 2 as implanted,
including a lead extending to the patient's brain;
[0029] FIG. 4 is a block diagram illustrating a system context in
which an implantable neurostimulator according to the invention is
implanted and operated;
[0030] FIG. 5 is a block diagram illustrating the major functional
subsystems of an implantable neurostimulator according to the
invention;
[0031] FIG. 6 is a drawing of an exemplary brain hemisphere and an
exemplary cortical electrode positioned over the cingulate
gyrus;
[0032] FIG. 7 is a drawing of an exemplary brain hemisphere and an
exemplary depth electrode positioned in the cingulate gyrus;
[0033] FIG. 8 is a block diagram illustrating the functional
components of the detection subsystem of the implantable
neurostimulator shown in FIG. 5;
[0034] FIG. 9 is a block diagram illustrating the components of the
waveform analyzer of the detection subsystem of FIG. 8;
[0035] FIG. 10 is a flow chart setting forth an illustrative
process performed by hardware functional components of the
neurostimulator of FIG. 5 in treating psychiatric disorders
according to the invention;
[0036] FIG. 11 is a flow chart illustrating a process
advantageously used by a system according to the invention to treat
major depression;
[0037] FIG. 12 is a flow chart illustrating a process
advantageously used by a system according to the invention to treat
bipolar disorder;
[0038] FIG. 13 is a flow chart illustrating a process
advantageously used by a system according to the invention to treat
anxiety and obsessive-compulsive disorders;
[0039] FIG. 14 is a flow chart illustrating a process
advantageously used by a system according to the invention to treat
post-traumatic stress disorder;
[0040] FIG. 15 is a flow chart illustrating a process
advantageously used by a system according to the invention to treat
addiction;
[0041] FIG. 16 is a flow chart illustrating a process
advantageously used by a system according to the invention to treat
schizophrenia;
[0042] FIG. 17 is a flow chart illustrating a process
advantageously used by a system according to the invention to treat
autism and other developmental disorders; and
[0043] FIG. 18 illustrates a set of therapy waveforms for
electrical stimulation that may be used by a neurostimulator
according to the invention to treat psychiatric disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0044] The invention is described below, with reference to detailed
illustrative embodiments. It will be apparent that a system
according to the invention may be embodied in a wide variety of
forms. Consequently, the specific structural and functional details
disclosed herein are representative and do not limit the scope of
the invention.
[0045] FIG. 1 illustrates, schematically, an implantable
neurostimulator device 110 in communication with various locations
within a patient's brain 112, particularly the cingulate gyrus 114.
In a system according to the invention, the neurostimulator device
receives signals from the patient's brain 112 (or other
physiological indicators) and responsively treats symptoms or
conditions of psychological illness.
[0046] FIG. 2 depicts an intracranial implantation of the device
110 according to the invention, which in one embodiment is a small
self-contained responsive neurostimulator. As the term is used
herein, a responsive neurostimulator is a device capable of
detecting or predicting neurological events, such as abnormal
electrical activity, and providing electrical stimulation to neural
tissue in response to that activity, where the electrical
stimulation is specifically intended to terminate the abnormal
activity, treat a neurological event, prevent an unwanted
neurological event from occurring, or lessen the severity or
frequency of certain symptoms of a neurological disorder. As
disclosed herein, the responsive neurostimulator detects abnormal
neurological activity by systems and methods according to the
invention.
[0047] Preferably, an implantable device according to the invention
is capable of detecting or predicting any kind of neurological
event that has a representative electrographic signature. While the
disclosed embodiment is described primarily as responsive to
symptoms and conditions present in psychiatric disorders, it should
be recognized that it is also possible to respond to other types of
neurological disorders, such as epilepsy, movement disorders (e.g.
the tremors characterizing Parkinson's disease), migraine
headaches, and chronic pain. Preferably, neurological events
representing any or all of these afflictions can be detected when
they are actually occurring, in an onset stage, or as a predictive
precursor before clinical symptoms begin.
[0048] In the disclosed embodiment, the neurostimulator is
implanted intracranially in a patient's parietal bone 310, in a
location anterior to the lambdoid suture 312 (see FIG. 3). It
should be noted, however, that the placement described and
illustrated herein is merely exemplary, and other locations and
configurations are also possible, in the cranium or elsewhere,
depending on the size and shape of the device and individual
patient needs, among other factors. The device 110 is preferably
configured to fit the contours of the patient's cranium 314. In an
alternative embodiment, the device 110 is implanted under the
patient's scalp 212 (see FIG. 2) but external to the cranium; it is
expected, however, that this configuration would generally cause an
undesirable protrusion in the patient's scalp where the device is
located. In yet another alternative embodiment, when it is not
possible to implant the device intracranially, it may be implanted
pectorally (not shown), with leads extending through the patient's
neck and between the patient's cranium and scalp, as necessary.
[0049] It should be recognized that the embodiment of the device
110 described and illustrated herein is preferably a responsive
neurostimulator for detecting and treating various psychiatric
disorders and related disorders by detecting neurophysiological
conditions, symptoms, or their onsets or precursors, and preventing
and/or relieving such conditions and symptoms.
[0050] In an alternative embodiment of the invention, the device
110 is not a responsive neurostimulator, but is an apparatus
capable of detecting neurological conditions and events and
performing actions in response thereto. The actions performed by
such an embodiment of the device 110 need not be therapeutic, but
may involve data recording or transmission, providing warnings to
the patient, or any of a number of known alternative actions. Such
a device will typically act as a diagnostic device when interfaced
with external equipment, as will be discussed in further detail
below.
[0051] The device 110, as implanted intracranially, is illustrated
in greater detail in FIG. 3. The device 110 is affixed in the
patient's cranium 314 by way of a ferrule 316. The ferrule 316 is a
structural member adapted to fit into a cranial opening, attach to
the cranium 314, and retain the device 110.
[0052] To implant the device 110, a craniotomy is performed in the
parietal bone 310 anterior to the lambdoid suture 312 to define an
opening 318 slightly larger than the device 110. The ferrule 316 is
inserted into the opening 318 and affixed to the cranium 314,
ensuring a tight and secure fit. The device 110 is then inserted
into and affixed to the ferrule 316.
[0053] As shown in FIG. 3, the device 110 includes a lead connector
320 adapted to receive one or more electrical leads, such as a
first lead 322. The lead connector 320 acts to physically secure
the lead 322 to the device 110, and facilitates electrical
connection between a conductor in the lead 322 coupling an
electrode to circuitry within the device 110. The lead connector
320 accomplishes this in a substantially fluid-tight environment
with biocompatible materials.
[0054] The lead 322, as illustrated, and other leads for use in a
system or method according to the invention, is a flexible
elongated member having one or more conductors. As shown, the lead
322 is coupled to the device 110 via the lead connector 320, and is
generally situated on the outer surface of the cranium 314 (and
under the patient's scalp 212), extending between the device 110
and a burr hole 324 or other cranial opening, where the lead 322
enters the cranium 314 and is coupled to a depth electrode (e.g.,
one of the sensors 512-518 of FIG. 5) implanted in a desired
location in the patient's brain. If the length of the lead 322 is
substantially greater than the distance between the device 110 and
the burr hole 324, any excess may be urged into a coil
configuration under the scalp 212. As described in U.S. Pat. No.
6,006,124 to Fischell on Dec. 21, 1999, et al. entitled "MEANS AND
METHODS FOR THE PLACEMENT OF BRAIN ELECTRODES," which is hereby
incorporated by reference as though set forth in full herein, the
burr hole 324 is sealed after implantation to prevent further
movement of the lead 322; in an embodiment of the invention, a burr
hole cover apparatus is affixed to the cranium 314 at least
partially within the burr hole 324 to provide this
functionality.
[0055] The device 110 includes a durable outer housing 326
fabricated from a biocompatible material. Titanium, which is light,
extremely strong, and biocompatible, is used in analogous devices,
such as cardiac pacemakers, and would serve advantageously in this
context. As the device 110 is self-contained, the housing 326
encloses a battery and any electronic circuitry necessary or
desirable to provide the functionality described herein, as well as
any other features. As will be described in further detail below, a
telemetry coil may be in the interior of the device 110 or provided
outside of the housing 326 (and potentially integrated with the
lead connector 320) to facilitate communication between the device
110 and external devices.
[0056] The neurostimulator configuration described herein and
illustrated in FIG. 3 provides several advantages over alternative
designs. First, the self-contained nature of the neurostimulator
substantially decreases the need for access to the device 110,
allowing the patient to participate in normal life activities. Its
small size and intracranial placement causes a minimum of cosmetic
disfigurement. The device 110 will fit in an opening in the
patient's cranium, under the patient's scalp, with little
noticeable protrusion or bulge. The ferrule 316 used for
implantation allows the craniotomy to be performed and fit verified
without the possibility of breaking the device 110, and also
provides protection against the device 110 being pushed into the
brain under external pressure or impact. A further advantage is
that the ferrule 316 receives any cranial bone growth, so at
explant, the device 110 can be replaced without removing any bone
screws--only the fasteners retaining the device 110 in the ferrule
316 need be manipulated.
[0057] As stated above, and as illustrated in FIG. 4, a
neurostimulator according to the invention operates in conjunction
with external equipment. The implantable neurostimulator device 110
is mostly autonomous (particularly when performing its usual
sensing, detection, and stimulation capabilities), but preferably
includes a selectable part-time wireless link 410 to external
equipment such as a programmer 412. In the disclosed embodiment of
the invention, the wireless link 410 is established by moving a
wand (or other apparatus) having communication capabilities and
coupled to the programmer 412 into communication range of the
implantable neurostimulator device 110. The programmer 412 can then
be used to manually control the operation of the device, as well as
to transmit information to or receive information from the
implantable neurostimulator 110. Several specific capabilities and
operations performed by the programmer 412 in conjunction with the
device will be described in further detail below.
[0058] The programmer 412 is capable of performing a number of
advantageous operations in connection with the invention. In
particular, the programmer 412 is able to specify and set variable
parameters in the implantable neurostimulator device 110 to adapt
the function of the device to meet the patient's needs, upload or
receive data (including but not limited to stored EEG waveforms,
parameters, or logs of actions taken) from the implantable
neurostimulator 110 to the programmer 412, download or transmit
program code and other information from the programmer 412 to the
implantable neurostimulator 110, or command the implantable
neurostimulator 110 to perform specific actions or change modes as
desired by a physician operating the programmer 412. To facilitate
these functions, the programmer 412 is adapted to receive clinician
input 414 and provide clinician output 416; data is transmitted
between the programmer 412 and the implantable neurostimulator 110
over the wireless link 410.
[0059] The programmer 412 may be used at a location remote from the
implantable neurostimulator 110 if the wireless link 410 is enabled
to transmit data over long distances. For example, the wireless
link 410 may be established by a short-distance first link between
the implantable neurostimulator 110 and a transceiver, with the
transceiver enabled to relay communications over long distances to
a remote programmer 412, either wirelessly (for example, over a
wireless computer network) or via a wired communications link (such
as a telephonic circuit or a computer network).
[0060] The programmer 412 may also be coupled via a communication
link 418 to a network 420 such as the Internet. This allows any
information uploaded from the implantable neurostimulator 110, as
well as any program code or other information to be downloaded to
the implantable neurostimulator 110, to be stored in a database 422
at one or more data repository locations (which may include various
servers and network-connected programmers like the programmer 412).
This would allow a patient (and the patient's physician) to have
access to important data, including past treatment information and
software updates, essentially anywhere in the world where there is
a programmer (like the programmer 412) and a network connection.
Alternatively, the programmer 412 may be connected to the database
422 over a trans-telephonic link.
[0061] In yet another alternative embodiment of the invention, the
wireless link 410 from the implantable neurostimulator 110 may
enable a transfer of data from the neurostimulator 110 to the
database 422 without any involvement by the programmer 412. In this
embodiment, as with others, the wireless link 410 may be
established by a short-distance first link between the implantable
neurostimulator 110 and a transceiver, with the transceiver enabled
to relay communications over long distances to the database 422,
either wirelessly (for example, over a wireless computer network)
or via a wired communications link (such as trans-telephonically
over a telephonic circuit, or over a computer network).
[0062] In the disclosed embodiment, the implantable neurostimulator
110 is also adapted to receive communications from an initiating
device 424, typically controlled by the patient or a caregiver.
Accordingly, patient input 426 from the initiating device 424 is
transmitted over a wireless link to the implantable neurostimulator
110; such patient input 426 may be used to cause the implantable
neurostimulator 110 to switch modes (on to off and vice versa, for
example) or perform an action (e.g., store a record of EEG data).
Preferably, the initiating device 424 is able to communicate with
the implantable neurostimulator 110 through a communication
subsystem 530 (FIG. 5), and possibly in the same manner the
programmer 412 does. The link may be unidirectional (as with the
magnet and GMR sensor described below), allowing commands to be
passed in a single direction from the initiating device 424 to the
implantable neurostimulator 110, but in an alternative embodiment
of the invention is bidirectional, allowing status and data to be
passed back to the initiating device 424. Accordingly, the
initiating device 424 may be a programmable personal data assistant
(PDA) or other hand-held computing device, such as a PALM device or
POCKET PC. However, a simple form of initiating device 424 may take
the form of a permanent magnet, if the communication subsystem 530
(FIG. 5) is adapted to identify magnetic fields and interruptions
therein as communication signals.
[0063] The implantable neurostimulator 110 (FIG. 1) generally
interacts with the programmer 412 (FIG. 4) as described below. Data
stored in a memory subsystem 526 (FIG. 5) of the device 110 can be
retrieved by the patient's physician through the wireless
communication link 410, which operates through the communication
subsystem 530 of the implantable neurostimulator 110. In connection
with the invention, a software operating program run by the
programmer 412 allows the physician to read out a history of
neurological events detected including EEG information before,
during, and after each neurological event, as well as specific
information relating to the detection of each neurological event
(such as, in one embodiment, the time-evolving energy spectrum of
the patient's EEG). The programmer 412 also allows the physician to
specify or alter any programmable parameters of the implantable
neurostimulator 110. The software operating program also includes
tools for the analysis and processing of recorded EEG records to
assist the physician in developing optimized seizure detection
parameters for each specific patient.
[0064] In an embodiment of the invention, the programmer 412 is
primarily a commercially available PC, laptop computer, or
workstation having a CPU, keyboard, mouse and display, and running
a standard operating system such as MICROSOFT WINDOWS, LINUX, UNIX,
or APPLE MAC OS. It is also envisioned that a dedicated programmer
apparatus with a custom software package (which may not use a
standard operating system) could be developed.
[0065] When running the computer workstation software operating
program, the programmer 412 can process, store, play back and
display on the display the patient's EEG signals, as previously
stored by the implantable neurostimulator 110 of the implantable
neurostimulator device.
[0066] The computer workstation software operating program also has
the capability to simulate the detection and prediction of abnormal
electrical activity and other symptoms of psychiatric disorders.
Furthermore, the software operating program of the present
invention has the capability to allow a clinician to create or
modify a patient-specific collection of information comprising, in
one embodiment, algorithms and algorithm parameters for specific
activity detection. The patient-specific collection of detection
algorithms and parameters used for neurological activity detection
according to the invention will be referred to herein as a
detection template or patient-specific template. The
patient-specific template, in conjunction with other information
and parameters generally transferred from the programmer to the
implanted device (such as stimulation parameters, time schedules,
and other patient-specific information), make up a set of
operational parameters for the neurostimulator.
[0067] Following the development of a patient-specific template on
the programmer 412, the patient-specific template would be
downloaded through the communications link 410 from the programmer
412 to the implantable neurostimulator 110.
[0068] The patient-specific template is used by a detection
subsystem 522 and CPU 528 (FIG. 5) of the implantable
neurostimulator 110 to detect conditions indicating treatment
should be administered, and can be programmed by a clinician to
result in responsive stimulation of the patient's brain, as well as
the storage of EEG records before and after the detection,
facilitating later clinician review.
[0069] Preferably, the database 422 is adapted to communicate over
the network 420 with multiple programmers, including the programmer
412 and additional programmers 428, 430, and 432. It is
contemplated that programmers will be located at various medical
facilities and physicians' offices at widely distributed locations.
Accordingly, if more than one programmer has been used to upload
EEG records from a patient's implantable neurostimulator 110, the
EEG records will be aggregated via the database 422 and available
thereafter to any of the programmers connected to the network 420,
including the programmer 412.
[0070] FIG. 5 is an overall block diagram of the implantable
neurostimulator device 110 used for measurement, detection, and
treatment according to the invention. Inside the housing of the
neurostimulator device 110 are several subsystems making up the
device. The implantable neurostimulator device 110 is capable of
being coupled to a plurality of sensors 512, 514, 516, and 518
(each of which may be individually or together connected to the
implantable neurostimulator device 110 via one or more leads),
which in an embodiment of the invention are electrodes used for
both sensing and stimulation as well as the delivery of other
treatment modalities. In the illustrated embodiment, the coupling
is accomplished through a lead connector. Although four sensors are
shown in FIG. 5, it should be recognized that any number is
possible, and in the embodiment described in detail below, eight
electrodes are used as sensors. In fact, it is possible to employ
an embodiment of the invention that uses a single lead with at
least two electrodes, or two leads each with a single electrode (or
with a second electrode provided by a conductive exterior portion
of the housing in one embodiment), although bipolar sensing between
two closely spaced electrodes on a lead is preferred to minimize
common mode signals including noise.
[0071] The sensors 512-518 are in contact with the patient's brain
or are otherwise advantageously located to receive EEG signals or
provide electrical stimulation or another therapeutic modality.
Each of the sensors 512-518 is also electrically coupled to a
sensor interface 520. Preferably, the electrode interface is
capable of selecting each electrode as required for sensing and
stimulation; accordingly the electrode interface is coupled to a
detection subsystem 522 and a therapy subsystem 524 (which, in
various embodiments of the invention, may provide electrical
stimulation and other therapies). The sensor interface 520 may also
provide any other features, capabilities, or aspects, including but
not limited to amplification, isolation, and charge-balancing
functions, that are required for a proper interface with
neurological tissue and not provided by any other subsystem of the
device 110.
[0072] In an embodiment of the invention in which electrographic
signals are received by electrodes and analyzed, the detection
subsystem 522 includes and serves primarily as an EEG waveform
analyzer. It will be recognized that similar principles apply to
the analysis of other types of waveforms received from other types
of sensors. Detection is generally accomplished in conjunction with
a central processing unit (CPU) 528. The waveform analyzer function
is adapted to receive signals from the sensors 512-518, through the
sensor interface 520, and to process those EEG signals to identify
abnormal neurological activity characteristic of a disease or
symptom thereof. One way to implement such EEG analysis
functionality is disclosed in detail in U.S. Pat. No. 6,016,449 to
Fischell et al., incorporated by reference above. Additional
inventive methods are described in U.S. Pat. No. 6,810,285 to Pless
et al., filed on Jun. 28, 2001 and entitled "SEIZURE SENSING AND
DETECTION USING AN IMPLANTABLE DEVICE," of which relevant details
will be set forth below (and which is also hereby incorporated by
reference as though set forth in full). The detection subsystem may
optionally also contain further sensing and detection capabilities,
including but not limited to parameters derived from other
physiological conditions (such as electrophysiological parameters,
temperature, blood pressure, neurochemical concentration, etc.). In
general, prior to analysis, the detection subsystem performs
amplification, analog-to-digital conversion, and multiplexing
functions on the signals in the sensing channels received from the
sensors 512-518.
[0073] The therapy subsystem 524 is capable of applying electrical
stimulation or other therapies to neurological tissue. This can be
accomplished in any of a number of different manners. For example,
it may be advantageous in some circumstances to provide stimulation
in the form of a substantially continuous stream of pulses, or on a
scheduled basis. Preferably, therapeutic stimulation is provided in
response to abnormal neurological events or conditions detected by
the waveform analyzer function of the detection subsystem 522. As
illustrated in FIG. 5, the therapy subsystem 524 and the EEG
analyzer function of the detection subsystem 522 are in
communication; this facilitates the ability of therapy subsystem
524 to provide responsive electrical stimulation and other
therapies, as well as an ability of the detection subsystem 522 to
blank the amplifiers while electrical stimulation is being
performed to minimize stimulation artifacts. It is contemplated
that the parameters of a stimulation signal (e.g., frequency,
duration, waveform) provided by the therapy subsystem 524 would be
specified by other subsystems in the implantable device 110, as
will be described in further detail below.
[0074] In accordance with the invention, the therapy subsystem 524
may also provide for other types of stimulation, besides electrical
stimulation described above. In particular, in certain
circumstances, it may be advantageous to provide audio, visual, or
tactile signals to the patient, to provide somatosensory electrical
stimulation to locations other than the brain, or to deliver a drug
or other therapeutic agent (either alone or in conjunction with
stimulation).
[0075] Also the implantable neurostimulator device 110 contains a
memory subsystem 526 and the CPU 528, which can take the form of a
microcontroller. The memory subsystem is coupled to the detection
subsystem 522 (e.g., for receiving and storing data representative
of sensed EEG or other signals and evoked responses), the therapy
subsystem 524 (e.g., for providing stimulation waveform parameters
to the therapy subsystem for electrical stimulation), and the CPU
528, which can control the operation of (and store and retrieve
data from) the memory subsystem 526. In addition to the memory
subsystem 526, the CPU 528 is also connected to the detection
subsystem 522 and the therapy subsystem 524 for direct control of
those subsystems.
[0076] Also provided in the implantable neurostimulator device 110,
and coupled to the memory subsystem 526 and the CPU 528, is a
communication subsystem 530. The communication subsystem 530
enables communication between the device 110 and the outside world,
particularly an external programmer 412 and a patient-initiating
device 424, both of which are described above with reference to
FIG. 4. As set forth above, the disclosed embodiment of the
communication subsystem 530 includes a telemetry coil (which may be
situated inside or outside of the housing of the implantable
neurostimulator device 110) enabling transmission and reception of
signals, to or from an external apparatus, via inductive coupling.
Alternative embodiments of the communication subsystem 530 could
use an antenna for an RF link or an audio transducer for an audio
link. Preferably, the communication subsystem 530 also includes a
GMR (giant magnetoresistive effect) sensor to enable receiving
simple signals (namely the placement and removal of a magnet) from
a patient-initiating device; this capability can be used to
initiate signal recording as will be described in further detail
below.
[0077] If the therapy subsystem 524 includes the audio capability
set forth above, it may be advantageous for the communication
subsystem 530 to cause the audio signal to be generated by the
therapy subsystem 524 upon receipt of an appropriate indication
from the patient-initiating device (e.g., the magnet used to
communicate with the GMR sensor of the communication subsystem
530), thereby confirming to the patient or caregiver that a desired
action will be performed, e.g. that an EEG record will be
stored.
[0078] Several support components are present in the implantable
neurostimulator device 110, including a power supply 532 and a
clock supply 534. The power supply 532 supplies the voltages and
currents necessary for each of the other subsystems. The clock
supply 534 supplies substantially all of the other subsystems with
any clock and timing signals necessary for their operation,
including a real-time clock signal to coordinate programmed and
scheduled actions and the timer functionality used by the detection
subsystem 522 that is described in detail below.
[0079] In an embodiment of the invention, the therapy subsystem 524
is coupled to a thermal stimulator 536 and a drug dispenser 538,
thereby enabling therapy modalities other than electrical
stimulation. These additional treatment modalities will be
discussed further below. Any of the therapies delivered by the
therapy subsystem 524 is delivered to a therapy output at a
specific site; it will be recognized that the therapy output may be
a stimulation electrode, a drug dispenser outlet, or a thermal
stimulation site (e.g. Peltier junction or thermocouple) as
appropriate for the selected modality.
[0080] It should be observed that while the memory subsystem 526 is
illustrated in FIG. 5 as a separate functional subsystem, the other
subsystems may also require various amounts of memory to perform
the functions described above and others. Furthermore, while the
implantable neurostimulator device 110 is preferably a single
physical unit (i.e., a control module) contained within a single
implantable physical enclosure, namely the housing described above,
other embodiments of the invention might be configured differently.
The neurostimulator 110 may be provided as an external unit not
adapted for implantation, or it may comprise a plurality of
spatially separate units each performing a subset of the
capabilities described above, some or all of which might be
external devices not suitable for implantation. Also, it should be
noted that the various functions and capabilities of the subsystems
described above may be performed by electronic hardware, computer
software (or firmware), or a combination thereof. The division of
work between the CPU 528 and the other functional subsystems may
also vary--the functional distinctions illustrated in FIG. 5 may
not reflect the partitioning and integration of functions in a
real-world system or method according to the invention.
[0081] FIG. 6 depicts the previously illustrated hemisphere of a
patient's brain 112 with a distal end of an exemplary cortical lead
610 positioned thereupon. In the illustrated embodiment, the
cortical lead 610 approaches the cingulate cortex 114 from a
generally anterior direction; the lead 610 interfaces with the
neurostimulator device 110 (FIG. 1) at its proximal end (not
shown). The cortical lead may also be implanted from different
approaches, depending on the surgeon's preference. The distal end
of the cortical lead 610 bears four disc electrodes 612-618, each
of which is in contact with or in close proximity to the surface of
the cingulate gyrus 114. The entirety of the exemplary cortical
lead is formed from biocompatible materials such as silicone and
platinum.
[0082] FIG. 7 depicts the previously illustrated hemisphere of a
patient's brain 112 with a distal end of an exemplary depth lead
710 implanted therein. In the illustrated embodiment, the depth
lead 710 interfaces with the neurostimulator device 110 (FIG. 1) at
its proximal end (not shown). The distal end of the depth lead 710
bears four ring electrodes 712-718 preferably implanted into the
gray matter of the cingulate gyrus 114. As with the cortical lead
610, the depth lead 710 is fabricated from biocompatible
materials.
[0083] In the disclosed embodiment of the invention, the
neurostimulator device 110 is capable of receiving two leads, each
with four electrodes. One cortical lead 610 and one depth lead 710,
two cortical leads, or two depth leads can be used simultaneously
to achieve the desired coverage of the cingulate gyrus 114 or other
desired brain areas. It will be recognized that other embodiments
of a system according to the invention may receive more leads, or
leads and sensors in different forms than those specifically
disclosed herein.
[0084] FIG. 8 illustrates details of the detection subsystem 52
(FIG. 5). Inputs from the electrodes 512-518 are on the left, and
connections to other subsystems are on the right.
[0085] Signals received from the sensors 512-518 (as routed through
the sensor interface 520) are received in an input selector 810.
The input selector 810 allows the device to select which electrodes
or other sensors (of the sensors 512-518) should be routed to which
individual sensing channels of the detection subsystem 522, based
on commands received through a control interface 818 from the
memory subsystem 526 or the CPU 528 (FIG. 5). Preferably, when
electrodes are used for sensing, each sensing channel of the
detection subsystem 522 receives a bipolar signal representative of
the difference in electrical potential between two selectable
electrodes. Accordingly, the input selector 810 provides signals
corresponding to each pair of selected electrodes to a sensing
front end 812, which performs amplification, analog to digital
conversion, and multiplexing functions on the signals in the
sensing channels.
[0086] A multiplexed input signal representative of all active
sensing channels is then fed from the sensing front end 812 to a
waveform analyzer 814. The waveform analyzer 814 is preferably a
special-purpose digital signal processor (DSP) adapted for use with
the invention, or in an alternative embodiment, may comprise a
programmable general-purpose DSP. In the disclosed embodiment, the
waveform analyzer has its own scratchpad memory area 816 used for
local storage of data and program variables when the signal
processing is being performed. In either case, the signal processor
performs suitable measurement and detection methods described
generally above and in greater detail below. Any results from such
methods, as well as any digitized signals intended for storage
transmission to external equipment, are passed to various other
subsystems of the device 110, including the memory subsystem 526
and the CPU 528 (FIG. 5) through a data interface 820. Similarly,
the control interface 818 allows the waveform analyzer 814 and the
input selector 810 to be in communication with the CPU 528. The
waveform analyzer 714 is illustrated in detail in FIG. 9.
[0087] In the exemplary waveform analyzer illustrated in FIG. 9,
the interleaved digital data stream representing information from
all of the active sensing channels is first received by a channel
controller 910. The channel controller applies information from the
active sensing channels to a number of wave morphology analysis
units 912 and window analysis units 914. It is preferred to have as
many wave morphology analysis units 912 and window analysis units
914 as possible, consistent with the goals of efficiency, size, and
low power consumption necessary for an implantable device. In a
presently preferred embodiment of the invention, there are sixteen
wave morphology analysis units 912 and eight window analysis units
914, each of which can receive data from any of the sensing
channels of the sensing front end 812 (FIG. 8), and each of which
can be operated with different and independent parameters,
including differing sample rates, as will be discussed in further
detail below.
[0088] Each of the wave morphology analysis units 912 operates to
extract certain feature information from an input waveform.
Similarly, each of the window analysis units 914 performs certain
data reduction and signal analysis within time windows. Output data
from the various wave morphology analysis units 912 and window
analysis units 914 are combined via event detector logic 916. The
event detector logic 916 and the channel controller 910 are
controlled by control commands 918 received from the control
interface 818 (FIG. 8).
[0089] A "detection channel," as the term is used herein, refers to
a data stream including the active sensing front end 812 and the
analysis units of the waveform analyzer 814 processing that data
stream, in both analog and digital forms. It should be noted that
each detection channel can receive data from a single sensing
channel; each sensing channel preferably can be applied to the
input of any combination of detection channels. The latter
selection is accomplished by the channel controller 910. As with
the sensing channels, not all detection channels need to be active;
certain detection channels can be deactivated to save power or if
additional detection processing is deemed unnecessary in certain
applications.
[0090] In conjunction with the operation of the wave morphology
analysis units 912 and the window analysis units 914, a scratchpad
memory area 816 is provided for temporary storage of processed
data. The scratchpad memory area 816 may be physically part of the
memory subsystem 526 (FIG. 5), or alternatively may be provided for
the exclusive use of the waveform analyzer 814 (FIG. 8). Other
subsystems and components of a system according to the invention
may also be furnished with local scratchpad memory, if such a
configuration is advantageous.
[0091] A system according to the invention, particularly the
neurostimulator device 110, is contemplated to be capable of
multiple modalities of therapy. In general, regular or scheduled
therapy may be considered advantageous at certain times, and may be
scheduled to operate in parallel with responsive therapy modes.
Moreover, the neurostimulator device 110 is also gathering data to
enable therapy refinement in connection with the programmer 412
(FIG. 4) and other external equipment. This process is illustrated
in more detail in connection with FIG. 10.
[0092] A scheduler process maintained by the hardware of the
implantable neurostimulator device 110 (FIG. 1), typically in the
CPU 528 (FIG. 5), allows multiple tasks to be performed by the
neurostimulator device 110 in rapid sequence, effectively in
parallel. In general, the scheduler allows subsidiary data
collection, therapy delivery, and data analysis functions to be
performed regularly. The scheduler is initially checked (step
1010). If it is time to collect data (step 1012)--as specified,
generally, in a table of data collection times generated by the
programmer 412 (FIG. 4)--then a record of data is collected (step
1014). Various types of sensor data, including electrographic
signal waveforms, may be collected by a system according to the
invention. If it is time to deliver an episode of scheduled therapy
(step 1016), then therapy is delivered (step 1018). It should be
noted that various types of therapy may be delivered, including but
not limited to electrical stimulation and the administration of a
dose of a therapeutic agent. As with data collection times, therapy
times may be uploaded from the programmer 412 based on
patient-specific observations made in the past or on some other
desired dose schedule.
[0093] Inputs and other conditions are then observed (step 1020). A
responsive therapy decision is made (step 1022) based on the
conditions observed by the neurostimulator device 110, including
but not limited to electrographic activity, brain chemistry,
temperature, other indicia of physiological conditions and
metabolic rate, and patient intent (as indicated by a signal
received from the patient initiating device 424 (FIG. 4). Details
on the conditions and information considered in a therapy decision
are treated in more detail below with reference to FIGS. 11-17. If
therapy is indicated, therapy is delivered (step 1024).
[0094] It should be noted that the scheduler function may also
trigger other types of functions by the neurostimulator device 110,
such as administrative functions. The nature of these additional
functions would be understood by an engineer competent in designing
real-time systems.
[0095] A number of lines of evidence identify the cingulate as a
key region of the brain involved in major depression. Functional
and structural brain neuroimaging in persons with major depressive
disorder reveal abnormalities in the anterior cingulate cortex
(also referred to as the "ACC"). Anterior cingulate cortex volume
is reduced in persons with major depression as demonstrated by MRI
and by post-mortem study. PET scans show reduced cingulate
activation in depressed persons performing cognitive tasks. Such
abnormalities improve with relief of symptoms and worsen with
worsening symptoms.
[0096] These observations suggest that modulation of cingulate
metabolism by electrical stimulation in a dynamic and responsive
fashion could relieve depressive symptoms. Continuous recording of
electrocorticographic activity or of other biological markers
enables monitoring of disease state and can direct the therapeutic
electrical stimulation. Changes in metabolic activity could prompt
delivery of electrical stimulation that is determined by the
direction of change--that is stimulation that is primarily
excitatory can be applied when metabolism is inappropriately low
and an inhibitory stimulation applied when metabolism is abnormally
active. Stimulation can also be modified according to patient
symptoms. Another advantage of this system is that applying
stimulation only when the patient is symptomatic should extend
battery life beyond the battery life of a system providing
continuous stimulation.
[0097] Referring now to FIG. 11, a specific method for treating
depression begins by identifying baseline conditions (step 1110) in
metabolic rates and electrographic activity. Ideally, this step is
performed while the patient is feeling relatively symptom-free or
when the patient is at his or her usual level of depression. A
system according to the invention then receives inputs (step 1112)
and analyzes physiological activity (step 1114). If the patient's
metabolic rates, as determined by observing electrographic activity
and other indicia of metabolic rate, are abnormally low (step 1116)
in comparison to the baseline, excitatory therapy is applied (step
1118). Excitatory therapy may include electrical stimulation having
excitatory characteristics (or applied to a pathway that tends to
excite the target area) or the release of a therapeutic agent
having excitatory effects. If the patient's metabolic rates are
abnormally high (step 1120) in comparison to the baseline,
inhibitory therapy is applied (step 1122). Inhibitory therapy may
include electrical stimulation having inhibitory characteristics
(or applied to a pathway that tends to inhibit the target area) or
the release of a therapeutic agent having inhibitory effects.
[0098] Preferably, the method of treating depression includes the
ability to correlate symptom data to observed inputs (step 1124).
If the patient, using the initiating device 424 (FIG. 4) indicates
that an episode of depression or an exacerbation of depressive
symptoms is occurring, the neurostimulator device 110 can store a
record of data to be analyzed either by the CPU 528 (FIG. 5) or
offline by a programmer 412 (FIG. 4) or other device. Later
observations of the same or similar data will then suggest an
episode of depression, even when no patient input is received.
[0099] Bipolar disorder is associated with disturbances in
attention, cognition and impulse regulation thought to be related
to disturbances in the cingulate gyrus. There are structural
abnormalities in the cingulate in persons with bipolar disorder,
such as cellular and volumetric abnormalities. Functional MRI in
persons with bipolar disorder shows differential activation in the
cingulate depending upon whether the patient is depressed or is
experiencing elevated mood.
[0100] Similar to major depression, these findings imply that
metabolism, electrical activity, and neurochemicals vary with mood
and that stimulation therapy applied to the cingulate will be most
effective if it can be modified according to the patient's
symptoms. Mood changes in persons with bipolar disorder may occur
over months, weeks, days or even hours. Therefore, a responsive
system with modifiable stimulation parameters would appear to be of
great interest as a treatment for this disorder.
[0101] In FIG. 12, a specific method for treating bipolar disorder
begins by identifying baseline conditions (step 1210) in metabolic
rates and electrographic activity. Ideally, this step is performed
while the patient is feeling relatively symptom-free or when the
patient is at a known level of depression or mania. A system
according to the invention then receives inputs (step 1212) and
analyzes physiological activity (step 1214). If the patient's
metabolic rates, as determined by observing electrographic activity
and other indicia of metabolic rate, are abnormally low (step 1216)
in comparison to the baseline, excitatory therapy is applied (step
1218). Excitatory therapy may include electrical stimulation having
excitatory characteristics (or applied to a pathway that tends to
excite the target area) or the release of a therapeutic agent
having excitatory effects. If the patient's metabolic rates are
abnormally high (step 1220) in comparison to the baseline,
inhibitory therapy is applied (step 1222). Inhibitory therapy may
include electrical stimulation having inhibitory characteristics
(or applied to a pathway that tends to inhibit the target area) or
the release of a therapeutic agent having inhibitory effects.
[0102] As with depression, the method of treating bipolar disorder
preferably includes the ability to correlate observations to
information of interest (step 1224), in this case time. As noted,
bipolar disorder tends to be cyclic and episodic, and advantages
may be obtained by observing patterns in detected symptoms, thereby
enabling better scheduled therapy (as illustrated in FIG. 10) or
enhanced detection. Later observations of the same or similar data
at similar times of day, week, or month would then suggest an
episode of depression or mania, even when no patient input is
received.
[0103] The cingulate cortex is a structure implicated in
Obsessive-Compulsive Disorder (OCD) and anxiety disorders. Animal
models of anxiety and chronic behavioral stress reveal structural
and metabolic changes in the cingulate cortex. Persons with anxiety
disorders show abnormally high activation of the cingulate cortex
on fMRI during decision making. PET studies in patients with OCD
show variable changes in metabolism depending on symptoms.
Increased cingulate activation is observed in persons with OCD and
significant anxiety while those with compulsive hoarding have
decreased cingulate activation. Electroencephalographic
abnormalities are also described in persons with OCD.
Magnetoencephalography performed in patients with OCD and extreme
anxiety revealed paroxysmal rhythmic activity from the cingulate
and in other regions of the limbic cortex.
[0104] The neurostimulator system described herein promises benefit
to persons with OCD and anxiety disorders. Obsessive-compulsive
disorder is dynamic in that symptom severity varies over the
short-term and long-term. Symptom fluctuations must reflect changes
in brain physiology, such as the changes already observed in
metabolism and electrical activity. The capacity of the device 110
to record from the cingulate will offer advantages as
electroencephalographic markers of disease activity are further
defined and if other biological markers are discovered. This
provides further capacity to modify therapy in response to dynamic
organic processes and to provide responsive stimulation therapy
with or without scheduled stimulation.
[0105] In FIG. 13, a specific method for treating anxiety and
obsessive-compulsive disorders begins by receiving inputs (step
1310) and analyzing electrographic activity (step 1312).
[0106] If abnormal activation is observed (step 1314), typically by
monitoring metabolic rates or electrographic activity in comparison
to a baseline level, a first therapy is applied (step 1316).
Abnormally high activation would trigger delivery of an inhibitory
therapy, while abnormally low activation would trigger excitatory
therapy. As above, excitatory therapy may include electrical
stimulation having excitatory characteristics (or applied to a
pathway that tends to excite the target area) or the release of a
therapeutic agent having excitatory effects, while inhibitory
therapy may include electrical stimulation having inhibitory
characteristics (or applied to a pathway that tends to inhibit the
target area) or the release of a therapeutic agent having
inhibitory effects.
[0107] If persistent abnormal neurologic activity is observed (step
1318), a second therapy is applied (step 1320). The nature of the
second therapy may be the same as or different from that of the
first therapy, and whether activation or inhibition is desired. The
therapy desired in turn may depend on whether the patient tends to
exhibit OCD plus anxiety or compulsive hoarding, to name the
examples set forth above. Other patient-specific therapies may also
be applicable and may depend on clinical observations. When
possible, information is collected and correlated with observations
to generate trends (step 1322) and improve performance.
[0108] Post-Traumatic Stress Disorder (PTSD) is characterized by
exaggerated emotional and behavioral responses (hyperarousal) to
stimuli associated with a traumatic experience. Many investigators
propose that the anterior cingulate--a brain region that appears to
be involved in fear-conditioning--is dysfunctional in PTSD.
Quantitative MRI reveals a reduction in volume in the cingulate of
persons with PTSD. Functional MRI investigations describe
significantly less activation of the anterior cingulate gyrus than
expected with presentation of stressful stimuli. Observations that
chronic behavioral stress induces architectural and neurochemical
changes in the cingulate gyrus also suggest that this structure may
be an appropriate target for treating PTSD.
[0109] An exemplary specific course of treatment for PTSD using an
implantable neurostimulator device 110 is illustrated in FIG. 14.
Initially, as PTSD can be characterized by physiological changes, a
first course of non-responsive therapy is applied (step 1410). This
therapy may include electrical stimulation or any of the other
treatment modalities discussed herein. This initial course of
therapy is continued until conditions change (step 1412) and
improvement is observed.
[0110] Following the initial course of therapy and a change in
conditions, the neurostimulator device processes inputs (step 1414)
and analyzes electrographic or other physiological brain activity
(step 1416). If less activation is observed and a low level of
electrographic or other brain activity is noted (step 1418), then a
second therapy is applied (step 1420), typically excitatory. The
nature of the therapy may vary from patient to patient. Finally,
where possible, observations of low activation are correlated (step
1422) with stressful stimuli, as indicated by a patient using the
initiating device 424 (FIG. 4) or by other means, thereby
facilitating analysis of the correlation (either by the device 110
or offline), enhancement of detection parameters, and improved
performance in the future.
[0111] PET scans in substance addicted individuals display
metabolic activation of the cingulate during intoxication, craving
and binging. In contrast, there is cingulate hypometabolism during
withdrawal. A hypothesis is advanced that changes in dopamine
release and in dopamine receptors lead to changes in cingulate
metabolic rates during intoxication, withdrawal, and craving. These
observations suggest that disease activity can be monitored
directly from the cingulate and that modulating cingulate
metabolism by providing electrical stimulation therapy may lessen
the biologically based withdrawal and craving that leads to
relapse.
[0112] In a system according to the invention, the hypometabolism
observed during withdrawal is sought to be treated as illustrated
in FIG. 15. Initially, baseline metabolism conditions are observed
(step 1510). Baseline conditions may include typical electrographic
activity and other indicia of metabolism as discussed elsewhere in
this document. Following that, the neurostimulator device 110
processes inputs (step 1512) and analyzes electrographic activity
(step 1514). If the patient's metabolic rates, as determined by
observing electrographic activity and other indicia of metabolic
rate, are abnormally low (step 1516) in comparison to the baseline,
excitatory therapy is applied (step 1518). As stated above,
excitatory therapy may include electrical stimulation having
excitatory characteristics (or applied to a pathway that tends to
excite the target area) or the release of a therapeutic agent
having excitatory effects.
[0113] Preferably, observations of low metabolic rate are
correlated (step 1520) with the patient's symptoms by allowing
input via initiating device 424 (FIG. 4). In this manner, the
patient can confirm episodes of withdrawal that are observed by the
device 110 as periods of low metabolic rate, thereby validating the
approach and enabling refinement of detection and therapy according
to the invention. Also, the device can enable the patient to
self-deliver therapy in response to symptoms of craving or
withdrawal, much as patient-delivered devices deliver narcotic
medications for pain. The device would be programmed in such a way
that the patient would not be able to deliver stimulation or other
therapy that could be harmful.
[0114] The anterior cingulate cortex (ACC) is a key region within
the human prefrontal cortex that has been shown to be dysfunctional
in schizophrenic patients. PET scans demonstrate hypometabolism of
the cingulate in patients with schizophrenia during cognitive
processing tasks as well as in the resting state. Abnormalities in
this functional neuroimaging likely reflect underlying disturbances
in cingulate anatomy and neurochemistry. Specific reductions in the
volume of the cingulate cortex is described by MRI in patients with
schizophrenia and is also detected by estimating total cell number
in cytoarchitectonically defined areas from the prefrontal cortex.
Neurochemical abnormalities described in the cingulate cortex of
persons with schizophrenia include a reduction the dopamine D2
receptors and dysfunction of excitatory neurotransmitters such as
glutamate.
[0115] Persons with schizophrenia have electroencephalographic
abnormalities in the cingulate cortex. Electrophysiological
recordings from the cingulate cortex in animals and in persons with
epilepsy indicate that background activity is similar to that of
the hippocampus. However, persons with schizophrenia have poor
synchronization of the EEG in the cingulate and abnormalities
specifically in frequencies of about 40 Hz. These fast gamma
frequencies cannot be detected by scalp EEG but are well
represented with intracranial recordings. Persons with
schizophrenia also have abnormal electrophysiological activity in
the anterior cingulate cortex during various cognitive activation
tasks as demonstrated by three-dimensional source location with
low-resolution electromagnetic tomography (LORETA), including a
significant increase in delta EEG activity.
[0116] This critical mass of research supports the premise that
therapy targeted to the cingulate cortex will favorably influence
schizophrenic symptoms. Anatomical, neurochemical and
electrophysiological abnormalities in the resting and activated
states will provide biological markers for responsive therapy.
[0117] The neurostimulator system provides extensive coverage of
the cingulate cortex from it's anterior to posterior extent, which
enables anatomically targeted therapy. Continuous recording enables
detection of changes in electrographic activity and will provide
information critical to refining our understanding of the
functional disturbances of the cingulate in this disease state.
Accumulating data regarding the electrophysiology of the cingulate
in schizophrenia will also be key to optimizing electrical
stimulation therapy--both to correct any basal abnormalities as
well as to respond to event related electrical disturbances.
[0118] In FIG. 16, a specific method for treating schizophrenia
begins by receiving inputs (step 1610) and analyzing electrographic
activity (step 1612). If the patient's metabolic rate is low (step
1614), or poor synchronization is observed (step 1616), or abnormal
gamma activity is observed (step 1618), or abnormal delta activity
is observed (step 1620), then the totality of circumstances is
analyzed to determine whether therapy is indicated (step 1622). If
so, then therapy is applied (step 1624), and may be either
excitatory or inhibitory, as clinical circumstances dictate.
[0119] In a system according to the invention, synchronization (or
the lack thereof), and activity in various frequency bands may be
determined with an appropriately configured wave morphology
analysis unit, such as one that analyzes the duration and amplitude
of signal half waves. See, e.g., U.S. Pat. No. 6,810,285 to Pless
et al. entitled "SEIZURE SENSING AND DETECTION USING AN IMPLANTABLE
DEVICE," issued Oct. 26, 2004. The disclosure of the application on
which that patent issued is hereby incorporated by reference as
though set forth in full herein. Such a device can respond to the
fluctuating symptoms of schizophrenia, such as hallucinations and
delusions. This device also provides a distinct advantage to
pharmacological therapy. Failure of therapy in persons with
schizophrenia is often related to non-compliance. This device
removes the need for the patient to remember and be willing to take
medications multiple times per day.
[0120] Dysfunction of the cingulate cortex is implicated in the
social disability associated with autism and pervasive
developmental delay. Persons with autism have qualitative
impairment in social interaction and communication. The cingulate
is believed to be essential for higher cognitive function and in
the expression and recognition of affect. Cytoarchitectonic changes
are described in the cingulate cortex as well as the hippocampus,
subiculum and entorhinal cortex of persons with autism studied
post-mortem. Significant reductions in metabolic activity in
cingulate gyri are visualized in persons with autism spectrum
disorders imaged by PET scans. Stimulation over the cingulate
cortex could activate those centers mediating these social
behaviors.
[0121] There is a high prevalence of epilepsy in persons with
autism. Epileptiform discharges are described in medial frontal
regions in persons with autism. Similar to frontal lobe epilepsy,
these discharges often activate with sleep. Some persons with
autism improve cognitively when treated with antiepileptic drugs. A
system according to the invention can detect and treat such
abnormal electrographic discharges via cortical electrodes placed
over the cingulate cortex, as more fully described in U.S. Pat. No.
6,597,954 to Pless et al. entitled "SYSTEM AND METHOD FOR
CONTROLLING EPILEPTIC SEIZURES WITH SPATIALLY SEPARATED DETECTION
AND STIMULATION ELECTRODES," issued Jul. 22, 2003 and entitled
"System and Method for Controlling Epileptic Seizures with
Spatially Separated Detection and Stimulation Electrodes," the
disclosure of which is hereby incorporated by reference as though
set forth in full herein, and others.
[0122] An exemplary method according to the invention for treating
autism is illustrated in FIG. 17, on the premise that a short-term
depression in metabolic rate may be indicative of increased
symptoms. Initially, as autism and certain developmental disorders
are characterized by physiological changes, a first course of
non-responsive therapy is applied (step 1710). This therapy may
include electrical stimulation or any of the other treatment
modalities discussed herein. This initial course of therapy is
continued until conditions change (step 1712) and improvement is
observed.
[0123] Following the initial course of therapy and a change in
conditions, the neurostimulator device processes inputs (step
1714). Then, essentially in parallel, electrographic activity is
analyzed (step 1716) and metabolic rate is analyzed (step 1718). If
the metabolic rate is abnormally low (step 1720), a second course
of therapy, typically excitatory, is provided (step 1722) to
correct the level of function. At substantially the same time, if
epileptiform electrographic activity is observed (step 1724), then
an appropriate third therapy is delivered (step 1726). For details
on an exemplary method for detecting and treating undesired
epileptiform activity, see U.S. Pat. No. 6,810,285, referenced
above.
[0124] Referring now to FIG. 18, in addition to traditional
biphasic pulse waveforms used for neurostimulation, other wave
morphologies may have advantageous applications herein. A
sinusoidal stimulation signal 1810 can be produced and used for
non-responsive or responsive brain stimulation according to the
invention. In general, sinusoidal and quasi-sinusoidal waveforms
may be delivered at low frequencies to have an inhibitory effect,
where low frequencies are 0.5 to 10 Hz delivered for 0.05 to 60
minutes at a time. Such waveform may be applied as a result of
determining that inhibition is desired on a scheduled basis, or
after conditions indicate that responsive stimulation should be
applied. Higher frequency sinusoidal or quasi-sinusoidal waveforms
may be used for activation. Amplitudes in the range of 0.1 to 10 mA
would typically be used, but attention to safe charge densities is
important to avoid neural tissue damage (where a conservative limit
is 25 .mu.C/cm.sup.2 per phase). It should be noted that the
inhibitory and activating functions of various sinusoidal
stimulation parameters may vary when applied to different parts of
the brain; the above is merely exemplary.
[0125] Sinusoidal and quasi-sinusoidal waveforms presented herein
would be constructed digitally by the therapy subsystem 524 (FIG.
5) of the implantable neurostimulator device 110. As a result, the
sinusoid 1810 is really generated as a stepwise approximation, via
a series of small steps 1812. The time between steps is dependent
upon the details of the waveform being generated, but an interval
of 40 microseconds has been found to be a useful value. It is
anticipated that the stair step waveform 1812 may be filtered to
arrive at a waveform more similar to 1814, which would allow for
longer periods of time between steps and larger steps. Likewise,
for the waveforms 1816, 1820, and 1822 (described below), it is
assumed that they may be created with a series of steps
notwithstanding their continuous appearance in the figures.
[0126] A truncated ramp waveform 1814 is also possible, where the
rate of the ramp, the amplitude reached and the dwell at the
extrema are all selectable parameters. The truncated ramp has the
advantage of ease of generation while providing the physiological
benefits of a sinusoidal or quasi-sinusoidal waveform.
[0127] A variable sinusoidal waveform 1816 where the amplitude and
frequency are varied while the waveform is applied is also
illustrated. The rate and amplitude of the variation may be varied
based upon a predefined plan, or may be the result of the implanted
neurostimulator sensing signals from the brain during application
or between applications of the waveform, and adjusting to achieve a
particular change in the sensed signals. The variable waveform 1816
is illustrated herein as having a positive direct current
component, but it should be noted that this waveform, as well as
any of the others described herein as suitable for use according to
the invention, may or may not be provided with a direct current
component as clinically desired.
[0128] Waveforms 1820 and 1822 depict variations where the
stimulating waveform is generated having a largely smooth waveform,
but having the additional feature where the interval between
waveforms is set by varying a selectable delay, as would be used
with the traditional biphasic pulse waveforms described previously.
In waveform 1820, the stimulating waveforms are segments of a sine
wave separated in time (of course the same technique could be used
for the truncated ramp, or other arbitrary morphologies). Waveform
1822 shows a variation where the derivative in time of the waveform
approaches zero as the amplitude approaches zero. The particular
waveform 1822 is known as a haversine pulse.
[0129] Although the term "haversine pulse" is useful to describe
the waveform of 1822, it should be noted that all of the waveforms
represented in FIG. 18 are considered herein to be generally
"non-pulsatile," in contrast with waveforms made up of traditional
discontinuous (e.g. square) pulses. As the term is used herein,
"non-pulsatile" can also be applied to other continuous,
semi-continuous, discontinuous, or stepwise-approximated waveforms
that are not exclusively defined by monophasic or biphasic square
pulses.
[0130] In the disclosed embodiment, the default stimulation
behavior provided by a neurostimulator according to the invention
is to stimulate with charge-balanced biphasic pulses. This behavior
is enforced by stimulation generation hardware that automatically
generates a symmetric equal-current and equal-duration but
opposite-polarity pulse as part of every stimulation pulse; the
precise current control enabled by the present invention makes this
approach possible. However, the neurostimulator is preferably
programmable to disable the automatic charge balancing pulse,
thereby enabling the application of monophasic pulses (of either
polarity) and other unbalanced signals.
[0131] Alternatively, if desired, charge balancing can be
accomplished in software by programming the neurostimulator to
specifically generate balancing pulses or signals of opposite
phase. Regardless of whether charge balancing is accomplished
through hardware or software, it is not necessary for each
individual pulse or other waveform component to be counteracted by
a signal with identical morphology and opposing polarity; symmetric
signals are not always necessary. It is also possible, when charge
balancing is desired, to continuously or periodically calculate the
accumulated charge in each direction and ensure that the running
total is at or near zero over a relatively long term and
preferably, that it does not exceed a safety threshold even for a
short time.
[0132] To minimize the risks associated with waveforms that are
either unbalanced or that have a direct current component, it is
advantageous to use electrodes having enhanced surface areas. This
can be achieved by using a high surface area material like platinum
black or titanium nitride as part or all of the electrode. Some
experimenters have used iridium oxide advantageously for brain
stimulation, and it could also be used here. See Weiland and
Anderson, "Chronic Neural Stimulation with Thin-Film, Iridium Oxide
Electrodes," IEEE Transactions on Biomedical Engineering, 47:
911-918 (2000).
[0133] An implantable version of a system according to the
invention advantageously has a long-term average current
consumption on the order of 10 microamps, allowing the implanted
device to operate on power provided by a coin cell or similarly
small battery for a period of years without need for replacement.
It should be noted, however, that as battery and power supply
configurations vary, the long-term average current consumption of a
device according to the invention may also vary and still provide
satisfactory performance.
[0134] It should be observed that while the foregoing detailed
description of various embodiments of the present invention is set
forth in some detail, the invention is not limited to those details
and an implantable neurostimulator or neurological disorder
detection device made according to the invention can differ from
the disclosed embodiments in numerous ways. In particular, it will
be appreciated that embodiments of the present invention may be
employed in many different applications to responsively treat
psychiatric disorders. It will be appreciated that the functions
disclosed herein as being performed by hardware and software,
respectively, may be performed differently in an alternative
embodiment. It should be further noted that functional distinctions
are made above for purposes of explanation and clarity; structural
distinctions in a system or method according to the invention may
not be drawn along the same boundaries. Hence, the appropriate
scope hereof is deemed to be in accordance with the claims as set
forth below.
* * * * *