U.S. patent application number 11/624590 was filed with the patent office on 2007-10-18 for evoked response to stimulation.
This patent application is currently assigned to MEDTRONIC, INC.. Invention is credited to Ivan Osorio.
Application Number | 20070244407 11/624590 |
Document ID | / |
Family ID | 38370450 |
Filed Date | 2007-10-18 |
United States Patent
Application |
20070244407 |
Kind Code |
A1 |
Osorio; Ivan |
October 18, 2007 |
Evoked Response to Stimulation
Abstract
In an embodiment, an evoked response of an electrode may be
determined. The evoked response may be compared to other evoked
responses to determine the location of the electrode. The evoked
response may be measured during electrode implantation so that
desired changes can be made and if electrodes are being implanted
in both the right and left hemisphere, it can be determined that
both electrodes are positioned in the same target in both the right
and left hemisphere. The evoked responses may be used to determine
if the stimulation target has functional connectivity with the
treatment areas. Stimulation parameters for the electrodes may be
determined in a closed-loop configuration and used to stimulation
the electrodes in an open-loop configuration designed to reduce the
probability of neurological events such as seizures.
Inventors: |
Osorio; Ivan; (Leawood,
KS) |
Correspondence
Address: |
BANNER & WITCOFF, LTD.
TEN SOUTH WACKER DRIVE
SUITE 3000
CHICAGO
IL
60606
US
|
Assignee: |
MEDTRONIC, INC.
710 Medtronic Parkway NE
Minneapolis
MN
55432-5604
|
Family ID: |
38370450 |
Appl. No.: |
11/624590 |
Filed: |
January 18, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11380752 |
Apr 28, 2006 |
|
|
|
11624590 |
Jan 18, 2007 |
|
|
|
60780954 |
Mar 10, 2006 |
|
|
|
Current U.S.
Class: |
600/544 |
Current CPC
Class: |
A61N 1/361 20130101;
A61B 5/4094 20130101; A61B 5/369 20210101; G16H 20/70 20180101;
A61B 5/0006 20130101; G16H 50/20 20180101; A61N 1/36082
20130101 |
Class at
Publication: |
600/544 |
International
Class: |
A61B 5/0476 20060101
A61B005/0476 |
Claims
1. A method of treating a patient with a neurological disorder,
comprising: (a) implanting a first electrode approximate a first
target site in a first hemisphere of the patient's brain; (b)
determining an evoked response of the first electrode; (c)
implanting a second electrode in a location approximate a second
target site in a second hemisphere of the patient's brain; and (d)
verifying the location of the second electrode corresponds to the
location of the first electrode by using an evoked response of the
second electrode.
2. The method of claim 1, wherein the verify in (d) comprises (i)
determining the evoked response of the second electrode; and (ii)
in response to the evoked response of the second electrode not
corresponding to the evoked response of the first electrode,
adjusting the position of the second electrode until the evoked
response of the second electrode does correspond to the evoked
response of the first electrode.
3. The method of claim 1, further comprising: (e) adjusting a
position of the first electrode in response to the evoked
response.
4. The method of claim 1, wherein the first target site is a
region.
5. The method of claim 1, wherein the evoked response comprises
parameters associated with amplitude, latency, conduction velocity,
number of peaks, polarity and shape.
6. The method of claim 1, wherein the first target site is
comprises a location selected from a list consisting of anterior
thalamic nuclei, nucleus Reticulatus polaris, nucleus
Latero-polaris, nucleus Antero-medialis, nucleus Ventro-oralis
Internus, nucleus Antero-principalis, nucleus Lateropolaris and
Campus Forelli Pars H2.
7. The method of claim 1, further comprising: (e) verifying a
location of the first electrode corresponds a desired location
associated with a treatment area.
8. The method of claim 7, wherein the verifying in (e) comprises:
(i) obtaining a reproducible evoked response with well defined
latency, amplitudes and morphology in at least two separate
stimulation trials; (ii) comparing the evoked response to an
expected evoked response; and (iii) in response to a determination
that the evoked response does not correspond to the expected evoked
response, adjusting the position of the first electrode until the
evoked response of the first electrode does correspond to the
expected evoked response.
9. The method of claim 1, further comprising: (e) implanting an
implantable medical device in the patient; and (f) applying a
closed-loop stimulation pattern to the first and second
electrodes.
10. The method of claim 9, wherein the applying open-loop
stimulation pattern in (f) comprises: (i) configuring the first and
second electrode as a cathode; and (ii) configuring a case of the
implantable medical device as an anode.
11. The method of claim 10, wherein the applying of open-loop
stimulation in (f) comprises: (iii) providing stimulation at
between 145 Hz and 200 Hz in a repeating pattern that includes one
minute of stimulation followed by five minutes of no
stimulation.
12. The method of claim 11, wherein the stimulation is applied at
175 Hz at an intensity of 5 volts.
13. A method of treating a patient with a neurological disorder,
comprising: (a) implanting a plurality of electrodes approximate a
target region of the patient's brain; (b) verifying the location of
at least one of the plurality of electrodes using an evoked
response; (c) determining stimulation parameters using the
implanted electrodes and a closed-loop detection algorithm; (d)
coupling the plurality of electrodes to an implantable medical
device; and (e) applying open-loop stimulation to the plurality of
electrodes with the implanted medical device based on the
determined stimulation parameters.
14. The method of claim 13, wherein the verifying of the location
in (b) comprises comparing the morphology, latency and polarity of
the evoked response to determine the location of the implanted
electrode.
15. The method of claim 13, wherein the applying of open-loop
stimulation comprises: (i) configuring the plurality of electrodes
as a cathode; and (ii) configuring a case of the implantable
medical device as an anode.
16. The method of claim 13, wherein the evoked response is done
while implanting the plurality of electrodes.
17. The method of claim 16, wherein the evoked response is measured
using scalp electrodes.
18. The method of claim 16, wherein the evoked response is measured
using intracranial electrodes.
19. The method of claim 13, wherein the verifying the location of
the at least one electrode includes a determination of
functionality connectivity between a structure being stimulated by
the electrode and one of an ipsilateral and a contralateral
structure, and wherein the applying of the open-loop stimulation
stimulates a single side.
20. The method of claim 13, wherein the verifying the location of
the at least one electrode includes a determination of
functionality connectivity between a structure being stimulated by
the electrode and one of an ipsilateral and a contralateral
structure, and wherein the applying of the open-loop stimulation
alternates stimulation between sides.
21. A computer readable medium comprising computer readable
instructions, comprising: (a) receiving an evoked response
generated by applying a stimulation pulse applied to an implanted
electrode; (b) determining that the evoked response matches an
known evoked response; and (c) providing an indication that the
evoked response matches the known evoked response.
22. The computer readable medium of claim 21, wherein the
indication is rendered on a display.
23. The method of claim 22, wherein the indication provides
information regarding a location of the implanted electrode.
24. A method of determining the existence of functional
connectivity between a stimulation target and a treatment area,
comprising: (a) implanting a first electrode in the stimulation
target; (b) implanting a second electrode in the treatment area;
(c) stimulating the first electrode with an electrical pulse; (d)
obtaining an evoked response from the second electrode; and (e) if
the evoked response is not reproducible, repositioning the first
electrode and repeating (c)-(d) until a reproducible evoked
response is obtained from the second electrode.
25. The method of claim 24, wherein the treatment area comprises an
abnormal brain area.
Description
[0001] This is a continuation-in-part of U.S. application Ser. No.
11/380,752, filed Apr. 28, 2006 (Attorney Docket No. 011738.00310),
which in turn claims priority to U.S. Provisional Application Ser.
No. 60/780,954 filed Mar. 10, 2006 (Attorney Docket No.
011738.00294), both of which are incorporated herein by reference
in their entirety.
BACKGROUND OF THE INVENTION
[0002] The invention relates to the evaluation, warning and
treatment of neurological disorders such as epilepsy, devices for
such evaluation, warning and treatment, including external and
implantable devices and systems, and methods and techniques by
which the devices and systems operate, and the methods by which
patients suffering disorders such as epilepsy are evaluated,
warned, and treated by electrical stimulation or some other
modality. Specifically, the invention discloses a probabilistic
approach for issuing warnings and/or triggering therapy delivery
without relying on conventional event detection or prediction
approaches. This may result in therapy delivery before the onset of
a neurological event, such as seizure, or even before the onset of
a pre-event state, thus preventing the neurological event from
occurring.
BRIEF DESCRIPTION OF THE PRIOR ART
[0003] The objective of currently approved seizure therapies,
whether pharmacological or electrical, is to treat seizures through
an "open-loop" approach. In the case of drugs, these are dosed
based on their half-life and therapeutic ratio, so as to maintain
relatively constant drug serum concentrations round-the-clock and
avoid large fluctuations (drops or rises in concentrations), that
may leave the subject relatively unprotected (if low) or may cause
dose-related side effects (if high). In the case of electrical
stimulation such as with the Neurocybernetic prosthesis
(Cyberonics, Houston, Tex.), currents are delivered periodically,
round-the-clock.
[0004] For drugs and electrical stimulation, the dosing/stimulation
schedule (not the dose or electrical current intensity) of approved
therapies does not take into account the actual frequency of
seizures or their temporal (e.g., circadian) distributions: The
approach is fundamentally the same for a subject with multiple
daily seizures or for one with only one every few years, or if the
seizures occur only at night or at any time during the daylight.
Adjustments in treatment, if any, are made at certain time
intervals based on the number of seizures reported by the subject
(by seizure diary) or on the frequency and type of side effects
over that interval.
[0005] Since the advent of automated means for detecting seizures
(see, e.g., U.S. Pat. No. 5,995,868 Osorio et al.; Neuropace; Litt)
and of methods that allegedly predict the onset of seizures (see,
e.g., patents issued to lasemidis; Litt; Hively, Lenhertz), warning
and closed-loop therapeutic intervention in response to the output
of those methods is now possible. This approach is potentially
highly temporo-spatially selective, minimizing adverse effects and
unnecessary treatments and in theory, may be superior to open-loop.
However, all known, useful prior-art closed-loop therapies restrict
intervention to be contingent upon discrete event detections and
require that signals (EEG or other types) be continuously monitored
(around the clock and for the life of the subject) to enable these
event detections.
[0006] In the case of seizure detection-based closed-loop control,
known devices attempt to detect the occurrence of a seizure through
analysis of biological signals and respond with electrical
stimulation or other therapy. In the case of seizure
prediction-based closed-loop control, known devices attempts to
detect the occurrence of a pre-seizure state, again through some
analysis of biological signals, and respond with delivery of some
contingent therapy.
[0007] These approaches to closed-loop control remain based on
relatively short time scales of changes (seconds to minutes in the
case of seizure detection, seconds to a few hours in the case of
seizure prediction) and typically are based on the assumption that
the detection is connected in a dynamically contiguous way with the
ongoing or impending seizure. In addition, these approaches ignore
temporal correlations between seizures including long-range
dependencies.
SUMMARY OF THE INVENTION
[0008] The following represents a simplified summary of some
embodiments of the invention in order to provide a basic
understanding of various aspects of the invention. This summary is
not an extensive overview of the invention. It is not intended to
identify key or critical elements of the invention or to delineate
the scope of the invention. Its sole purpose is to present some
embodiments of the invention in simplified form as a prelude to the
more detailed description that is presented below.
[0009] In an embodiment, a first electrode may be implanted in a
patient's brain in a first hemisphere. By applying stimulation
pulses to the first electrode, a first evoked response may be
measured. The first evoked response may be compared to previous or
subsequent evoked responses to determine the part of the brain that
is being stimulated by the first electrode. A second electrode may
be implanted in a second hemisphere of the patient's brain and
evoked responses from the second electrode may be measured. The
evoked response from the second electrode may be compared with the
response evoked by stimulation of the first electrode to verify
that the first and second electrodes are stimulating the same part
of the brain, just in different hemispheres. In an embodiment this
may be done inter-operatively (e.g., during the electrode
implanting process).
[0010] In an embodiment, a closed-loop detection algorithm may be
used to determine stimulation parameters that reduce the
probability of a neurological disorder such as a seizure. An
implantable medical device may be implanted and used to provide
electrical stimulation in accordance with the parameters to the
first and second electrodes in an open-loop manner. In an
embodiment, the stimulation may be in a monopolar configuration
with the first and second electrodes being used as cathodes while a
case of the implantable medical device is used an anode.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] The present invention is illustrated by way of example and
not limited in the accompanying figures in which like reference
numerals indicate similar elements and in which:
[0012] FIG. 1 is a schematic view of a medical device implanted in
a patient that monitors cardiac and nervous system disorders in
accordance with an aspect of the invention.
[0013] FIG. 2 is a simplified block diagram of the medical device
shown in FIG. 1 in accordance with an aspect of the invention.
[0014] FIG. 3 is a graphical representation of various signals
sensed by the medical device as shown in FIG. 1 in accordance with
an aspect of the invention.
[0015] FIG. 4 shows an apparatus that supports reporting
neurological data in accordance with an aspect of the
invention.
[0016] FIG. 5 is a schematic diagram of a system utilizing the
above-described embodiments and allowing remote monitoring and
diagnostic evaluation of at risk patients in accordance with an
aspect of the invention.
[0017] FIG. 6 is a schematic diagram of an alternative system
utilizing the above-described embodiments and allowing remote
monitoring and diagnostic evaluation of at risk patients in
accordance with an aspect of the invention.
[0018] FIG. 7 is a chart of seizure frequency as a function of time
of day in some subjects.
[0019] FIG. 8 is a chart of simulated probability of seizure as a
function of time of day, for a supposed patient.
[0020] FIG. 9 is a chart of probability of seizures as a function
of time during a stimulation cycle in some subjects.
[0021] FIG. 10 is a chart of probability of seizures as a function
of time from onset of stimulation in some subjects.
[0022] FIG. 11 is a chart of probability of seizures as a function
of time from beginning of seizure in some subjects.
[0023] FIG. 12 is a chart of probability of seizures as a function
of time relative to therapy delivery in some subjects.
[0024] FIG. 13 illustrates a process of determining the location of
an electrode using an evoked response in accordance with an aspect
of the invention.
[0025] FIG. 14 illustrates a process of applying stimulation to an
electrode in accordance with an aspect of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Overview
[0026] The following discloses approaches to patient evaluation,
warning and treatment, referred herein to as "probabilistic"
approaches, that are not based on a strict binary approach for
discrete event detection (i.e., "0" for no detection and "1" for
detection), or prediction (i.e., "0" for no issuance of prediction
and "1" for issuance of a prediction). Instead, disclosed are
techniques that estimate probability distribution functions or
cumulative distribution functions, "built" relying on
representative historical profiles, comprising information in short
and/or long timescales obtained at times that may be intermittent
or temporally discontinuous from each other or from other events of
interest.
[0027] Conventional "open-loop" control (i.e., that which is
implemented in the absence of immediate information or "feedback")
is comparatively easy to implement, as it does not require that a
device monitor in real-time, the state of the subject and decipher
the relevant information. Conventional closed-loop control is a
more powerful class of therapy than conventional open-loop, and
while more expensive/complicated than open-loop, it offers greater
opportunity for success in certain cases. Both approaches,
closed-loop and open-loop, as currently utilized, have advantages
and disadvantages relative to one another. In the embodiments
disclose herein are techniques, termed "probabilistic closed-loop,"
that provide a new approach to therapy or control that draws on the
strengths of the two approaches and attempts to advance beyond what
may be perceived as their respective limitations.
[0028] In the embodiment of treating or controlling seizures,
probabilistic control of seizures is based on the following
observations: (1) the probability of seizure occurrence is not
solely a function of signal changes in the system but of multiple
factors; (2) seizure probability changes as a function of state,
being lowest in the period immediately following the termination of
seizures; and (3) the anti-seizure effects of closed-loop
electrical stimulation, either local (delivered directly to
epileptogenic tissue) or remote (delivered to epileptogenic tissue
via a structure connected to it), of epileptogenic tissue are both
closely temporally correlated with delivery of currents (immediate
effect) and persist for some time beyond cessation of stimulation
("carry-over" effect) [Osorio et al 05, Annals of Neurology].
[0029] Depending on the duration and degree of protective
"carry-over" effect, stimulation parameters may be adjusted to
attain a state of protection that minimizes seizure occurrence
probability and whose level or degree of protection is a function
of this probability. This strategy, referred to as probabilistic
closed-loop, may be in certain cases, preferable to conventional
closed-loop treatment, which operates only in response to event
detections (either seizure detections or, in the case of
"prediction," the detection of a pre-seizure state) and provides
event detection-contingent therapy. Of course, both options may be
used together, i.e., one does not necessarily preclude the other.
For example, contingent therapy such as stimulation may be used to
treat breakthrough seizures. Moreover, if future studies show, as
did one study [Osorio 05], that short closed-loop trials help
identify efficacious parameters, they may be followed by open-loop
phases, making open-loop intelligent or adaptive ("intelligent
open-loop").
[0030] The "probabilistic closed-loop" may evolve, under certain
circumstances and in certain cases, into "intelligent" open-loop
defined as lacking immediate or real-time information/"feedback",
but operating according to changes in estimates of seizure
probability (as a function of time and/or state) which were
calculated using past information and which may be updated/improved
(as a function of time and/or state) but not in real-time, using
new information. "Intelligent" open-loop does not require that
implantable monitoring devices be used for real-time signal
processing/analysis for the detection/prediction/quantification of
seizures nor that in-hospital monitoring be performed. Instead,
portable monitoring devices for ambulatory/home monitoring may be
used. The monitoring devices may obtain signals such as EEG, ECoG,
EKG or others, preferably via telemetry and periods of intensive
monitoring and parameter optimization (with or without closed-loop
therapy) may be carried out as often as indicated. By decreasing
reliance on continuous signal monitoring, this alternative
therapeutic regimen simplifies operation and decreases power
requirements, factors that translate into smaller, more efficient
and less costly implantable therapy devices.
[0031] As used herein, "open-loop" control is generally therapy
that is administered according to a program that depends on time,
without taking into account real-time information about the state
of the subject. "Closed-loop" is generally refers to the
administration of therapy that is dependent upon information about
the state of the subject and therapy is triggered if and when
seizures are either detected or predicted.
[0032] As used herein, "intelligent open-loop" is generally the
triggering of interventions dictated by changes in probability of
seizure occurrence estimated using past information. For example,
if the mean or median half-life duration of the protective
carry-over effect of electrical stimulation in a given patient
lasts 20 minutes, as determined with closed-loop or probabilistic
closed-loop modalities, electrical stimulation will be delivered
again 20 min after each trial, round-the clock. This modality does
not use real-time but past information.
[0033] As described herein, "probabilistic closed-loop" does not
require detection or prediction of seizures for triggering an
intervention/therapy delivery, but rather, probabilities that are
associated with: (a) an unacceptable value (for the subject or for
the situation, etc.) related to safety, social or other risks; (b)
a change in value which is rapid and/or large in magnitude for that
subject, brain/systems state, time of day or activity; (c)
weakening of the "steady-state" of protection (loss of a
"carry-over" effect) afforded by previous therapy delivery or
inability to attain the sufficient degree of "carry-over"
protection following therapy delivery.
Embodiments of the Medical Device System
[0034] In an embodiment, the invention may be implemented within an
implantable neurostimulator system, however, those skilled in the
art will appreciate that the techniques disclosed herein may be
implemented generally within any implantable medical device system
including, but not limited to, implantable drug delivery systems,
and implantable systems providing stimulation and drug delivery.
The implantable medical device may provide therapeutic treatment to
neural tissue in any number of locations in the body including, for
example, the brain (which includes the brain stem), the vagus
nerve, the spinal cord, peripheral nerves, etc. The treatment
therapies can include any number of possible modalities alone or in
combination including, for example, electrical stimulation,
magnetic stimulation, drug infusion, brain temperature control,
and/or any combination thereof.
[0035] In addition, aspects of the invention may be embodied in
various forms to analyze and treat nervous system and other
disorders, namely disorders of the central nervous system,
peripheral nervous system, and mental health and psychiatric
disorders. Such disorders include, for example without limitation,
epilepsy, Sudden Unexpected Death in Epilepsy Patients (SUDEP),
Parkinson's disease, essential tremor, dystonia, multiple sclerosis
(MS), anxiety (such as general anxiety, panic, phobias, post
traumatic stress disorder (PTSD), and obsessive compulsive disorder
(OCD)), mood disorders (such as major depression, bipolar
depression, and dysthymic disorder), sleep disorders (narcolepsy),
obesity, tinnitus, stroke, traumatic brain injury, Alzheimer's, and
anorexia.
[0036] In certain embodiment, the biological signals that may
selected, stored and/or reported in accordance with various aspects
of the invention may include any number of sensed signals. Such
biological signals can include, for example, electrical signals
(such as EEG, ECoG and/or EKG), chemical signals (such as change in
quantity of neurotransmitters), temperature signals, pressure
signals (such as blood pressure, intracranial pressure or cardiac
pressure), respiration signals, heart rate signals, pH-level
signals, activity signals (e.g., detected by an accelerometer),
and/or peripheral nerve signals (cuff electrodes on a peripheral
nerve). Such biological signals may be recorded using one or more
monitoring elements such as monitoring electrodes or sensors. For
example, U.S. Pat. No. 6,227,203 provides examples of various types
of sensors that may be used to detect a symptom or a condition or a
nervous system disorder and responsively generate a neurological
signal. In addition, various types of physiologic activities may be
sensed including, for example, brain, heart and/or respiration.
[0037] As discussed, the techniques disclosed herein are suitable
for use within any implantable medical device system that receives
signals associated with the physiological conditions being sensed,
a memory component, and a processing component (logic or software)
that stores data records in data structures. Certain techniques are
also suitable for implantable medical devices with even lesser
functionality. For example, in an embodiment where the implantable
unit applies open-loop electrical stimulation in a desired pattern,
the implantable device may include only those elements necessary to
provide the pattern of electrical stimulation. However, an
implantable medical device with greater functionality may also be
used to provide open-loop stimulation as well as one or more of the
additional features discussed herein.
[0038] Manual indication of a seizure or other event may be
achieved through an external programmer device. The patient (or
caregiver) may push a button on the external programmer device,
while communicating with the implanted device. This may provide a
marker of the sensed data (for example, in the event the patient is
experiencing a neurological event).
[0039] In assessing the risk of SUDEP, for example, prolonged ECG
recordings may be possible (e.g., recording all data during sleep
since the incidence of SUDEP is highest in patients during sleep).
Post-processing of the signal can occur in the implanted device,
the patient's external device, a clinician external device, and/or
another computing device. Intermittently (e.g., every morning,
once/week, following a seizure), a patient may download data from
the implantable device to the patient external device (as will be
discussed further herein), which may then be analyzed by the
external device (and/or sent through a network to the physician) to
assess any ECG abnormalities. If an abnormality is detected, the
device may notify the patient/caregiver. At that time, the
patient/caregiver may inform the healthcare provider of the alert
to allow a full assessment of the abnormality. The clinician
external device may also be capable of obtaining the data from the
implanted device and conducting an analysis of the stored signals.
If a potentially life-threatening abnormality is detected, the
appropriate medical treatment may be prescribed (e.g., cardiac
abnormality: a pacemaker, an implantable defibrillator, or a heart
resynchronization device may be indicated or respiration
abnormality: CPAP, patient positioning, or stimulation of
respiration may be indicated). These data may be used to build
probability estimates as a function of time, state (asleep or in
seizure) and activities (exercising) to enable therapies at times
of high risk to prevent an event or, in the case of SUDEP, a fatal
outcome.
[0040] Moreover, the implantable medical device may also monitor
EEG signals from intracranially implanted leads. This may allow the
implanted medical device to collect cardiovascular and neurological
signals in close proximity to detected neurological events as well
as notify the patient/caregiver of a prolonged event (and/or status
epilepticus). The implantable medical device may detect
neurological events and analyze the peri-ictal signals and initiate
loop recording.
[0041] Again, it will be appreciated that alternative embodiments
of the implantable medical device may also be utilized. For
example, cardiac lead(s), a sensor stub, and/or a wearable patch
may be used to facilitate detection of a neurological event and the
recording of data and signals pre and post event. An integrated
electrode may also be used that senses ECG signals as described in
U.S. Pat. No. 5,987,352. Optionally, the implantable medical device
may warn/alert the patient 12 via buzzes, tones, beeps or spoken
voice (as substantially described in U.S. Pat. No. 6,067,473) via a
piezo-electric transducer incorporated into the housing of
implantable medical device. The sound may be transmitted to the
patient's inner ear.
[0042] In another embodiment, the monitor may be implanted
cranially in the patient 12 (FIG. 1). In such an embodiment, the
monitor may be constructed as substantially described in U.S. Pat.
Nos. 5,782,891 and 6,427,086. EEG sensing may be accomplished by
the use of integrated electrodes in the housing of the monitor,
cranially implanted leads, and or leadless EEG sensing.
[0043] FIG. 1 illustrates an implantable system 10 including an
implantable medical device 20 implanted in a patient 12.
Optionally, the implantable medical device 100 may monitor one or
more biological signals/conditions of the patient via lead 19 and
monitoring/sensing elements 30 and 32 (in the embodiment, the
biological conditions are cardiac and neurological functions of
patient 12). Stored diagnostic data may be uplinked and evaluated
by an external computing device 23 (e.g., a patient's or
physician's programmer) via a 2-way telemetry, using for example,
antenna 24 to relay radio frequency signals 22, 26 between
implantable medical device 100 and external computing device 23. An
external patient activator that may be located on external
computing device 23 may optionally allow patient 12, or care
provider (not shown), to manually activate the recording of
diagnostic data.
[0044] FIG. 2 depicts a block diagram of the electronic circuitry
of implantable medical device 100 of FIG. 1 in accordance with an
embodiment of the invention. Implantable medical device 100
comprises a primary control circuit 220 and may be similar in
design to that disclosed in U.S. Pat. No. 5,052,388. Primary
control circuit 220 includes sense amplifier circuitry 224, a
crystal clock 228, a random-access memory and read-only memory
(RAM/ROM) unit 230, a central processing unit (CPU) 232, digital
logic circuit 238, a telemetry circuit 234, and stimulation engine
circuitry 236, all of which are generally known in the art.
[0045] Implantable medical device 100 may include internal
telemetry circuit 234 so that it is capable of being programmed by
means of external programmer/control unit 23 via a 2-way telemetry
link. External programmer/control unit 23 communicates via
telemetry with implantable medical device 100 so that the
programmer can transmit control commands and operational parameter
values to be received by the implanted device, and so that the
implanted device can communicate diagnostic and operational data to
the programmer 23. For example, programmer 23 may be Models 9790
and CareLink.RTM. programmers, commercially available from
Medtronic, Inc., Minneapolis, Minn. Various telemetry systems for
providing the necessary communications channels between an external
programming unit and an implanted device have been developed and
are well known in the art. Suitable telemetry systems are
disclosed, for example, in U.S. Pat. Nos. 5,127,404; 4,374,382; and
4,556,063.
[0046] Typically, telemetry systems such as those described in the
above referenced patents are employed in conjunction with an
external programming/processing unit. Most commonly, telemetry
systems for implantable medical devices employ a radio-frequency
(RF) transmitter and receiver in the device, and a corresponding RF
transmitter and receiver in the external programming unit. Within
the implantable device, the transmitter and receiver utilize a wire
coil as an antenna 24 for receiving downlink telemetry signals and
for radiating RF signals for uplink telemetry. The system is
modeled as an air-core coupled transformer. An example of such a
telemetry system is shown in U.S. Pat. No. 4,556,063.
[0047] In order to communicate digital data using RF telemetry, a
digital encoding scheme such as is described in U.S. Pat. No.
5,127,404 can be used. In particular, a pulse interval modulation
scheme may be employed for downlink telemetry, wherein the external
programmer transmits a series of short RF "bursts" or pulses in
which the interval between successive pulses (e.g., the interval
from the trailing edge of one pulse to the trailing edge of the
next) is modulated according to the data to be transmitted. For
uplink telemetry, a pulse position modulation scheme may be
employed to encode uplink telemetry data. For pulse position
modulation, a plurality of time slots are defined in a data frame,
and the presence or absence of pulses transmitted during each time
slot encodes the data. For example, a sixteen-position data frame
may be defined, wherein a pulse in one of the time slots represents
a unique four-bit portion of data.
[0048] Programming units such as the above-referenced Medtronic
Models 9790 and CareLink.RTM. programmers typically interface with
the implanted device through the use of a programming head or
programming paddle, a handheld unit adapted to be placed on the
patient's body over the implant site of the patient's implanted
device. A magnet in the programming head effects reed switch
closure in the implanted device to initiate a telemetry session.
Thereafter, uplink and downlink communication takes place between
the implanted device's transmitter and receiver and a receiver and
transmitter disposed within the programming head.
[0049] As previously noted, primary control circuit 220 includes
central processing unit 232 which may be an off-the-shelf
programmable microprocessor or microcontroller, but in an
embodiment of the invention it may be a custom integrated circuit.
Although specific connections between CPU 232 and other components
of primary control circuit 220 are not shown in FIG. 2, it will be
apparent to those of ordinary skill in the art that CPU 232
functions to control the timed operation of sense amplifier circuit
224 under control of programming stored in RAM/ROM unit 230. In
addition to or as an alternative embodiment digital logic 238 may
also be provided and utilized. In another alternative embodiment, a
processing module that contains either a processor or digital
circuitry may also be utilized. Those of ordinary skill in the art
will be familiar with such an operative arrangement.
[0050] With continued reference to FIG. 2, crystal oscillator
circuit 228 provides main timing clock signals to primary control
circuit 220. The various components of implantable medical device
100 are powered by means of a power source such as a battery 239,
which is contained within the hermetic enclosure of implantable
medical device 100. For the sake of clarity in the figures, the
connections between the battery 239 and the other components of
implantable medical device 100 are not shown. Sense amplifier 224
is coupled to monitoring/sensing elements 30 and 32. Where cardiac
intrinsic signals are sensed, they may be sensed by sense amplifier
224 as substantially described in U.S. Pat. No. 6,505,067.
[0051] Processing by CPU 232 or digital logic 238 allows detection
of cardiac and neural electrical characteristics and anomalies. CPU
232 or digital logic 238, under control of firmware resident in
RAM/ROM 230, may initiate recording of the appropriate diagnostic
information into RAM of RAM/ROM 230.
[0052] It will be appreciated that alternative embodiments of
implantable medical device 100 may also be utilized. As discussed
above, implantable medical device 100 may sense any number of
physiologic conditions of the patient 12 for purposes of detecting,
and storing data relating to, any number of the neurological
events. For example, various lead(s) may be used to facilitate
detection of a neurological event and the recording of data and
signals pre and post event.
[0053] In another aspect of the invention, an electrode 32 located
distally on a sensor stub may be used to facilitate detection of a
neurological event and the recording of data and signals pre and
post event. See U.S. Pat. No. 5,987,352. In alternative embodiments
of the invention, the implantable medical device 100 may also sense
respiration parameters such as respiration rate, minute ventilation
and apnea via measuring and analyzing the impedance variations
measured from the implanted implantable medical device 100 case to
the electrode located distally on the sensor stub lead as
substantially described in U.S. Pat. Nos. 4,567,892 and
4,596,251.
[0054] In yet another aspect of the invention, an external wearable
device such as a wearable patch, a wristwatch, or a wearable
computing device may be used to continuously sense implantable
medical device cardiac functions of patient 12. Optionally, a
button (not shown) on the external wearable device may be activated
by the patient 12 (or a caregiver) to manually activate data
recording (for example, in the event the patient is experiencing a
neurological event). The external wearable device may comprise an
amplifier, memory, microprocessor, receiver, transmitter and other
electronic components as substantially described in U.S. Pat. No.
6,200,265. In the embodiment of a wearable patch, the device may
consist of a resilient substrate affixed to the patient's skin with
the use of an adhesive. The substrate flexes in a complimentary
manner in response to a patient's body movements providing patient
comfort and wearability. The low profile patch is preferably
similar in size and shape to a standard bandage, and may be
attached to the patient's skin in an inconspicuous location.
[0055] The above embodiments illustrate that the disclosed
techniques may be implemented within any number of medical device
systems (drug delivery, electrical stimulation, pacemaking,
defibrillating, cochlear implant, and/or diagnostic). Thus, for
example without limitation, the implanted medical component may
utilize one or more monitoring elements (e.g., electrodes or other
sensors), a memory component having a plurality of data structures
(and/or data structure types), a processing component (such as a
CPU or digital logic), and a telemetry component.
[0056] FIG. 4 shows apparatus 1200 that supports reporting
physiological data in accordance with an aspect of the invention.
With apparatus 1200, the implanted component 1205 of the medical
device system communicates with the relaying module 1215 via
telemetry antenna 1210. Similarly, the external component 1225
communicates with the relaying module 1215 via antenna 1220. In the
embodiment, a telemetry link 1221 between relaying module 1215 and
antenna 1220 comprises a 3 MHz body wave telemetry link. To avoid
interference, the relaying module 1215 may communicate with the
external and implanted components using differing communication
schemes. In some embodiments, the reverse direction and the forward
direction of telemetry link 1221 may be associated with different
frequency spectra. The relaying module 1215 thereby provides a
greater range of communications between components of medical
device system. For example, in the embodiment of an implanted
system, an external programmer may communicate with an implanted
device from a more remote location. The external programmer may be
across the room and still be in communication via the relaying
module 1215. With the telemetry booster stage, the use of an
implanted system is more convenient to the patient, in particular
at night while sleeping or when taking a shower, eliminating the
need for an external device to be worn on the body.
[0057] As shown in FIG. 5, in an embodiment, the system allows the
residential, hospital or ambulatory monitoring of at-risk patients
and their implanted medical devices at any time and anywhere in the
world. Medical support staff 1306 at a remote medical support
center 1314 may interrogate and read telemetry from the implanted
medical device and reprogram its operation while the patient 12 is
at very remote or even unknown locations anywhere in the world.
Two-way voice communications 1310 via satellite 1304, via cellular
link 1332 or land lines 1356 with the patient 12 and
data/programming communications with the implanted medical device
1358 via a belt worn transponder 1360 may be initiated by the
patient 12 or the medical support staff 1306. The location of the
patient 12 and the implanted medical device 1358 may be determined
via GPS 1302 and link 1308 and communicated to the medical support
network in an emergency. Emergency response teams can be dispatched
to the determined patient location with the necessary information
to prepare for treatment and provide support after arrival on the
scene. See, e.g., U.S. Pat. No. 5,752,976.
[0058] An alternative or addition to the system as described above
in conjunction with FIG. 5 is shown in the system 1450 of FIG. 6,
which shows a patient 12 sleeping with an implantable Monitor 1458
and/or optional therapy device as described above in connection
with the above-described systems. The implantable device 1458, upon
detection of a neurological event may alert a remote monitoring
location via local remote box 1452 (as described in U.S. Pat. No.
5,752,976), telephone 1454 and phone lines 1456 or the patient's
care provider via an RF link 1432 to a pager-sized remote monitor
1460 placed in other locations in the house or carried (i.e., belt
worn) by the care provider 1462. The remote caregiver monitor 1460
may include audible buzzes/tones/beeps, vocal, light and/or
vibration to alert the caregiver 1462 of patient's monitor in an
alarm/alert condition. The RF link may include RF portable phone
frequencies, power line RF links, HomeRF, Bluetooth, ZigBee, WIFI,
MICS band (medical implant communications service), or any other
interconnect methods as appropriate.
Probabalistic Treatment Therapy
[0059] Suppose that a subject with seizures is being treated with
an open loop control program. This subject may be simultaneously
monitored using some means to log seizures. Example means include
but are not limited to: [0060] a. Quantifying the signal's seizure
content using a method such as the algorithm in U.S. Pat. No.
5,995,868, without necessarily using the output to effect changes
in real-time; [0061] b. Logging time of seizure occurrences as well
as brain state (e.g., awake); physical state (e.g., inactive);
cognitive status (e.g., inattentive); metabolic status (e.g., blood
glucose concentration); brain and body temperature; time from
previous seizure(s); previous seizure(s)' intensity, severity and
spread; and exposure to precipitants (e.g., light as measured using
a light meter), without necessarily using the data to effect
changes in real-time. Other markers of cerebral excitability such
as GABA and glutamate concentrations and others listed in U.S. Pat.
No. 6,934,580 may be included in the estimation of seizure
probability; and/or [0062] c. an event button with clock and
memory.
[0063] Let t=time elapsed since beginning of delivery of a
particular therapy program. Let {t.sub.i|i=1, 2, . . . } be a
sequence of reference time points ("fiducial times"). Let
t.sub.REL=t (mod max {t.sub.i|t.sub.i<=t}). Here t.sub.REL
corresponds to the time elapsed since the most recent fiducial
time. Examples: [0064] a. t.sub.i=sequence of times corresponding
to midnight on each day of monitoring. Then t.sub.REL is simply the
time of day. [0065] b. t.sub.i=sequence of times corresponding to
beginning of menses in a female subject. Then t.sub.REL is the time
in the subject's menstrual cycle. [0066] c. t.sub.i=sequence of
times corresponding to beginning of each administration of
treatment or intervention. Then t.sub.REL is the time elapsed since
the beginning of the last stimulation. [0067] d. t.sub.i=sequence
of seizure start (or end) times. Then t.sub.REL is the time elapsed
since the start (resp., end) of the last seizure.
[0068] At any point in time, the probability of a seizure occurring
is given by P(t)=P(Sz occurring at time t). Knowing P(t) would be
of value in treating epilepsy. The inventors have developed a
framework that does not rely on conventional on-line, real-time
seizure detection or prediction but utilizes available information
(history) to issue warnings and/or deliver therapy based on this
developed probability function (as opposed to specific, binary,
event detections). This probability function and related decisions
of whether or not to issue a warning or deliver therapy can
incorporate useful dependency of factors such as type of present
activity and its inherent risk of injury, social embarrassment, and
importance to preserve cognitive functions.
[0069] For any relative time, .tau. in Range {t.sub.REL}, given a
reasonable length of monitoring, T, of the subject utilizing the
current control program, one may compute and use the empirical
probability of a seizure occurring at any point in time for this
subject as: pE(.tau.; T)=(# of seizures with t.sub.REL=.tau.)/(# of
times t.sub.REL=.tau.).
[0070] This "empirical probability density of seizures relative to
time with respect to a fiducial sequence" is an approximation of
the unknown probability of interest, namely, P(Sz occurring at time
t.sub.REL=.tau.)
[0071] This empirical probability function can be used to compare
one therapy control program against another (or against the
untreated subject) in order to determine which is more effective
and enables adjustment of therapy to improve efficacy.
ILLUSTRATIVE EXAMPLES
[0072] As depicted in FIG. 7, the probability of seizure occurrence
is known to change as a function of time of day (from Osorio I,
Frei M G, Manly B F J, Sunderam S, Bhavaraju N C, and Wilkinson S
B. J Clin Neurophysiol. 2001 November; 18(6):533-44). Moreover, it
is known that some patients are much more likely to have seizures
while they are asleep ("nocturnal epilepsy"). By examining seizure
frequency of occurrence as a function of time of day, one can
determine the effect of circadian variations on seizures for a
particular subject and use this information to better control their
seizures as illustrated in the following example.
Example 1
[0073] Suppose a subject with primarily nocturnal seizures is
monitored continuously for one month (or some period of time that
yields a representative or useful sample) with no therapy enabled,
and then for a second month (or other period), while being treated
with an open loop control program that consists of 5 mA of
stimulation at 100 Hz for 1 minute every 10 minutes (i.e., on 1
minute, off 9 minutes). Using time-of-day in generating t.sub.REL
(as in above example), the graphs in FIG. 8 illustrate PE(.tau.)
for months 1 (solid) and 2 (dash-dot), respectively. In this
example, it is apparent that the therapy program had a
seizure-reduction effect during the night, but may have increased
seizure frequency during the day. Given this information, the user
(subject or caretaker) may improve the overall efficacy of therapy
by developing a new control program that is obtained by combining
the approaches to produce a second control program that is equal to
the previous one (on 1 minute, off 9 minutes) during the night, but
is off completely between 8:30 and 15:30. Under the assumption that
the effect of therapy is relatively instantaneous and lacking
significant temporal carry-over effect, this revised control can be
expected to result in improved therapy for the subject. While one
skilled in the art will appreciate that the aforementioned
assumptions need not be valid, the information obtained from the
method allows the user to quantify the linearity of the response
and the size and duration of the carry-over effect and to suitably
modify the control program.
[0074] FIG. 9 depicts observed changes in seizure duration and
intensity as a function of time from onset of stimulation (from S.
Sunderam et al., Brain Research 918 (2001) 60-66). In another
embodiment, the times of stimulation are used as fiducial times to
examine the effect on seizure longevity and optimize the
stimulation parameters. Seizure probability and severity may also
be estimated as a function of time of delivery of therapy (such as
electrical stimulation) and may depend upon other relevant
parameters such as intensity, duration, frequency, stimulation
polarity, etc.
Example 2
[0075] Consider a subject that is being treated with a closed-loop
stimulation program. For example, after a period of no therapy, the
treatment program provides for 2.5 s of continuous stimulation to
the anterior thalamic nucleus, triggered by every other seizure
detection (generated by an automated seizure detection algorithm).
The subject continues to have seizures, so the stimulation duration
is increased to 30 s of continuous stimulation, administered to the
same brain location, again triggered by every other seizure
detection. After a period of time, the monitoring data is collected
and analyzed as described above with the fiducial times equal to
the starting time of each stimulation. The corresponding
probabilities of seizure survival, relative to elapsed time from
start of stimulation, are shown in FIGS. 10 and 11. In this manner,
the system enables the user to determine the duration of
stimulation that has optimal effect in terms of seizure reduction
(approximately 15 s), beyond which efficacy is not improved
further.
[0076] FIG. 10, depicts a subject where every other seizure is
treated by 2.5 s stimulation beginning at seizure onset. The curves
show probability of being in seizure as a function of time from
beginning of seizure. The upper curve indicates probability for
stimulated seizures, and the lower curve represents those seizures
that were not stimulated. No significant difference is evident.
[0077] In FIG. 11, depicts a subject where every other seizure is
treated by 30 s stimulation beginning at seizure onset. The curves
show probability of being in seizure as a function of time from
beginning of seizure. The lowest curve indicates probability for
stimulated seizures, the middle curve indicates probability for
those seizures that were not stimulated, and the highest curve
indicates the baseline probability from pre-treatment phase
recordings.
Example 3
[0078] A subject that is being treated with an open-loop therapy
may be equipped with a device for intensive continuous monitoring
of biological signals (such as EEG or EKG), which will detect and
quantify features of these signals (e.g., epileptiform brain
activity or heart rate changes) associated with seizures for a
period of time (e.g., 48 hr). The monitored activity will be
analyzed with respect to some fiducial time sequence (e.g., times
of onset of stimulation delivery, times of changing of stimulation
intensity, time of day, etc.) and the empirical probability density
of seizures relative to time with respect to the fiducial sequence
is generated.
[0079] FIG. 12 provides an illustration of such information, in
which the fiducial times are the times of onset of trains of
electrical stimulation delivered for 30 s every 10 minutes. From
this analysis it becomes apparent that the open-loop stimulation
program provides very little immediate effect, but has a
carry-over, protective effect against seizures that lasts for 2.5
minutes beyond the end of stimulation. This implies that the
open-loop stimulation program should be altered to provide 30 s of
stimulation every 3 minutes. Similar subsequent analysis can be
used to determine the potential benefit of additional fine-tuning
of the therapy program.
[0080] The approach illustrated in the above example can be
indirectly tested in future open-loop trials, by measuring changes
in seizure frequency over pre-specified time periods as a function
of stimulation cycle length (e.g., 1 min ON-5 min OFF vs. 1 min
ON-2.5 min OFF); greater reductions in seizure frequency with
shorter off cycles than with longer off cycles would demonstrate
the direction and benefit of utilizing "carry-over" effect
information in seizure prophylaxis or abatement. Applicants note
that potentially greater benefits may be provided with stimulation
applied at relatively high frequencies. For example, Applicants
have determined that applying stimulation pulses at frequencies
such as 175 Hz to the anterior thalamic nuclei (or neighboring
locations) may allow for substantial reductions in seizures in
patients that suffer from otherwise inoperable pharmaco-resistant
seizures if the stimulation pulses are provided at a rate of one
minute stimulation-on, five minutes stimulation-off. High frequency
electrical stimulation, defined as 100 Hz minimum, may (1) induce
synaptic plasticity in the form of short-term depression, long-term
depression, or both; (2) upregulate glutamic acid decarboxylase and
downregulate calcium-and calmodulin-dependent protein kinase II,
the net effect of which is to enhance inhibition at or near the
stimulated site. In addition, high frequency electrical stimulation
increases the seizure threshold in the rat pentylenetetrazol model
when delivered to the anterior thalamic nuclei and therefore may
have a similar effect in humans. Such a stimulation signal may be
applied with an intensity of 5 volts and an initial round of
closed-loop testing may be used to determine the stimulation
signal's parameters such as shape, duration, amplitude and any
other signal parameter that may be controlled.
[0081] The intervention delivered by the probabilistic closed-loop
methods disclosed herein may be tailored for individual or
subject-specific warning and/or treatment based on the frequency
and/or severity of seizures, circadian patterns, occupational
hazards, social factors, employment demands, etc.
[0082] The probabilistic closed-loop approach, which encompasses
the concept of "intelligent open-loop," may be used to issue
"graded" or incremental warnings and/or therapy. For example, the
seizure probability in a given patient is estimated to be 40% at a
given time. This probability estimate may trigger a warning
(vibration or sound) that is half as intense as one associated with
a probability twice as high (i.e., 80%). The intensity or type of
warning in this embodiment changes as a function of changes in
probability, either decreasing or increasing as a function of its
value. Further, a warning associated with a certain probability
estimate may change as a function of risk of injury or of social
embarrassment should a seizure occur; a 40% seizure probability in
a patient sitting in a chair at home would be much less intense
than if the subject was operating a vehicle. Temperature sensors,
accelerometers and/or EKG among other means, may be used to
determine the level of activity (sedentary vs. in motion) and its
relative duration to automatically adjust the level or type of
warning. Operation of power equipment or of vehicles may be
factored into the warning scale by the patient simply pressing a
button prior to initiating these activities. Cars or power
equipment may be also equipped with devices that upgrade the
warning level as they are turned ON and a disabling device that
communicates with the patient's device may be activated should the
seizure probability be at an unsafe level. An identical approach
may be taken for therapy: The type of therapy and parameters/dose
used when the seizure probability is 40% may be different that when
it is 80% or when the subject changes activity from a low to a high
risk for injury.
[0083] In other embodiments, other thalamic stimulation targets may
be applied for treatment of the neurological disorder, including
particularly mesial temporal and mesial frontal intractable
epilepsies. These targets include anterior thalamic nuclei, nucleus
Reticulatus polaris, nucleus Latero-polaris, nucleus
Antero-medialis, nucleus Ventro-oralis Internus, nucleus
Antero-principalis and nucleus Lateropolaris. It is noted that
while the anterior thalamic nuclei is a known target for
stimulation, success has been experienced when stimulating
neighborhood targets. Thus, in an embodiment a stimulation target
may be a region, which is defined as more than one nucleus or
thalamic structure, rather than a single thalamic nucleus or
structure. In addition, another possible target is the Campus
Forelli Pars H2, which is not a direct neighbor of the anterior
thalamic nuclei. Other targets are also contemplated and would vary
depending on the type of disorder.
[0084] While it has been determined that neighborhood targets may
also provide suitable candidates so as to allow the physician
implanting the electrode in the target greater latitude in the
selection of the target, for certain treatment procedures it is
desirable to stimulate the same target in both the right and left
hemisphere of the patient's brain. Therefore, the evoked response
methodology discussed below provides certain benefits when
attempting to implant electrodes in particular regions and/or
locations of the brain.
[0085] In general, evoked responses are generated by applying a
stimulation pulse with an implanted target electrode and measuring
the resultant response at other electrodes such as scalp electrodes
or other depth electrodes. Measurements of amplitude, latency and
conduction velocity provide information that allows a determination
of the location of the implanted electrode being used to stimulate.
Additionally, the morphology and polarity of the responses provide
information about the uniformity of electrode placement intra- and
inter-individually since they depend on the nature, location and
orientation of the current sources, as well as on volume conduction
characteristics which are determined by the electrical and
geometric properties of the tissue. This location information also
provides information on the connection that the electrode
stimulation site has to the desired treatment site, thus indicating
whether the stimulation site is a neighboring site of the desired
treatment site. In an embodiment, evoked responses may be used to
assess the precision of lead placement intra- and
inter-individually. This complements MRI or other imaging based
techniques and is particularly useful for targets that as the ATN,
than unlike the STN (for treatment of movement disorders) appear to
lack easily identifiable electrophysiological markers. Accurate
in-vivo localization of electrodes/contacts and identification of
functional or electrographic target markers loom as challenges that
must be successfully addressed to identify, with reproducible
accuracy in humans, structures with seizure gating capabilities and
properly assess the therapeutic value/ratio of open- or closed-loop
electrical stimulation. Although evoked responses techniques as
used in a recent investigation do not provide direct information
about lead localization, they may be used (a) to indirectly
determine if the Epileptogenic Zone(s) and the leads'targets share
anatomical connections; and (b) as tools to assess intra- as well
as inter-individual uniformity/precision of lead placement.
Applicants have determined that the intra- and inter-individual
differences in evoked responses in these subjects may accurately
predict the probable differences in lead location. The basis for
this claim is that the potential or waveform (defined by polarity,
morphology and amplitude) at any location in the brain may vary
depending on: (1) the nature, location and orientation of the
current sources; and (2) volume conduction characteristics which
are determined by the electrical and geometric properties of the
tissue. That is, potentials or waveforms of different amplitude,
morphology and polarity, recorded from the same site, are not
generated by the same current source or structure. Indirect or
direct electrical stimulation of brain structures generates
reproducible waves or oscillations (i.e., evoked responses), that
may be recorded from the scalp (or intra-cerebrally) and have
shapes and latencies that are unique for each structure. For
example, the responses generated by stimulation of structures
involved in the processing of sensory signals, have characteristic
shapes and latencies that are highly similar among different
subjects and are easily distinguishable, from those generated by
structures involved in processing acoustic stimuli which are also
highly similar inter-individually. It follows, therefore, that
direct or indirect stimulation of the same structure in each
cerebral hemisphere elicits highly similar, if not identical,
reproducible responses that may be recorded from the scalp, using
electrodes placed according to the 10-20 system, or, any other
standardized system of electrode placement. For example, bi-phasic
square pulses (0.7 Hz; 0.1 ms/phase; 5.1 mA/phase) may be applied
to electrodes near the planned treatment area and the responses
record so as to determine the location of the electrodes. These
responses may be also reliably and reproducibly recorded
intra-cerebrally from structures connected to those being
stimulated. Differences in evoked responses elicited from
relatively selective unilateral electrical or chemical stimulation
of a given cerebral structure, compared to a) responses elicited by
stimulation of the homologous contra-lateral structure or b)
responses elicited in other individuals, suggest the structures
being stimulated are different. Thus, it can be determined that the
leads through which the currents are being passed are not in
homologous structures or regions. This allows safe, repetitive and
accurate assessment of precision of placement without the need to
resort to magnetic resonance or computerized tomography. In
addition, precise determination of the placement of the leads can
also reduce the subjectivity inherent to visual localization of
leads since evoked responses are quantitative.
[0086] It should be noted that evoked responses may be used to find
out if the structure where the stimulation electrode is being
placed has functional connectivity with the remote area whose
abnormal activity is being controlled or abated. The presence of
reproducible evoked responses in the abnormal or treatment area,
defined as responses with identical latency, morphology and
amplitude obtained from at least 2 separate stimulation trials, is
strong evidence that the stimulation area and the abnormal area
have functional connectivity. Furthermore, placement of the
stimulation electrode may be optimized by monitoring changes in
latency, amplitude and morphology in response to small changes in
the position (in the x, y or z planes) of the electrode or by
changing the part or contact of that electrode through which
currents are passed. If stimulation parameters are kept constant
and a change in the position of the contact and/or a change in the
contact provides a decreases in latencies and/or increases in
amplitude without changes in overall morphology then the change
indicates improved placement. Evoked responses may be also used to
find out if a stimulation target has functional connectivity with
structures in the opposite hemisphere. This has important practical
and clinical applications: If a structure in one hemisphere has
functional connectivity with ipsi-lateral and contra-lateral
homologous structures, stimulation of one side may suffice, or
intermittent stimulation of the two sides may be alternated to
provide full time protection. In other words, the total stimulation
energy may be reduced because only side is stimulated at a time.
This can extend the life of an implantable medical device with a
limited power source and can also potentially reduce any negative
cognitive effects that the stimulation might have.
[0087] FIG. 13 illustrates an embodiment of implanting and locating
electrodes using evoked responses. In step 410 an electrode is
positioned in a first hemisphere of the patient's brain. In an
embodiment, the electrode may be shaped to stimulate more than one
target site (for example, may be shaped like a shaft) and in
another embodiment the electrode may be one of a plurality of
electrodes in an array on a lead.
[0088] In step 420, a stimulation pulse is applied and the evoked
response measured. In step 320, the evoked response is compared to
an evoked response of an electrode positioned in a desired
location, either in the current patient or in another patient. If
the electrode is not in the desired position, steps 410 and 420 are
repeated. It should be noted that in an embodiment where the
electrode is one of a plurality of electrodes in an array, some
portion of the electrodes may be selected and stimulated and step
420 may be repeated for each contact that is selected. As can be
appreciated, in such an embodiment there may be no need to adjust
the position of the lead if the first electrode is not properly
positioned, rather the position of the selected contact on the lead
can be changed until an electrode is determined to be positioned in
a desired location. It should be noted that in a situation where a
region is the intended target, the location of the first electrode
is acceptable as long as the location is within the target
region.
[0089] Once the first electrode is properly positioned, a second
electrode is positioned in a second hemisphere in step 440. For
example, if the first electrode is positioned in the left
hemisphere, then the second electrode may be positioned in the
right hemisphere. In step 450 the a stimulation pulse is applied to
the second electrode and in step 460 a check is made to see if the
location of the second electrode correspond to the position of the
first electrode. If the location of the second electrode is
determined to not match the desired location, steps 440-460 may be
repeated. Therefore, in an embodiment the position of the second
electrode can be made to correspond to the position of the first
electrode by ensuring the evoked response of the second electrode
is substantially identical to the evoked response of the first
electrode.
[0090] It should be noted that modifications and additions to the
steps of the process depicted in FIG. 13 are contemplated. For
example, if the second electrode is one of a portion of electrodes
in an array, the positioning of the second electrode can be simply
selecting a different electrode from the array of electrodes. In
addition, if the evoked response is determined to match an evoked
response associated with a particular location, an indication,
which may be textual or graphical, can be provided on a display so
that the person implanting the electrode has a visual feedback on
the location of the electrode. Therefore, the depicted process is
representative and is not intended to be limiting unless otherwise
noted.
[0091] FIG. 14 illustrates an embodiment of applying open-loop
stimulation in accordance with one or more embodiments of the
present invention. First in step 510, a plurality of electrodes is
implanted at the desired location. It should be noted that precise
electrode placement is not an easy task; therefore, a check may be
made to determine the location of a plurality of implanted
electrodes during the implanting process as discussed above in FIG.
13. It should be noted that plurality of electrodes may be situated
in an array and may be situated on more than one lead. In step 520,
an initial analysis is conducted with the electrodes. This analysis
may use the probabilistic algorithms discussed above to determine
stimulation parameters for reducing the occurrence of seizures when
stimulation is applied at the one or more electrodes. It should be
noted that using multiple electrodes has the advantage of
potentially being able to stimulate a greater volume of brain
tissue and, therefore, the application of a stimulation pulse to
two or more electrodes may be desirable for certain types of
treatment.
[0092] Once the parameters are determined, an implantable medical
device may be implanted in step 530. It should be noted that for
situations where open-loop stimulation is being used, the implanted
medical device does not need to sense neurological signals and does
not have to store events in an on-board memory. However, if
desired, the stimulation device may also include recording features
so that sensed signals may be analyzed at a later time. In
addition, the implantable medical device may also be configured to
record events, such as seizures, generated by a user actuating a
programmer. In such a configuration the implantable medical device
may communicate via telemetry in a known manner.
[0093] In step 550, the implantable medical device begins to
provide stimulation in an open-loop fashion. In an embodiment, the
stimulation may be bi-phasic at a high frequency such as 175 Hz and
the electrodes that are selected may be the cathode (-) and the
device case, which may be in the patient's chest, the anode (+) (a
"monopolar" type configuration). Such a configured allows the
electrodes that are in the proper location to encompass as much of
the stimulation target as possible. In an embodiment the
stimulation may be at an intensity of 5 volts with a repeating
pattern of a period of one minute of stimulation followed by five
minutes of no stimulation. It has been determined that, while other
patterns are possible, such a pattern is well tolerated in initial
patient studies and has a substantially beneficial effect on the
reduction of seizures while having minimal or at least an
acceptable impact on cognitive and motor-sensory functionality so
as to improve the patient's quality of life.
[0094] In step 560, analysis is conducted to determine the efficacy
of the treatment program. In an embodiment where the implanted
medical device detects and stores events such as seizures, the
information may be downloaded from the implanted device in a known
manner and analyzed. As can be appreciated, with a suitable relay
system this process can be initiated and conducted remotely. The
analysis may include a determination of the reduction in seizure
frequency and/or severity as well as an evaluation of cognitive and
motor-sensory skills to determine a more complete picture of the
effects of the treatment.
[0095] As can be appreciated, additional steps may be added and
steps may be omitted or reordered as desired. For example, the
implantable medical device may be implanted and first used in a
closed-loop configuration to determine the desired stimulation
parameters and/or the location of the electrodes and then be
switched to an open-loop stimulation mode to conserve power.
[0096] The usefulness of the invention should be apparent to one
skilled in the art. The use of any and all examples or exemplary
language herein (e.g., "such as") is intended merely to better
illuminate the invention and does not pose a limitation on the
scope of the invention unless otherwise claimed. No language in the
specification should be construed as indicating any non-claimed
element as essential to the practice of the invention.
[0097] The present invention has sometimes been described in terms
of preferred and illustrative embodiments thereof. Numerous other
embodiments, modifications and variations within the scope and
spirit of the appended claims will occur to persons of ordinary
skill in the art from a review of this disclosure.
* * * * *