U.S. patent application number 15/129407 was filed with the patent office on 2017-05-18 for assessing neural state from action potentials.
This patent application is currently assigned to SALUDA MEDICAL PTY LTD. The applicant listed for this patent is Saluda Medical Pty Ltd. Invention is credited to John Louis PARKER.
Application Number | 20170135624 15/129407 |
Document ID | / |
Family ID | 54193790 |
Filed Date | 2017-05-18 |
United States Patent
Application |
20170135624 |
Kind Code |
A1 |
PARKER; John Louis |
May 18, 2017 |
Assessing Neural State from Action Potentials
Abstract
The neural health or state of a subject is assessed. A recording
is obtained of a compound action potential arising in neural tissue
of the subject. The recording is processed to determine whether a
profile of the recorded compound action potential is anomalous,
such as by exhibiting doublets, peak broadening or deformation, or
other anomaly. An indication is output regarding the neural state
of the subject based on determined anomalies in the recorded
compound action potential.
Inventors: |
PARKER; John Louis;
(Artarmon, AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Saluda Medical Pty Ltd |
Artarmon |
|
AU |
|
|
Assignee: |
SALUDA MEDICAL PTY LTD
Artarmon
AU
|
Family ID: |
54193790 |
Appl. No.: |
15/129407 |
Filed: |
March 27, 2015 |
PCT Filed: |
March 27, 2015 |
PCT NO: |
PCT/AU2015/050135 |
371 Date: |
September 26, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/0478 20130101;
A61B 5/4824 20130101; A61B 5/4836 20130101; A61N 1/36135 20130101;
A61N 1/36185 20130101; A61B 5/4041 20130101; A61B 5/407 20130101;
A61B 5/4076 20130101; A61B 5/04001 20130101; A61N 1/36071
20130101 |
International
Class: |
A61B 5/00 20060101
A61B005/00; A61N 1/36 20060101 A61N001/36; A61B 5/04 20060101
A61B005/04 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 28, 2014 |
AU |
2014901110 |
Claims
1. A method of assessing a neural state of a subject, the method
comprising: obtaining a recording of a compound action potential
arising in neural tissue of the subject; processing the recording
to determine whether a profile of the recorded compound action
potential is anomalous; and outputting an indication regarding the
neural state of the subject based on determined anomalies in the
recorded compound action potential.
2. The method of claim 1 wherein the detection of anomalies in the
recorded response comprises determining whether more than three
peaks exist in the recorded compound action potential.
3. The method of claim 1 wherein the detection of anomalies in the
recorded response comprises determining whether a peak in the
recorded compound action potential is unexpectedly broad.
4. The method of claim 1 wherein the detection of anomalies in the
recorded response comprises determining whether a peak in the
recorded compound action potential has an atypically swift rate of
rise.
5. The method of claim 1 wherein the detection of anomalies in the
recorded response comprises determining whether anomalous frequency
components exist in the recorded compound action potential when
assessed in the frequency domain.
6. The method of claim 1 wherein the detection of anomalies in the
recorded response comprises determining a degree of deviation of
the recorded compound action potential from a predefined expected
response profile and, if the degree of deviation exceeds a
predetermined threshold, indicating that the recorded response is
anomalous.
7. The method of claim 1 wherein the detection of anomalies in the
recorded response comprises identifying a locus of neuropathic pain
by applying stimuli to first and second neural sites and
determining which stimulus gives rise to greatest anomalies in a
recorded neural response profile.
8. The method of claim 1 when performed intra-operatively to affect
effect electrode array implantation site optimisation.
9. The method of claim 1 when performed during an implant
programming stage in order to optimise electrode selection.
10. The method of claim 1 when performed intra-operatively during a
sympathectomy procedure, in order to provide an intra-operative
progressive indication of efficacy of the sympathectomy.
11. A method of treating a neural disease, the method comprising:
ordering or requesting the result of the method of claim 1; and
administering or modifying a therapy in a manner responsive to the
ordered result.
12. A method for determining whether a human patient has
neuropathic disease, comprising: obtaining a recording of a
compound action potential arising in neural tissue of the patient;
and diagnosing the patient as having neuropathic disease if a
profile of the recorded compound action potential is anomalous.
13. A non-transitory computer readable medium for assessing a
neural state of a subject, comprising instructions which, when
executed by one or more processors, causes performance of the
following: obtaining a recording of a compound action potential
arising in neural tissue of the subject; processing the recording
to determine whether a profile of the recorded compound action
potential is anomalous; and outputting an indication regarding the
neural state of the subject based on determined anomalies in the
recorded compound action potential.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of Australian
Provisional Patent Application No. 2014901110 filed 28 Mar. 2014,
which is incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to assessing a neural state
from neural potentials, and in particular relates to obtaining a
recording of a neural potential arising on neural tissue, and
monitoring for an anomalous profile of the recording, in order to
assess the existence, state or progress of a neural disease.
BACKGROUND OF THE INVENTION
[0003] Neuropathic pain arises from damage or disease affecting the
somatosensory system, and may result from disorders of the
peripheral nervous system or the central nervous system. For
example, complex regional pain syndrome (CRPS) is a severe type of
pain disorder.
[0004] There is no known single pathognomonic symptom or sign of
neuropathic disease. Consequently, it is difficult to diagnose
neuropathic disease and to monitor the progress of neuropathic
disease. No conclusive objective diagnostic exists for neuropathic
pain, and clinicians must rely largely on a subjective clinical
observation of the patient's responses. Neuropathic pain is also
difficult to treat and often responds poorly to standard pain
treatments.
[0005] A range of medications for treating neuropathic pain exist,
including gabapentin for example. Careful documentation and
appropriate monitoring of treatment are important for the safe and
effective use of such medications, however this is difficult to
achieve due to the difficulty of determining the disease state or
monitoring the progress of the disease or symptoms. Advanced
therapies for treating neuropathic pain include spinal cord
stimulation.
[0006] Any discussion of documents, acts, materials, devices,
articles or the like which has been included in the present
specification is solely for the purpose of providing a context for
the present invention. It is not to be taken as an admission that
any or all of these matters form part of the prior art base or were
common general knowledge in the field relevant to the present
invention as it existed before the priority date of each claim of
this application.
[0007] Throughout this specification the word "comprise", or
variations such as "comprises" or "comprising", will be understood
to imply the inclusion of a stated element, integer or step, or
group of elements, integers or steps, but not the exclusion of any
other element, integer or step, or group of elements, integers or
steps.
[0008] In this specification, a statement that an element may be
"at least one of" a list of options is to be understood that the
element may be any one of the listed options, or may be any
combination of two or more of the listed options.
SUMMARY OF THE INVENTION
[0009] According to a first aspect the present invention provides a
method of assessing a neural state of a subject, the method
comprising:
[0010] obtaining a recording of a compound action potential arising
in neural tissue of the subject;
[0011] processing the recording to determine whether a profile of
the recorded compound action potential is anomalous; and
[0012] outputting an indication regarding the neural state of the
subject based on determined anomalies in the recorded compound
action potential.
[0013] A method for determining whether a human patient has
neuropathic disease, comprising:
[0014] obtaining a recording of a compound action potential arising
in neural tissue of the patient; and
[0015] diagnosing the patient as having neuropathic disease if a
profile of the recorded compound action potential is anomalous.
[0016] A non-transitory computer readable medium for assessing a
neural state of a subject, comprising instructions which, when
executed by one or more processors, causes performance of the
following:
[0017] obtaining a recording of a compound action potential arising
in neural tissue of the subject;
[0018] processing the recording to determine whether a profile of
the recorded compound action potential is anomalous; and
[0019] outputting an indication regarding the neural state of the
subject based on determined anomalies in the recorded compound
action potential.
[0020] The detection of irregularities or anomalies in the recorded
response may comprise any one or more of:
[0021] determining whether more than three peaks exist in the
recorded compound action potential;
[0022] determining whether a peak in the recorded compound action
potential is unexpectedly broad;
[0023] determining whether a peak in the recorded compound action
potential has an atypically swift rate of rise;
[0024] determining whether anomalous frequency components exist in
the recorded compound action potential when assessed in the
frequency domain;
[0025] determining a degree of deviation of the recorded compound
action potential from a predefined expected response profile and,
if the degree of deviation exceeds a predetermined threshold,
indicating that the recorded response is anomalous.
[0026] Some embodiments may determine whether more than three peaks
exist in the recorded compound action potential by measuring an
amplitude or power of the recorded compound action potential in a
time window positioned after cessation of a normal response. The
amplitude or power of the recorded compound action potential in
such a time window can be used to assess the presence or absence of
an abnormal response arising later than a normal P2 peak.
Additionally or alternatively, a matched filter or other signal
processing means may be used to detect the presence of an extra
lobe in the recorded compound action potential.
[0027] Some embodiments of the present invention thus recognise
that when considering a recorded compound action potential (CAP)
obtained from a person suffering from an altered neural state such
as CRPS, rather than the CAP taking a typical three lobed profile,
lobe deformation or additional lobes referred to herein as doublets
can be observed to arise in the ECAP. Moreover, the degree of lobe
deformation and/or the relative size of the additional lobes
appearing in the response can be measured, in order to give not
only a binary diagnosis but also a quantitative measure of the
severity of the disease suffered by the person. Absence of such
response profile anomalies may be used to eliminate some diseases
from a diagnosis for the person. Repeated assessment of the
recorded response profile from time to time, for example throughout
administration of a therapy, may be used to assess disease state,
disease progress, and therapy efficacy, and may be used to guide
therapy modifications and optimisation over time. Therapy
modifications may include modifications of dosage of a medicament
and/or modification of a stimulus regime applied by a spinal column
stimulator.
[0028] Accordingly, the present invention recognises that
monitoring for the occurrence and severity of anomalies such as
doublets in the recorded response profile gives a diagnostic for
neuropathic pain or neural damage or in general any neural disease
which gives rise to atypical neural response profiles.
[0029] Notably, some embodiments of the present invention further
recognise that when application of a stimulus to a first neural
site gives rise to anomalies in a recorded neural response profile,
application of the same stimulus to an alternative neural site
might give rise to a recorded neural response without
abnormalities. Such embodiments may thus provide for identifying a
locus of neuropathic pain.
[0030] The method of the present invention may in some embodiments
be performed intra-operatively for example to effect electrode
array implantation site optimisation. The method of the present
invention may additionally or alternatively be performed during an
implant programming stage in order to optimise electrode selection
to a site at which a locus of neuropathic pain is identified.
[0031] The invention may further provide for intra-operative
monitoring of the response profile during a sympathectomy
procedure, in order to provide an intra-operative progressive
indication of efficacy of the sympathectomy.
[0032] According to a further aspect the present invention provides
a method of treating a neural disease, the method comprising:
[0033] ordering or requesting the result of the method of the first
aspect; and
[0034] administering or modifying a therapy in a manner responsive
to the ordered result.
[0035] The compound action potential may arise from deliberate
stimulation, whether peripheral stimulation or direct spinal column
stimulation, for example.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] An example of the invention will now be described with
reference to the accompanying drawings, in which:
[0037] FIG. 1a schematically illustrates an implanted spinal cord
stimulator suitable for implementing the present invention;
[0038] FIG. 1b is a block diagram of the implanted
neurostimulator;
[0039] FIG. 1c is a schematic illustrating interaction of the
implanted stimulator with a nerve;
[0040] FIG. 2a illustrates the typical form of an electrically
evoked compound action potential of a healthy subject, and FIGS. 2b
and 2c illustrate how the CAP manifests in the recording when using
a differential recording arrangement with an epidural ground;
[0041] FIG. 3 illustrates an actual ECAP recording obtained from a
subject having a normal neural state;
[0042] FIG. 4 illustrates anomalous ECAP recordings obtained from a
subject suffering a neural disease;
[0043] FIG. 5 illustrates anomalous ECAP recordings obtained from
another subject suffering a neural disease;
[0044] FIG. 6 is a plot of the differences between the N1, N2 peaks
measured doublets;
[0045] FIG. 7 shows the normalised antidromic responses from three
patients plotted together;
[0046] FIG. 8 shows an example of a large doublet response in the
antidromic response of one patient;
[0047] FIG. 9 is a plot of the normalized masker probe results for
the refractory period of three patients;
[0048] FIGS. 10-12 illustrate the relative severity of doublet
formation for three respective patients; and
[0049] FIG. 13 illustrates a control system by which a therapy may
be modified in accordance with one embodiment of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0050] FIG. 1 schematically illustrates an implanted spinal cord
stimulator 100 suitable for implementing the present invention.
Stimulator 100 comprises an electronics module 110 implanted at a
suitable location in the patient's lower abdominal area or
posterior superior gluteal region, and an electrode assembly 150
implanted within the epidural space and connected to the module 110
by a suitable lead. Numerous aspects of operation of implanted
neural device 100 are reconfigurable by an external control device
192. Moreover, implanted neural device 100 serves a data gathering
role, with gathered data being communicated to external device
192.
[0051] FIG. 1b is a block diagram of the implanted neurostimulator
100. Module 110 contains a battery 112 and a telemetry module 114.
In embodiments of the present invention, any suitable type of
transcutaneous communication 190, such as infrared (IR),
electromagnetic, capacitive and inductive transfer, may be used by
telemetry module 114 to transfer power and/or data between an
external device 192 and the electronics module 110.
[0052] Module controller 116 has an associated memory 118 storing
patient settings 120, control programs 122 and the like. Controller
116 controls a pulse generator 124 to generate stimuli in the form
of current pulses in accordance with the patient settings 120 and
control programs 122. Electrode selection module 126 switches the
generated pulses to the appropriate electrode(s) of electrode array
150, for delivery of the current pulse to the tissue surrounding
the selected electrode(s). Measurement circuitry 128 is configured
to capture measurements of neural responses sensed at sense
electrode(s) of the electrode array as selected by electrode
selection module 126.
[0053] FIG. 1c is a schematic illustrating interaction of the
implanted stimulator 100 with a nerve 180, in this case the spinal
cord however alternative embodiments may be positioned adjacent any
desired neural tissue including a peripheral nerve, visceral nerve,
parasympathetic nerve or a brain structure. Electrode selection
module 126 selects a stimulation electrode 2 of electrode array 150
to deliver an electrical current pulse to surrounding tissue
including nerve 180, and also selects a return electrode 4 of the
array 150 for stimulus current recovery to maintain a zero net
charge transfer.
[0054] Delivery of an appropriate stimulus to the nerve 180 evokes
a neural response comprising a compound action potential which will
propagate along the nerve 180 as illustrated, for therapeutic
purposes which in the case of a spinal cord stimulator for chronic
pain might be to create paraesthesia at a desired location. To this
end the stimulus electrodes are used to deliver stimuli at 30 Hz.
To fit the device, a clinician applies stimuli which produce a
sensation that is experienced by the user as a paraesthesia. When
the paraesthesia is in a location and of a size which is congruent
with the area of the user's body affected by pain, the clinician
nominates that configuration for ongoing use.
[0055] The device 100 is further configured to sense the existence
and intensity of compound action potentials (CAPs) propagating
along nerve 180, whether such CAPs are evoked by the stimulus from
electrodes 2 and 4, or otherwise evoked. To this end, any
electrodes of the array 150 may be selected by the electrode
selection module 126 to serve as measurement electrode 6 and
measurement reference electrode 8. Signals sensed by the
measurement electrodes 6 and 8 are passed to measurement circuitry
128, which for example may operate in accordance with the teachings
of International Patent Application Publication No. WO2012155183 by
the present applicant, the content of which is incorporated herein
by reference.
[0056] FIG. 2a illustrates the typical form of an electrically
evoked compound action potential of a healthy subject. The shape of
the compound action potential shown in FIG. 2a is predictable
because it is a result of the ion currents produced by the ensemble
of axons generating action potentials in response to stimulation.
The action potentials generated among a large number of fibres sum
to form a compound action potential (CAP). The CAP is the sum of
responses from a large number of single fibre action potentials.
The CAP recorded is the result of a large number of different
fibres depolarising. The propagation velocity is determined largely
by the fibre diameter. The CAP generated from the firing of a group
of similar fibres is measured as a positive peak potential P1, then
a negative peak N1, followed by a second positive peak P2. This is
caused by the region of activation passing the recording electrode
as the action potentials propagate along the individual fibres. An
observed CAP signal will typically have a maximum amplitude in the
range of microvolts.
[0057] The CAP profile takes a typical form and can be
characterised by any suitable parameter(s) of which some are
indicated in FIG. 2a. The positions and amplitudes of the peaks can
for example be used alone or in combination to generate a
correlation between them and the state and severity of a central
nervous system (CNS) disorder. Depending on the polarity of
recording, a normal recorded profile may take an inverse form to
that shown in FIG. 2a, i.e. having two negative peaks N1 and N2,
and one positive peak P1.
[0058] FIG. 2b illustrates how the CAP manifests in the recording,
when using a differential recording arrangement with an epidural
ground. In FIG. 2b a normal ECAP shape (A) is inverted and delayed
by the propagation distance to the epidural ground electrode (B),
and so the differential measure will look like the envelope of C.
FIG. 2c shows the corresponding manifestation in relation to an
anomalous CAP (D). The anomalous CAP has a strong doublet, which is
inverted and delayed by the propagation distance to the epidural
ground electrode (E), and so the differential measure will look
like the envelope of F. As shown in FIG. 2c, and also being the
case for FIG. 2b, the actual recording obtained typically does not
include the first positive peak as it is obscured by the
stimulus.
[0059] The present invention thus recognises that the shape or
profile of the compound action potential reflects changes in the
ion channel characteristics as a result of pathological or natural
change.
EXAMPLES
[0060] Comparison of ECAP measurements from the dorsal column of a
number of different human subjects was undertaken in order to
identify systematic differences which relate to either genetic or
pathological differences between subjects. Measurements of dorsal
column evoked compound action potentials show distinct differences
between the ECAP shapes measured at different electrodes along the
array.
[0061] FIG. 3 shows a "normal" ECAP, being a triphasic P1, N1, P2
response, as obtained from "patient 25". The use of epidural ground
inverts the N1 at a time when the response passes the ground
electrode. As the recorded response of FIG. 3 exhibits no
significant abnormalities as compared to the predicted response of
FIG. 2, Patient 25 can be diagnosed as having no measurable
neuropathic disease.
[0062] In contrast, FIG. 4 shows data from patient 34, measured in
both the orthodromic and antidromic directions at respective
electrodes either side of the stimulus electrode, each spaced apart
from the stimulus electrode by three electrodes. The N1 peak 402 is
broader in the orthodromic direction, displays a faster rise time
and is larger in amplitude. Moreover, an additional lobe 404 has
emerged in the orthodromic response, in deviation from the expected
response of FIG. 3. Any or all of these abnormalities may be
detected and/or quantified in order to produce an automated
diagnosis of the existence or severity of neural disease in patient
34. For example in some embodiments a measurement may be taken of
the signal amplitude or power occurring within a time window
covering the anomalous peak 404. When the amplitude or power in
such a time window exceeds a threshold the response may be flagged
as being anomalous.
[0063] FIG. 5 illustrates the recordings of the corresponding
orthodromic and antidromic responses arising from patient 22. As
seen at 502 in the N1 peak of the orthodromic response, the N1 peak
502 is broader in the orthodromic direction, displays a faster rise
time and is larger in amplitude. An additional lobe 504 has emerged
in the orthodromic response, in deviation from the expected
response of FIG. 3. Thus patient 22 exhibits doublets which may be
detected and/or quantified in order to produce an automated
diagnosis of the existence or severity of neural disease in patient
22.
[0064] FIG. 6 is a histogram of N1 peak latencies in ms, measured
at the same stimulus electrode to recording electrode separation,
for a large number of patients. This illustrates that N1 peak
latency is predictable within quite a narrow time range as the
peaks have quite a narrow spread over a large number of
patients.
[0065] FIG. 7 shows the normalised antidromic responses from three
patients plotted together. The N1 peaks have very similar
latencies. The peak shapes 702 and 704 are normal, noting the
effects described in relation to FIGS. 2b and 2c.
[0066] FIG. 8 shows an example of a large doublet response in the
antidromic response of one patient, illustrating that severity of
the neural state can be distinguished, for example by comparing the
normalised height of lobe 804 to say lobe 404 or 504.
[0067] To explore the question of ectopic discharge, the refractory
period was investigated using the "masker probe" techniques set
forth in International Patent Application Publication No.
WO2012/155189, the contents of which are incorporated herein by
reference. FIG. 9 is a plot of the normalized masker probe results
for 3 patients, denoted patient nos 16, 19 and 35 respectively. For
patient 35 the masked amplitude was divided by the unmasked
amplitude. To allow for differences in the measurement mode for
patients 16 and 19, the results were normalized against the
responses at .about.5000 micro seconds inter-stimulus interval
(ISI). In general the results are consistent between patients. As
shown in FIGS. 10-12, the CAP profile of patient 35 had the largest
double peaks or doublets of the three patients, and also at short
ISI's of the order of 100-200 us patient 35 had the largest
additional recruitment as indicated at 902. The data for patient 16
was collected with an 80 us pulse width, and so this will affect
the additional recruitment at the short ISI's.
[0068] FIG. 10 illustrates the progression of CAP profile as the
CAP travels away from the stimulus site, for patient 35. This
indicates that the existence of an atypical CAP profile may best be
detected by making recordings very close to the stimulus site. It
is noted that the anomalous peaks propagate with distance, which
indicates that they are neural responses from the same group or
class of fibres. FIG. 11 shows a response obtained from patient 16,
and FIG. 12 shows a response obtained from patient 19, revealing
that of these three patients Patient 35 has the most severe doublet
formation in their neural response.
[0069] There appears to be little consistency between the N1
latency and the appearance of the double response so N1 latency may
not be a suitable parameter for diagnosing neural state.
[0070] Some embodiments may provide for repeated assessment of the
recorded response profile from time to time, for example throughout
administration of a therapy, in order to assess disease state,
disease progress, and therapy efficacy, and may be used to guide
therapy modifications and optimisation over time. Therapy
modifications may include modifications of dosage of a medicament
and/or modification of a stimulus regime applied by a spinal column
stimulator. FIG. 13 illustrates a control loop by which drug dosage
or electrical stimuli dosage is adjusted in a dynamic manner, with
the magnitude of the doublet (404, 504) being used as a control
variable for a feedback loop.
[0071] It will be appreciated by persons skilled in the art that
numerous variations and/or modifications may be made to the
invention as shown in the specific embodiments without departing
from the spirit or scope of the invention as broadly described. The
present embodiments are, therefore, to be considered in all
respects as illustrative and not restrictive.
* * * * *