U.S. patent application number 15/323238 was filed with the patent office on 2018-07-05 for system and signatures for a multi-modal physiological periodic biomarker assessment.
The applicant listed for this patent is CERORA, INC.. Invention is credited to David M. Devilbiss, Adam J. SIMON.
Application Number | 20180184964 15/323238 |
Document ID | / |
Family ID | 55019937 |
Filed Date | 2018-07-05 |
United States Patent
Application |
20180184964 |
Kind Code |
A1 |
SIMON; Adam J. ; et
al. |
July 5, 2018 |
SYSTEM AND SIGNATURES FOR A MULTI-MODAL PHYSIOLOGICAL PERIODIC
BIOMARKER ASSESSMENT
Abstract
Methods for diagnosing Autism and/or Autism Spectrum Disorder
(ASD) of a subject include establishing baseline brain wave
patterns of the subject by having the subject perform a series of
task and measuring brain waves during the tasks using an EEG
measurement device, applying a light stimulus or images to the
subject's eyes and capturing eye movements and/or changes in facial
expression in response to the light stimulus or images, and giving
a neuropsychological and cognition battery of tasks to the subject
to generate a provoked cognitive assessment of the subject. A
processing device correlates the baseline brain wave patterns, eye
movements and/or facial expressions, and provoked cognitive
assessment of the subject to profile data indicative of Autism
and/or ASD. The corresponding system may also include an auditory
testing device that tests the subject's sensitivity to sound and
records the subject's speech in response to verbal tasks. The
processing device performs language processing of the recorded
speech and correlates the processed language to the profile data
indicative of Autism and/or ASD.
Inventors: |
SIMON; Adam J.; (Yardley,
PA) ; Devilbiss; David M.; (Madison, WI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CERORA, INC. |
Bethlehem |
PA |
US |
|
|
Family ID: |
55019937 |
Appl. No.: |
15/323238 |
Filed: |
June 30, 2015 |
PCT Filed: |
June 30, 2015 |
PCT NO: |
PCT/US2015/038684 |
371 Date: |
December 30, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/0482 20130101;
A61B 5/7475 20130101; A61B 5/167 20130101; A61B 5/163 20170801;
A61B 5/7405 20130101; A61B 5/0006 20130101; A61B 5/0478 20130101;
A61B 5/4884 20130101; G06F 1/14 20130101; A61B 5/0017 20130101;
A61B 5/02405 20130101; A61B 5/0533 20130101; A61B 5/0484 20130101;
A61B 5/044 20130101; H04W 4/70 20180201; G16H 50/20 20180101; A61B
5/168 20130101; A61B 5/1176 20130101; H04L 67/12 20130101; A61B
5/162 20130101; G09C 1/00 20130101; A61B 5/002 20130101; A61B
5/6803 20130101; A61B 5/4803 20130101; A61B 5/125 20130101 |
International
Class: |
A61B 5/16 20060101
A61B005/16; G16H 50/20 20060101 G16H050/20; A61B 5/00 20060101
A61B005/00; A61B 5/0484 20060101 A61B005/0484; A61B 5/1171 20060101
A61B005/1171; A61B 5/12 20060101 A61B005/12; A61B 5/024 20060101
A61B005/024; A61B 5/053 20060101 A61B005/053 |
Claims
1. A method of diagnosing Autism and/or Autism Spectrum Disorder
(ASD) of a subject, comprising: a) establishing baseline brain wave
patterns of the subject by having the subject perform a series of
task and measuring brain waves during said tasks using an EEG
measurement device; b) applying a light stimulus or images to the
subject's eyes and capturing eye movements and/or changes in facial
expression in response to the light stimulus or images; c) giving a
neuropsychological and cognition battery of tasks to the subject to
generate a provoked cognitive assessment of the subject; and d)
correlating the baseline brain wave patterns, eye movements and/or
facial expressions, and provoked cognitive assessment of the
subject to profile data indicative of Autism and/or ASD.
2. A method as in claim 1, further comprising repeating steps a)
through d) periodically.
3. A method as in claim 1, wherein said step of establishing
baseline brain wave patterns includes performing saccade and/or
anti-saccade tests on the subject.
4. A method as in claim 1, wherein said step of applying light
stimulus or images to the subject's eyes include showing the
subject static images to evoke emotional responses.
5. A method as in claim 1, wherein said step of applying light
stimulus or images to the subject's eyes include showing the
subject dynamic images to evoke emotional responses.
6. A method as in claim 1, wherein said step of giving a
neuropsychological and cognition battery of tasks to the subject
includes testing of the subject's memory, attention, and/or
executive function.
7. A method as in claim 1, further comprising recording the
subject's speech in response to verbal tasks and performing
language processing of the recorded speech.
8. A method as in claim 1, further comprising measuring heart rate
variability of the subject during said battery of tasks.
9. A system used to diagnose Autism and/or Autism Spectrum Disorder
(ASD) of a subject, comprising: an EEG measurement device that
measures brain wave patterns of the subject while performing a
series of tasks to establish a baseline brain wave pattern; a
device adapted to apply a light stimulus or images to the subject's
eyes and to capture eye movements and/or changes in facial
expression in response to the light stimulus or images; an auditory
testing device that tests the subject's sensitivity to sound and
records the subject's speech in response to verbal tasks; and a
processing device that performs language processing of the recorded
speech and correlates the baseline brain wave pattern, eye
movements and/or facial expression, and processed language to a
profile data indicative of Autism and/or ASD.
10. A system as in claim 9, wherein the device adapted to apply a
light stimulus or images to the subject's eyes and to capture eye
movements and/or changes in facial expression in response to the
light stimulus or images comprises an eye tracking camera that
tracks the subjects eye movements and/or tracks changes in facial
expression of the subject in response to light stimulus or
images.
11. A system as in claim 9, wherein the device adapted to apply a
light stimulus or images to the subject's eyes and to capture eye
movements and/or changes in facial expression in response to the
light stimulus or images comprises biosensors that track eye gaze
position and duration and pupillary response.
12. A system as in claim 9, further comprising static probes that
measure parts of the subject's face.
13. A system as in claim 9, further comprising dynamic probes that
apply dynamic stimulus to the subject relating to an emotionally
evocative event and measure the subject's response to the dynamic
stimulus.
14. A system as in claim 9, further comprising a biosensor adapted
to measure the subject's heart rate variability during a
neuropsychological and cognition battery of tasks given to the
subject.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority benefit of U.S. Provisional
Patent Application No. 62/019,291 filed Jun. 30, 2014. The content
of that patent application is hereby incorporated by reference in
its entirety.
TECHNICAL FIELD
[0002] The invention relates to diagnosis and analysis of brain
health through the use of activated tasks and stimuli in a system
to dynamically assess one's brain state and function in a periodic
biomarker assessment.
BACKGROUND
[0003] Normal functioning of the brain and central nervous system
is critical to a healthy, enjoyable and productive life. Disorders
of the brain and central nervous system are among the most dreaded
of diseases. Many neurological disorders such as stroke,
Alzheimer's disease, and Parkinson's disease are insidious and
progressive, becoming more common with increasing age. Others such
as schizophrenia, depression, multiple sclerosis and epilepsy arise
at younger age and can persist and progress throughout an
individual's lifetime. Sudden catastrophic damage to the nervous
system, such as brain trauma, infections and intoxications can also
affect any individual of any age at any time.
[0004] Most nervous system dysfunction arises from complex
interactions between an individual's genotype, environment and
personal habits and thus often presents in highly personalized
ways. However, despite the emerging importance of preventative
health care, convenient means for objectively assessing the health
of one's own nervous system have not been widely available.
Therefore, new ways to monitor the health status of the brain and
nervous system are needed for normal health surveillance, early
diagnosis of dysfunction, tracking of disease progression and the
discovery and optimization of treatments and new therapies.
[0005] Unlike cardiovascular and metabolic disorders, where
personalized health monitoring biomarkers such as blood pressure,
cholesterol, and blood glucose have long become household terms, no
such convenient biomarkers of brain and nervous system health
exist. Quantitative neurophysiological assessment approaches such
as positron emission tomography (PET), functional magnetic
resonance imaging (fMRI) and neuropsychiatric or cognition testing
involve significant operator expertise, inpatient or clinic-based
testing and significant time and expense. One potential technique
that may be adapted to serve a broader role as a facile biomarker
of nervous system function is a multi-modal assessment of the brain
from a number of different forms of data, including (i)
electroencephalography (EEG), which measures the electrical
activity of the brain resulting from the generation and
transmission of information between different regions of the brain;
(ii) eye tracking, which measures the position of the eye (x,y) as
a function of time t (x,y,t); (iii) accelerometer based measures
for postural stability and balance, both static and dynamic; (iv)
visual probes that test the subject include how they think
cognitively as well as (v) other non-limiting biosensor based
measurements.
[0006] Alternate and innovative biomarker approaches are needed to
provide quantitative measurements of personal brain health that
could greatly improve the prevention, diagnosis and treatment of
neurological and psychiatric disorders, in particular, Autism
Spectrum Disorder (ASD). Unique multimodal devices and tests that
lead to biomarkers of Parkinson's disease, Alzheimer's disease,
concussion and other neurological and neuropsychiatric conditions
are a pressing need.
SUMMARY
[0007] Systems and methods are provided for diagnosing Autism, ASD,
and/or other neurological and neuropsychiatric conditions of a
subject. The method includes taking periodic baseline assessments
by performing the steps of:
[0008] establishing baseline brain wave patterns of the subject by
having the subject perform a series of task and measuring brain
waves during the tasks using an EEG measurement device;
[0009] applying a light stimulus or images to the subject's eyes
and capturing eye movements and/or changes in facial expression in
response to the light stimulus or images;
[0010] giving a neuropsychological and cognition battery of tasks
to the subject to generate a provoked cognitive assessment of the
subject; and
[0011] correlating the baseline brain wave patterns, eye movements
and/or facial expressions, and provoked cognitive assessment of the
subject to profile data indicative of Autism and/or ASD.
These steps are repeated periodically to determine changes over
time.
[0012] In exemplary embodiments, the step of establishing baseline
brain wave patterns includes performing saccade and/or anti-saccade
tests on the subject, while the step of applying light stimulus or
images to the subject's eyes include showing the subject static
images to evoke emotional responses and/or showing the subject
dynamic images to evoke emotional responses. The step of giving a
neuropsychological and cognition battery of tasks to the subject
includes testing of the subject's memory, attention, and/or
executive function. Other data may be collected and correlated to
Autism and/or ASD as well. For example, the subject's speech in
response to verbal tasks may be recorded and language processing of
the recorded speech may be performed by the processor. Heart rate
variability of the subject during the battery of tasks may also be
measured.
[0013] In addition to an EEG measurement device and a device
adapted to apply a light stimulus or images to the subject's eyes
and to capture eye movements and/or changes in facial expression in
response to the light stimulus or images, the system of the
invention may also include an auditory testing device that tests
the subject's sensitivity to sound and records the subject's speech
in response to verbal tasks. The processing device is programmed to
perform language processing of the recorded speech and to correlate
the baseline brain wave pattern, eye movements and/or facial
expression, provoked cognitive assessment of the subject, and
processed language to a profile data indicative of Autism and/or
ASD. The device adapted to apply a light stimulus or images to the
subject's eyes and to capture eye movements and/or changes in
facial expression in response to the light stimulus or images may
comprise an eye tracking camera or biosensors that track eye gaze
position and duration and pupillary response. Static probes may
also be used to measure parts of the subject's face and dynamic
probes may be used to apply dynamic stimulus to the subject
relating to an emotionally evocative event and to measure the
subject's response to the dynamic stimulus. Other biosensors may
measure the subject's heart rate variability during the
neuropsychological and cognition battery of tasks given to the
subject.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Embodiments of the invention can be better understood with
reference to the following drawings, of which:
[0015] FIG. 1 is a schematic diagram illustrating a human body
outfitted with multiple REM modules as well as a nearby peripheral
microprocessor (MCU) with direct or wireless access to electronic
medical records.
[0016] FIG. 2 is a schematic diagram illustrating the flow of data
from the human subject wearing a headset to the laptop, tablet or
smartphone where it is encrypted and transmitted to the cloud.
[0017] FIG. 3 is a schematic diagram illustrating a basic periodic
biosensor assessment including five elements.
[0018] FIG. 4 is a schematic diagram illustrating a more
complicated periodic biosensor assessment including multiple
biosensors and several more tasks and/or probes.
[0019] FIG. 5 is a schematic diagram illustrating a complicated
periodic biosensor assessment including many biosensors and many
tasks and/or probes.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0020] The invention will be described in detail below with
reference to FIGS. 1-5. Those skilled in the art will appreciate
that the description given herein with respect to those figures is
for exemplary purposes only and is not intended in any way to limit
the scope of the invention. All questions regarding the scope of
the invention may be resolved by referring to the appended
claims.
Definitions
[0021] By "electrode to the scalp" we mean to include, without
limitation, those electrodes requiring gel, dry electrode sensors,
contactless sensors and any other means of measuring the electrical
potential or apparent electrical induced potential by
electromagnetic means.
[0022] By "monitor the brain and nervous system" we mean to
include, without limitation, surveillance of normal health and
aging, the early detection and monitoring of brain dysfunction,
monitoring of brain injury and recovery, monitoring disease onset,
progression and response to therapy, for the discovery and
optimization of treatment and drug therapies, including without
limitation, monitoring investigational compounds and registered
pharmaceutical agents, as well as the monitoring of illegal
substances and their presence or influence on an individual while
driving, playing sports, or engaged in other regulated
behaviors.
[0023] A "medical therapy" as used herein is intended to encompass
any form of therapy with potential medical effect, including,
without limitation, any pharmaceutical agent or treatment,
compounds, biologics, medical device therapy, exercise, biofeedback
or combinations thereof.
[0024] By "EEG data" we mean to include without limitation the raw
time series, any spectral properties determined after Fourier or
other transformation into the frequency domain, any nonlinear
properties after non-linear analysis, any wavelet properties, any
summary biometric variables and any combinations thereof.
[0025] A "sensory and cognitive challenge" as used herein is
intended to encompass any form of sensory stimuli (to the five
senses), cognitive challenges (to the mind), and other challenges
(such as a respiratory CO.sub.2 challenge, virtual reality balance
challenge, hammer to knee reflex challenge, etc.).
[0026] A "sensory and cognitive challenge state" as used herein is
intended to encompass any state of the brain and nervous system
during the exposure to sensory stimuli and cognitive load
challenge.
[0027] An "electronic system" as used herein is intended to
encompass, without limitation, hardware, software, firmware, analog
circuits, DC-coupled or AC-coupled circuits, digital circuits,
optical circuits, FPGA, ASICS, visual displays, audio transducers,
temperature transducers, olfactory and odor generators, or any
combination of the above.
[0028] By "spectral bands" we mean without limitation the generally
accepted definitions in the standard literature conventions such
that the bands of the PSD are often separated into the Delta band
(f<4 Hz), the Theta band (4<f<7 Hz), the Alpha band
(8<f<12 Hz), the Beta band (12<f<30 Hz), and the Gamma
band (30<f<100 Hz). The exact boundaries of these bands are
subject to some interpretation and are not considered hard and fast
to all practitioners in the field.
[0029] By "calibrating" we mean the process of inputting known
signals into the system and adjusting internal gain, offset or
other adjustable parameters in order to bring the system to a
quantitative state of reproducibility.
[0030] By "conducting quality control" we mean conducting
assessments of the system with known input signals and verifying
that the output of the system is as expected. Moreover, verifying
the output to known input reference signals constitutes a form of
quality control which assures that the system was in good working
order either before or just after a block of data was collected on
a human subject.
[0031] By "biomarker" we mean an objective measure of a biological
or physiological function or process.
[0032] By "biomarker features or metrics" we mean a variable,
biomarker, metric or feature which characterizes some aspect of the
raw underlying time series data. These terms are equivalent for a
biomarker as an objective measure and can be used
interchangeably.
[0033] By "non-invasively" we mean lacking the need to penetrate
the skin or tissue of a human subject.
[0034] By "diagnosis" we mean any one of the multiple intended use
of a diagnostic including to classify subjects in categorical
groups, to aid in the diagnosis when used with other additional
information, to screen at a high level where no a priori reason
exists, to be used as a prognostic marker, to be used as a disease
or injury progression marker, to be used as a treatment response
marker or even as a treatment monitoring endpoint.
[0035] By "electronics module" or "EM" or "reusable electronic
module" or "REM" or "multi-functional biosensor" or "MFB" we mean
an electronics module or device that can be used to record
biological signals from the same subject or multiple subjects at
different times. By the same terms, we also mean a disposable
electronics module that can be used once and thrown away which may
be part of the future as miniaturization becomes more common place
and costs of production are reduced. The electronics module can
have only one sensing function or a multitude (more than one),
where the latter (more than one) is more common. All of these terms
are equivalent and do not limit the scope of the invention.
[0036] By "biosignals" or "bio signals" or "bio-signals" we mean
any direct or indirect biological signal measurement data streams
which either directly derives from the human subject under
assessment or indirectly derives from the human subject.
Non-limiting examples for illustration purposes include EEG
brainwave data recorded either directly from the scalp or
contactless from the scalp, core temperature, physical motion or
balance derived from body worn accelerometers, gyrometers, and
magnetic compasses, the acoustic sound from a microphone to capture
the voice of the individual, the stream of camera images from a
front facing camera, the heart rate, heart rate variability and
arterial oxygen from a pulse oximeter, the skin conductance
measured along the skin (Galvonic Skin Conductance/Resistance, also
called Electrodermal Activity), the cognitive task information
recorded as keyboard strokes, mouse clicks or touch screen events.
There are many other biosignals to be recorded as well.
A System of Multiple Transducers to Both Stimulate and Record
Physiological and Brain Response as a Periodic Biosensor Assessment
for Autism and Autism Spectrum Disorder (ASD)
[0037] The systems and methods of the invention comprise multiple
transducers to both stimulate and record the physiological response
of the brain and the body in order to assess its health and
function. Central to the system is the ability to directly record
brainwave activity from an electrode placed non-invasively on or
near the scalp. Moreover, additional information on brain health
and function can be derived from transducers that measure position
and motion, temperature, cardiovascular properties like heart rate,
heart rate variability, and arterial oxygen, as well as cognitive
information, speech, eye movement, and surface skin conductance to
name a few non-limiting additional biological signal measurement
data stream examples. It is often necessary to bring the system to
the human subject, getting out of the hospital or doctor's office
and enabling data collection in the home on or near the sports
field or combat theater, thus providing accessibility to the brain
health and function assessment from a lightweight and portable form
factor. Moreover, it would be advantageous to have a minimal cost
associated with the system so that it can be used around the globe
to help those in need of brain health and function assessments.
[0038] A solution to these problems includes the creation of a
system of body worn or body proximal electronic modules (EMs or
REMs) with the ability to both record biological signal measurement
data streams as well as present stimuli to the human subject in the
form of various sensory and cognitive challenges and tasks. In
particular, one such electronic module (EM) or reusable electronic
module (REM) can be placed in the vicinity of the head and be
either reused over and over if it does not touch the human body or
disposed of if it comes in direct contact with the human body.
[0039] In one embodiment of the system, as illustrated in FIG. 1, a
human subject 3 is outfitted on their head 4 with an electronic
module (EM) or reusable electronic module (REM) 5, which has
several sensors and transducers within it to both stimulate the
human subject and to record biological signal measurement data
streams ("bio signals") in a precise fashion driven via software
either embedded within the REM on a local microprocessor control
unit or microcontroller unit (MCU) or running on a nearby
peripheral MCU. In this system, limb 6 in the form of an arm or
limb 7 in the form of a leg can hold additional REM modules 8 or 10
for additional readout and acquisition of additional biological
signals. As desired, an REM module 9 is placed on the trunk of the
human subject or up by the chest or around the neck. Nearby,
typically connected via wireless interface, a peripheral MCU 11
would both control the standardized application of sensory and
cognitive stimuli as well as coordinate the extensive data
acquisition of the biological signals derived from the human
subject 3. The peripheral MCU 11 is either a laptop, tablet PC or
smartphone, or perhaps it may be sitting in a separate location
altogether from where a human subject is immersed in an audio-video
like home theater of image, sound, and other sensory stimuli,
so-called virtual reality. It is contemplated that the REM modules
could eventually interface with each other via newer RF technology
which enables long distance communication with large bandwidth.
Importantly, peripheral MCU 11 may have database access either
locally via a hard wire 12 to a mass storage device like a hard
drive 13 or, alternatively, it may be connected via a wired or
wireless network interface 14 (e.g. ethernet cable, Wi-Fi, cellular
data modem, satellite data modem to name a few non-limiting
examples) to a remote mass storage device 15 with remote MCU
capability. The purpose of the access to a database is to enable
the system of the present invention to access and pull down
additional information about a human subject from electronic
records that may exist in some other location and where either
downloaded locally to the peripheral MCU 11 or available remotely
through network connectivity 14 to remote data base 15 (for
instance to pull genetic information or other lab results into the
system to make predictive signatures more accurate or precise with
the inclusion of blood type, last recorded blood pressure, or ApoE
genotype status as non-limiting examples). In either case, once a
unique patient identification number has been entered and proper
security clearance made (such as two factor authentication), then
many additional variables of data can be pulled out of the data
base records stored on mass storage device 13 and/or 15.
[0040] Another embodiment of the invention includes a data
recording and analysis system that includes at least one REM placed
on the head of a human subject 3 to record brain related biological
health signals, a peripheral MCU, and a cloud based enterprise
information technology infrastructure to process and report the
data that has been collected. In particular, FIG. 2 illustrates an
electronic REM module 306 on a subject's head transmitting wireless
data to peripheral MCU (in the form of a tablet PC) 304. While the
data is being collected through the Bluetooth port in the MCU 304,
the camera 300 is recording a movie of images of the subject as
he/she performs tasks to not only verify their identity but also to
analyze their eye and facial movement for features of interest
(including saccade and emotional state). Microphone 312 records the
voice of the subject for voice recognition analysis, while built-in
accelerometer and gyrometer 302 measure the stability or lack
thereof of the subject, while touch screen 304 of the peripheral
MCU records events at precise times and spatial (x,y) locations on
the touch screen. Finally, when all the various data streams are
complete, along with demographic and personal health information,
the entire package of information is encrypted locally using
AES-128 or AES-256 bit encryption (or equivalent security measures)
308 before being transmitted at 310 to the virtual or remote based
servers through an internet connection 314 which could be Wi-Fi,
Ethernet, cellular, satellite, or other technology in nature.
Need for Early Diagnosis in Autism and Autism Spectrum Disorder
[0041] An area of particular interest and challenge is in the early
diagnosis and management of subjects who either have Autism or
Autism Spectrum Disorder or are being managed after having been
clinically diagnosed. Present theory holds that there is a critical
window before a child reaches the age of four or five years old.
During when therapeutic approaches have been shown to produce
excellent results in enhancing the cognitive and social function of
a child along the spectrum. That is the Cognitive Behavioral
Therapy (CBT) has been shown to significant shift patients towards
the normal end of the spectrum if they can get CBT when the child's
brain is still highly plastic, neural connections are actively
being tested and created. Thus, if an infant or toddler is properly
diagnosed in the first or second year of life, then CBT and other
therapy has been shown to shift individuals who are initially
believed moderate to mild, or in the case of a mild case towards
Asperger's, or potentially even towards normal developmental
status. Thus, there is a great opportunity to have a major health
impact in these individual's lives for many decades if they can be
diagnosed early.
[0042] Moreover, large pharmaceutical companies are actively
investigating drug and biologic interventions and therapies for
Autism and ASD. Thus, by improving our ability to diagnose an
individual early in life, one can dramatically shift their
prognosis by getting them the proper behavioral therapy, medical
therapy, and other possible therapeutic interventions including
medical technology such as neuro-feedback and other medical device
or medical technology related interventions.
[0043] Thus, if one can utilize the methods and systems of the
present invention, then patients identified with Autism or ASD or
Asperger's (even milder along the ASD spectrum) can promptly
receive the best that therapy has to offer and enhance the quality
of their lives for the next 50 to 70 years. Moreover, in the case
of those who are diagnosed later in the golden window, at age 2, 3,
or 4 years old, can also benefit from promptly receiving the best
therapy that is available. They may not experience as dramatic as
shift as may have been possible at an earlier age but can still
nevertheless improve their cognitive and social skills thereby
reducing their symptoms and enhancing their quality of life.
[0044] Additionally, in school aged children, pre-adolescent and
adolescent teenagers, a more objective diagnosis and monitoring of
the physiological biomarkers enabled by the biosensors of the
present invention, permit a more quantitative tracking of how any
given individual is progressing using much more objective
biomarkers than are presently available today. One could envision
that at some point, the methods and system of the present invention
could be part of an at-home diagnostic toolkit which would permit
parents to monitor on a weekly, bi-weekly, every third week or
monthly basis. This would allow a much more precise means of
measuring which therapeutic approaches are working and which are
not working. Moreover, it would enable a much better understanding
of the impact of nutrition and environment on the individual. One
example of this can be found in the use of the present invention
during the drug development process in order to help researchers
understand the effects, both positive and potentially negative, on
the clinical trial participants who are receiving a non-FDA
approved drug or active pharmaceutical agent. In this case, the
biomarkers extracted from the methods and system of the present
invention could enable at home measurements during the course of an
investigational clinical study, thereby significantly enhancing the
signal to noise ratio.
[0045] As a concrete example, if a pharmaceutical company or
biotechnology company is developing a therapy for Autism, ASD, or
Asperger's Syndrome (collectively "Autism"), then they would
typically see the patient after enrollment in the trial on a
quarterly or every 6 months basis. By utilizing the methods and
systems of the present invention, a therapy developer could train
the parents how to acquire the biosensor data and send the
equipment home with them to collect data on a much more regular
basis. According to the central limit theorem, for each independent
observation made, they are typically distributed equally according
to a "normal" or Gaussian distribution (the so-called bell curve)
such that in the limit of large numbers of observations, the sample
mean approaches the true value. Further mathematical manipulation
can show that the signal to noise ratio typical scales with the
square root of the number of observations N in the sample for that
subject or patient. Thus if one could measure every other week over
the course of a 6 month trial, then that would amount to N=13
observations, rather than one at the beginning and the end. Thus,
bi-weekly assessments over a six month trial represents a square
root of 13=3.65 fold increase in the signal to noise ratio, thus
enabling a therapy developer to understand with much better clarity
if a given intervention is working or not. This is an enormous
benefit that the systems and methods of the present invention
provide via the neuroscience biomarkers gleaned from the present
invention.
Development of Diagnostic Algorithms, Predictive Models, and
Biomarkers
[0046] The methods and system of the present invention can also be
put to use in the diagnostic classification of individuals based on
the biosensor data collected and the analytic tools built into the
present invention. In particular, the system and methods provide
the means to synchronize raw streams of biosensor data and
accurately synchronize this to probe stimuli otherwise jittery in
timestamp. This should enable enhanced data processing algorithms
whereby one channel of data is used to gate in or out another
channel of data. Other methods can include but are not limited to
the construction of continuous two point correlations of well
synchronized data streams to create new biomarker and biomarker
streams heretofore not possible.
[0047] Moreover, any and all the extracted features can be worked
into statistical predictive models which are designed to either
classify an unknown subject into category (so called categorical
classification) or regress to a continuous number in a regression
model with an index as the output variable. Standard techniques
well known in the field include logistic regression/classification
(including stepwise techniques which select candidate features
based on their classification accuracy and performance),
discriminant techniques (including linear discriminant analysis and
quadratic discriminant analysis), tree based methods (including
decision trees, as well as bagged and boosted techniques like
Random Forest), neural nets (with or without hidden layers and
various weighting functions), support vector machines and other
machine learning algorithms.
[0048] The idea amongst all of these techniques is first signal
pre-process the data to remove artifacts. Then, one runs signal
processing algorithms like the fast Fourier transform to extract
features from the raw times series data. Then from the extracted
features, on builds discovery predictive models on known subjects
and "trains" the model with known information in a "training" set
of data. The second step after discovery models have been built and
assessed is to test the performance or accuracy of the predictive
discovery model on subject data which was not used to build or
train the model. This test of the model with independent data is
termed model "verification" and comes from a second and different
verification set of data than that used to train the model. This is
then followed by the third step which consists of model validation
whereby the locked model with no adjustable parameters is evaluated
prospectively in another cohort of subjects, typically moving
forward in time. It is these sorts of algorithms and models that
are most interesting to the clinical and medical community because
they can supplement the subjective observations of a clinician with
objective biosensor data through a locked algorithm. The clinical
performance of a diagnostic algorithm or device is often
characterized by the clinical sensitivity and specificity.
[0049] Recall that the sensitivity is the probability that the
diagnostic test correctly identifies a truly positive case. The
clinical specificity is the probability for the diagnostic tool to
properly identify a negative case as negative. Thus, the most
desired outcome is 100% sensitivity and 100% specificity. In
neuroscience, it would be great to be above 80% in either category
let alone both. One can quickly see the clinical utility in using
the methods and system of the present invention to create
synchronized biosensor data streams with probe stimuli and to
enable advanced analytics to extract biomarkers and features for
predictive modelling.
Specific Embodiments of an Autism Periodic Biosensor Assessment
[0050] As illustrated in FIG. 3, a primary objective of such a
system in accordance with an exemplary embodiment is to make a
periodic biosensor assessment in school age ASD patients (6-17 yrs.
old) that fall on the mild-to-moderate level of severity as well as
adults. The system will demonstrate multiple recordings throughout
behavioral therapy to see changes within a given subject (looking
for a tendency in the biomarkers to move in the direction of
Developmental Normal subjects).
[0051] The detailed objectives around Periodic Biosensor Assessment
(PBA) is to develop objective, independent measures of core and
associated symptoms of ASDs to better define sub-populations for
research and to provide robust, objective assessment of treatment
response. The biology that the biosensors are designed to pick up
includes robust objective measures of core ASD symptoms, including
communication and social interaction, restrictive repetitive
behaviors (RRB), and anxiety. Generally, biomarkers fall into
various classes including (i) emotional, (ii) affect, (iii) neural
and (iv) relational information.
[0052] Biosensors fall into two major categories, continuous and
periodic. Continuous biosensors include measurement of native
activity, including fluctuations over the time course of a day.
They include actigraphy (typically from three dimensional
accelerometer measurements), Galvanic Skin Response (also called
electro dermal activity or EDA), Heart Rate Variability (HRV),
temperature (both ambient and skin), and vocalizations or language
use (if possible). Attributes of continuous biosensors include
waterproof, long battery life, co-registers data/time stamp for
linking and synchronizing data, Bluetooth or wireless upload of
data, balance of high measurement precision (accuracy)/sample rate
frequency, access to an application programming interface (API) and
the ability to record raw data, and can possibly possess
pre-existing normative data (or can be easily generated). In
addition, for children and adolescents one would like to see
features such as easy to wear, low footprint, and comfortable form
factor.
[0053] On the other hand, as shown in FIG. 3, PBA biosensors
include but are not limited to (i) EEG (ii) eye gaze or eye
tracking (either via an integrated sensor like a web cam or an
external device, (iii) cognition (neuropsychological tasks or
events), (iv) facial affect expression/recognition (typically via
webcam), and (v) language processing (via microphone). In one
particular embodiment of the present invention, the PBA includes:
[0054] Single lead EEG headset [0055] Eye tracking capability,
either through external hardware (e.g. Tobii, GazePoint, etc.) or
through web-cam API (e.g. Sticky) with sample rates of 30 Hz or
less to capture eye movements in response to light stimulus [0056]
Cognitive battery tasks [0057] Suitable probes [0058] Explore the
addition of other components, such as electrodermal activity (EDA)
and actigraphy. [0059] Image Presentation (direct vs averted gaze,
faces vs houses, cropped eye regions with emotional choice
selection) [0060] Movie Presentation (social interaction of mom
with school aged kid) [0061] Embedded Figure Task--to observe
hyper-performance (superlative) relative to Developmental Normal
(DN) kids
[0062] The PBA includes the following features: (i) at home use by
school aged ASD subjects with supervision by their parents; (2) a
prospective intended use population to include eventually both
pre-schoolers and adults; (3) hardware that is fit for its purpose;
(4) easy to use; (5) has a robust GUI that is adaptable to the form
factor; (6) the ability to swap tasks; (7) enjoyable to the extent
possible (e.g. leverage gamification where possible); and (8) a
hardware form factor which is a laptop or Android or iOS or Windows
tablet. A particularly preferred embodiment includes a Windows
laptop, Cerora MindReader.TM. EEG headset, and eye tracker. The
software would include a data acquisition or DAQ component, a cloud
based analysis code, and a data transfer/integration capability to
other databases and APIs.
[0063] Table I below illustrates the relationship between desired
clinical biology objective, literature supported biomarkers, and
chosen biosensor and biometric. The biology that the biosensors are
designed to assess includes robust objective measures of core
symptoms: (1) Communication and social interaction; (2) restrictive
repetitive behaviors (RRB); and (3) anxiety.
TABLE-US-00001 Behavioral Number ClinicalObjective Biomarker
Probe/Task Biosensor& biometric 1 Establish baseline Eyes open,
eyes closed, EEG standard tasks brain wave patterns saccade and
anti-saccade 2 Communication/ Display of static and ET (including
both gaze- Social Interaction dynamic images of mother tracking and
pupillometry, the specific tasks like people engaged in two measure
of the diameter of the classes: averted (usually to pupil); EEG
(with select the side) vs direct gaze parameters from the
literature) (directly towards the participant) 3 Static display and
ET; EEG observation of images of houses vs human faces 4 Static
display and ET; EEG; NPT observation of cropped images of the eyes
region of a human face; subject asked to select the emotion in the
image from amongst 4 choices in each quadrant outside the image 5
Dynamic display on the ET; EEG, GSR video monitor and observe
movies of mother-child interactions with zones of engagement such
as passing a ball or toy back and forth 6 Neuropsychological and
NPT cognition battery of tasks such as reaction time, choice serial
reaction time, one card back, one card learning 7 Embedded Figures
Test to EEG, ET, NPT assess the superlative behavior of ASD
subjects to find embedded figures within a complex graphic 8 Verbal
tasks such as reading LP passages of text, naming numbers off
saccade cards (such as the Pierce, King- Devick, Developmental Eye
Movement or Cerora Saccade Tests) 9 Anxiety, RRB Static display on
the video GSR, ET, EEG, Actigraphy monitor of two classes of (RRB)
images; averted vs direct gaze photos of parent like people 10
Display and presentation of GSR, ET, EEG, Actigraphy dynamic movies
of moms in (RRB) direct vs averted gaze towards the participant 11
Cognitive measures Attention, memory, and Cognitive tasks as well
as design executive function of cognitive tasks integrated into
paradigms above Abbreviation Key: ET = Eye Tracking EEG =
Electroencephalography NPT = Neuropsychological testing LP =
language processing or automated speech analysis (from the
microphone recording) GSR = Galvanic Skin Response (also called
Electrodermal Activity or EDA)
A Second (2.sup.nd) Embodiment of the Periodic Biosensor Assessment
(PBA) for Autism or ASD
[0064] An alternate or second embodiment of the PBA for Autism or
ASD would allow for the administration of a discrete set of
home-based, simple-to-use, periodically administered biosensors
that will help capture information that is correlated with or
sensitive to one or more ASD symptoms (core or associated), that
can be used as a surrogate measure for change in a subject, either
over time naturally or due to a possible therapeutic intervention,
including cognitive behavioral, pharmacodynamics and others. The
system of this embodiment can be seen in FIG. 4 including the
following non-limiting periodic biosensor assessments: (1) eye gaze
position (x,y,t) for each of the left and right eye, duration (eye
tracking, head position); (2) pupillary response (radius or
diameter as function of time); (3) EEG (waveform data, ERP or
evoked response potentials); (4) facial affect recognition; (5)
cognition; and (6) facial emotion expression.
[0065] A Provisional Task List would include non-limiting tasks
such as: (1) saccade and anti-saccade tasks for baseline EEG
patterns; (2) alternate saccade and anti-saccade tasks for baseline
Eye Tracking performance; (3) static display of houses vs faces
photos or images; (4) static display of cropped images of human
faces with the eyes visible where the subject is asked to select
the correct emotional response of the eyes shown from among the
four choices presented, one in each quadrant outside the cropped
facial photo showing only the eyes; (5) dynamic presentation of
short movies of social interaction (mother-child) where the
duration ranges from as short as 15-30 seconds up to 5 to 10
minutes, give or take; (6) dynamic presentation of short movies of
mother-like actresses in direct vs averted gaze towards the test
subject; (7) static display of Embedded Figures Test (from the
Autism published literature where someone tries to find embedded
figures within a complicated graphical visual display); (8) verbal
tasks for language processing including reading of passages of
text, reading of numbers, letters and elements within saccade
tests; and (9) neuropsychological testing or cognition testing to
include non-limiting assessment of brief attention, working memory,
and/or executive function.
[0066] The system of this present embodiment would include use of
control data from unaffected siblings where available or an
independent sample of non-related demographically matched
developmentally normal (DN) comparator subjects. The system would
establish tasks across various co-variate dimensions including: (1)
age where groups of age ranges for each task are established and
developing equivalent tasks across age ranges of: (a) 3-5 years;
(b) 6-12 years; (c) 13-17 years; (d) 18+ years. Moreover, the
system should assess and document the functional level of the test
subject, their severity of communication deficit and any possible
IQ impairment. Furthermore, levels of engagement of required tasks
should be considered and designed into the test battery.
[0067] Literature supported biomarker findings in the Autism or ASD
subjects motivate the selection of tasks and measurements across
several different task/probe and biosensor modalities.
[0068] In particular, several EEG findings have been reported in
the literature including: 1) EEG paroxysmal abnormalities in
patients with ASDs with and without seizures, mainly temporal and
central (Parmagianni 2010), Yasuhara (2010)) with findings in
frontal and central regions in ASD subjects with and without
epilepsy; 2) qEEG-increased delta-theta activity in frontal region
(Pop-Jordanova, 2010); 3) measurement of Event Related Potentials
(ERP) during face processing of infants show differential pattern
versus controls in infants (Webb, 2010); 4) ERP different for
inverted faces in control adults versus those with ASDs (Webb,
2009), despite poorer behavioral performance in ASD subjects, both
groups had comparable P1 and N170 responses; 5) adults with
ASD>alpha power (eyes-open) versus controls,
controls>occipital alpha suppression (eyes-open) versus ASD,
finding ASD eyes-open alpha power and coherence in posterior brain
regions were inversely correlated with attention to detail
(Mathewson, 2012); 6) High-frequency (gamma) spectral oscillations
with sustained visual attention in ASD boys 3-8 years (vs.
controls), correlated with developmental delay (Orekhova, 2012);
and 7) ERP (oddball task) of detection of eye gaze direction in
children ASD. The detection of a change in eye direction elicited
occipito-temporal negativity, which had two major differences
between children with and without autism. Occipito-temporal
negativity was right-lateral dominant and more pronounced in direct
gaze in typical children, while bilaterally distributed and less
pronounced (lower amplitude) to direct gaze in ASD (Senju,
2005).
[0069] Moreover, several eye tracking published findings motivate
the present approach and system including emotion recognition
ability, eye direction detection, decreased focus on eyes during
face scanning, greater focus on other parts of face and irrelevant
areas like feet or background objects.
[0070] Moreover, paradigms or outcome variables utilized in the
present embodiment include: 1) cognition; 2) performance on
attention, memory, and executive function tasks; 3) measure of
efficiency, coherence, and pattern of EEG during cognitive tasks;
4) measures of EEG to be included; 5) emotional processing and
expression, typically assessed using prototypic facial emotion
discrimination where the test subject is asked to classify or
accurately identify the emotion or facial expression; 6) also
facial emotion expression which measures the reactivity to
emotional scenes (e.g. fighting and arguments) or in response to
prompting for the expression of emotions (such as the Computer
Emotion Recognition Toolkit (CERT)).
[0071] Moreover, eye movements and gaze direction measures could
include: 1) pupil position using camera: tracking of focal
vision--gaze position and duration; 2) pupillary light reflect:
autonomic response, regulation of pupil size (infrared
pupillometer); 3) electro-oculography (EOG): resting potential of
retina to record eye movement); 4) corneal-reflexion photography:
(camera detects corneal reflection of infrared light to identify
eye movements); and 5) position-sensing system: account for head
movements to provide a steady stream of eye position data
(acoustic, or web-camera based).
A Third (3.sup.rd) Embodiment of the Periodic Biosensor Assessment
(PBA) for Autism or ASD
[0072] A third embodiment of the PBA for Autism or ASD would allow
for the elements and features of the second embodiment described
above plus the following differences and enhancements. In
particular, the use of static versus dynamic stimuli and probes
would be altered, as shown in FIG. 5.
[0073] In particular, the static probes would include, but not be
limited to: 1) parts of faces (e.g. the cropped eyes but could also
include the nose or forehead in addition); 2) stable faces where a
comparison of social images which involve humans/people compared to
non-social images which involve personified inanimate objects, e.g.
such as a talking coffee cup; 3) Morph picture animation where
strange evolution of images in time leads to a reaction from the
test subject; 4) point light displays; 5) simple caregiver dyad
videos; and 6) simulated social interactions between peer aged kids
or a peer aged subject and a parental figure.
[0074] In particular, the dynamic probes would include, but not be
limited to: 1) social versus non-social dyads or movies between a
parent and peer aged child actor compared to a talking coffee cup
or pencil and eraser and movies or dyads of emotionally pleasant
play versus emotionally charged interaction such as fighting,
bullying, humiliation or enormous pain. The elements of the present
embodiment include but are not limited to: 1) simple attention
engagement--social versus non-social dynamic stimuli; 2) dynamic
stimulus that has an emotionally evocative event (where distress is
shown by the actor in the autonomic and attentional response
literature as a measure of response to others' distress or the
ability to show/express empathy); and 3) response to social threat
(anxiety domain) such as angry or fearful faces.
[0075] Additional tasks of interest within the present embodiment
include but are not limited to: 1) repetitive behavior--cognitive
flexibility, inhibit a pre-potent response; 2) executive function
or Posner--disengagement task (e.g. a gap task) which is a classic
task used widely in ASD with several variations; 3) delayed
non-match-to-sample: both immediate and long term memory; 4) task
that measures rate of learning and neuroplasticity; and 5) several
auditory tasks. In particular, auditory tasks can include an
auditory list learning task as a language-based test where one
tends to see some decrement in language processing, fluency,
auditory memory span or general auditory memory. Understanding
semantic or pragmatic, gist or nuance, emotional prosody in the
voice (emotional sound embedded in language). The auditory tasks
can also include sensory sensitivity (auditory) and integration of
auditory and visual information including language that is being
presented. For example, for two speakers on the screen, does the
subject look at the matching face that is pronouncing the words
that the sound card is generating.
[0076] The system of the present embodiment would make measurements
using the following biosensors: 1) EEG; 2) autonomic responses; 3)
visual attention; 4) pupillometry; and 5) Heart Rate Variability
(HRV). In addition to the biosensors of the above description, or
their equivalents, the system should control or monitor the effect
of environment of the test subject.
[0077] Moreover, the system should have as many features as
possible which would document the effect of other covariates on PBA
biosensor data. As a non-limiting example, it would be advantageous
to measure and record movement artifact on EEG alpha sub-band
relative power as the test subject enters a repetitive behavior
phase. As one non-limiting embodiment, one could include a video
monitor recording behavior during the situation--post-hoc, one can
remove epochs or parts of the EEG where the test subject is
fidgeting or talking or not attending, or alternatively incorporate
a multi-axis accelerometer embedded in the REM or its skull
supported form factor (e.g. headband or eye glass frame).
[0078] Alternatively, one could build a customized chair for the
purpose of controlling behavior of the individual (e.g. reclined,
forcing the test subject to relax based on gravity and support).
Thus, by monitoring the video, through automated or through
manually examined video tape, one could in principal determine when
a test subject is not paying attention and then off-line gate on
attention to remove irrelevant or confounding EEG data.
[0079] An alternate approach to attention is sclera tracking with
an eye tracking camera. One can automate the detection of eyes
forward and eyes averted using video of faces. In fact, one could
prefer to do this from a web-cam obtained video of the test
subject. Additional embodiments include types of chairs that would
minimize movement, ones that keep the legs of the test subject
touching the ground (so as to not swing), has chair arms to support
the test subject's arms, etc.
[0080] Moreover, one can attempt to control the background in
addition to the foreground of the test subject's visual field. What
sounds are being isolated from the test subject and controlled for?
What is the ambient temperature in the test room? Is it warm and
thus inviting sleep or, alternatively, chilly, keeping the subject
awake and attentive? In particular, on could create a set of
instructions to optimize the environment for testing. In one
embodiment, one could create a puppet show theater stage or photo
booth. Alternatively, one could utilize a live web-cam based
observation, watching the test subject remotely. If the test
subject was not paying attention, one could use that signal to
toggle off and on the EEG or other signal of interest based on when
they were and when they were not paying attention.
[0081] In addition, the present embodiment includes the process
improvement of conducting training sessions in a controlled
environment before allowing practice sessions at home, to minimize
artifactual movement. One could establish a precise set of criteria
whereby a preferred entertainment video was only played when the
test subject sat still, using the entertainment video as a source
of motivation to behave well. This approach could be extended
further by conducting practice after training in the lab setting,
then practicing at home, with the motivation of an entertaining
stimulus. Entertaining, but also habituate, first in the lab, and
then in the home, before one proceeds to collect at home data. The
test subject is being asked to earn something for their
participation. Controls could be built into the system that measure
confounding variables that could be utilized to control for
spurious behavior.
A 4.sup.th PBA Embodiment for Autism or ASD
[0082] An alternate embodiment of the present invention includes
the following features and elements as described in Table 2.
TABLE-US-00002 TABLE 2 Features and elements as part of a Periodic
Biosensor Assessment for Autism. Discussion Action Use of Static vs
Dynamic Stimuli In addition to some novel tasks require sets of
stimuli Pursue whether there are existing which have already been
tested in the target population stimuli sets available and shown to
influence the variables to be measured. Possible contacts: Focus on
3 types of dynamic stimuli: .fwdarw. Theta, alpha, gamma EEG 1.
Simple attention engagement - social vs. non-social absolute power,
look at dynamic stimuli, can also include baseline condition
differences between social & non- with an abstract stimuli.
social interaction before and after 2. Dynamic stimulus that has an
emotionally evocative therapy Rx event (where distress is shown by
the actor such as crying or pretend cut finger with distress) -
robust literature with live people (not video). Look at autonomic
and attentional response. Measure of response to others' distress.
3. Response to social threat (anxiety domain). Angry or fearful
faces; also consider female actor with face away and not interact
vs face toward audience and interact socially; threat cues.
Additional tasks which may be of interest: 1. Repetitive
Restrictive Behavior - cognitive flexibility - Particular focus on
stimuli sets inhibition of a prepotent response 2. Executive
function disengagement of attention or "GAP" task, anti-saccade
away from the target after the background cue with delay 3. Rate of
Learning - May be impacted Therefore need a good task to capture
rate of learning - neuroplasticity 4. Auditory tasks a. Auditory
list learning task. Language-based test. Tend to see some decrement
in language processing, fluency, auditory memory span or general
auditory memory. Understanding semantic or pragmatic, gist or
nuance, emotional prosody in the voice (emotional sound embedded in
language). b. Sensory sensitivity (auditory). c. Integration of
auditory and visual information. Language that is being presented.
Two speakers on the screen, do they look at the matching speaker
(vs mismatch between shape of mouth and sounds/phonemes emerging).
5. Memory tasks Delayed match to sample Extra matrix shift -
categories Neuropsych testing - definition of parallel versions for
different ages What is being measured: EEG Autonomic responses
Visual attention Pupillometry Heart Rate Variability Consider
practicalities of testing at home and insure integrity of data
Consider what are sources of error? How can these What is he
measuring and how is be controlled? he controlling for behaviors?
Means to mitigate artifacts from at home testing fMRI/DTI artifact
reduction with 1. Monitor - automated or through examined
statistical control video tape removing EEG data when child is
tracking with eye tracking camera, moving or not attending sclera
of the eye 2. Design tasks that produce measures of child Set of
instructions/criteria to paying attention, e.g. use eye tracking to
detect optimize environment for testing eyes forward or averted,
gate one channel on Sources of entertaining/novel another video
which will be played as a reward for sitting still Discuss
Environmental Variables Control environmental factors like chairs
that Use additional equipment which minimize movement will allow
more isolated Background sound testing/less distractions
Temperature/humidity (sweating or not) Background EMF/RF noise Have
puppet show around the laptop to cut out visual distractions
"Easier than come to study site" for the parent as the alternative
Video monitor setup live via webcast, could have lab person toggle
switch that shows up on EEG record Site selection for PBA: clinic
1.sup.st, then go home? Compliance Procedures Operant Conditioning
works well in ASD Use of practice sessions - in lab first before go
home, then establish performance at home in practice sessions
before go live with study data collection Video which will only be
played when a child sits still; start with 100% entertainment, then
insert more and more testing within the entertainment to keep it
both fun and informative
A 5.sup.th PBA Embodiment for Autism or ASD
[0083] An alternate embodiment of the present invention includes
the following features and elements as described in Table 3. One
methodological aspect of the present invention includes working in
a staged or sequential fashion such that one starts in the clinic,
then go to analysis for high runners, then to next in home based
devices, which could be later ruggedized and put into the home
directly in the future. In particular, some wearable continuous
biosensor data can get correlated with a symptoms report or
neuropsychological report within an EMR/EHR system. Other
components, labs or a home based system with more tasked stimuli,
can assess and measure shifting behavior and attention.
[0084] One aspect of the present invention is the cross gating of
one modality of data within another so one only evaluates relevant
portions of a particular biosensor data stream. This will thus
increase the signal to noise ratio by cutting out irrelevant noisy
data epochs. One can easily use a mobile app to manually create
synchronization with the biosensors. For instance, a mother could
create a key stroke or mouse click or touch screen event as a
temporal book mark. Methods can automatically identify what is
normal and what is not normal but using rolling time window
statistical analysis, such as rolling 3 sigma gates that flag
anything that crosses outside of 3 sigma of the past N hour mean
and standard deviation sigma.
[0085] The fifth embodiment of the present invention is designed to
assess: 1) broad symptoms and cognitive function over a broad
spectrum in ASD; 2) target anxiety and hyper-reactivity; and 3)
pro-social, decrease social anxiety and increase social approach.
With children or adults, benign adverse events (AEs) can be used to
generate anxiety-related responses. It is suggested to move away
from strictly using static stimuli and instead to use dynamic
probes much more extensively.
[0086] If a later goal is to conduct the periodic biosensor
assessment in the home, then maybe small wearable biosensors can be
employed in order to correlate to a more tightly controlled
periodic biosensor assessment in the laboratory. One may need to
develop procedures to help parents utilize sensors and children to
wear the sensors. Those in greatest need may have largest aversion.
Thus, one embodiment suggests to videotape the procedures for
training parents. Another suggests use of the gaming paradigm like
mock-MRI scanner as well.
[0087] Biosensor modalities of this embodiment include: 1) EEG, 2)
eye gaze, 3) autonomic response, 4) facial expression detection
(assuming video record). One may also measure affect response to
social images versus images of their own circumscribed interest.
One may also use biosensors as means of visual exploration of
social and non-social information. For example, for ASD do a visual
search and correlate with RRBs using an eye tracking paradigm.
[0088] In one nonlimiting example, EEG data may be used to
determine whether brain activity is suppressed during social versus
non-social tasks and behavior; one may also determine an increase
in brain activity during emotion processing. In a second
non-limiting example, emotion processing of a subject during the
PBA may be used to assess the affective and cognitive perceptual
response to emotional stimuli (Expression, rows 6, 7, 8). If one
wants to examine the physiologic response to emotional stimuli, one
may also look at facial movements in response to stimuli.
[0089] The biosensor output may also be correlated with use of well
validated anxiety measures in ASD and anxiety without autism, with
intentional bias towards threats stimuli (passive viewing of pairs
of emotional faces). Some have bias towards threat stimuli with
disengagement of attention. For example, people have trouble
disengaging from threat if they have high anxiety. Such a test may
also be used with infants.
[0090] The biosensor data captured in accordance with the methods
of the invention is stored and provided to a processing device for
assessment. For example, the captured data is compared to
previously captured data from the same patient to identify changes
over time and/or is correlated to profile data indicative of
autism, ASD, an/or other neurological disorders.
[0091] Those skilled in the art will also appreciate that the
invention may be applied to other applications and may be modified
without departing from the scope of the invention. For example, the
signal processing described herein may be performed on a server, in
the cloud, in the electronics module, or on a local PC, tablet PC,
smartphone, or custom hand held device. Accordingly, the scope of
the invention is not intended to be limited to the exemplary
embodiments described above, but only by the appended claims.
* * * * *