# US 10,478,639 B2 · In vivo visualization and control of patholigical changes in neural circuits

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- Number: US 10,478,639 B2
- Document ID: US10478639B2
- Status: Granted
- Kind: B2
- Application number: 14/343,831
- Filed: 2012-09-10
- Published: 2014-12-11
- Granted: 2019-11-19
- Earliest claimed: 2011-09-09
- Assignees: The Regents of the University of California
- Applicants: Jin Hyung Lee; Zhongnan Fang
- Inventors: Jin Hyung Lee; Zhongnan Fang
- Web page: https://patentgrep.com/patent/US10478639B2

## CPC

- A61N 5/0622: {Optical stimulation for exciting neural tissue}
- A61B 5/0002: {Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network (endoradiosondes A61B5/07)}
- A61B 5/0036: {including treatment, e.g., using an implantable medical device, ablating, ventilating}
- A61B 5/055: involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
- A61B 5/1468: using chemical or electrochemical methods, e.g. by polarographic means
- A61B 5/4094: {Diagnosing or monitoring seizure diseases, e.g. epilepsy}
- A61N 5/062: {Photodynamic therapy, i.e. excitation of an agent}
- G01R 33/4806: {Functional imaging of brain activation}
- A61B 5/7232: {involving compression of the physiological signal, e.g. to extend the signal recording period}
- A61N 2005/0626: {Monitoring, verifying, controlling systems and methods}
- A61N 2005/0663: {Coloured light}
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- G01R: MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES (indicating correct tuning of resonant circuits H03J3/12)

## Abstract

Neurological Disease Mechanism Analysis for Diagnosis, Drug Screening, (Deep) Brain Stimulation Therapy design and monitoring, Stem Cell Transplantation therapy design and monitoring, Brain Machine Interface design, control, and monitoring.

## Claims

### Claim 1

A method for measuring and modifying nervous system function, the method comprising:
identifying a target cell population in a nervous system of a living organism, the living organism having a particular disease;
modifying a function of the target cell population by causing cells of the target cell population within the diseased living organism to express a plurality of microbial light-responsive trans-membrane conductance regulators from genetic constructs comprising a transcriptional promoter specific to the target cell population;
after modifying the function of the target cell population in the diseased organism, delivering targeted light to the target cell population in the diseased organism;
modifying a function of the target cell population in one or more additional living organisms by causing cells of the target cell population within the one or more additional living organisms to express the plurality of microbial light-responsive trans-membrane conductance regulators from genetic constructs comprising a transcriptional promoter specific to the target cell population, wherein the one or more additional living organisms do not have the particular disease;
after modifying the function of the target cell population in the one or more additional living organisms, delivering targeted light to the target cell population in the one or more additional living organism;
at a computing system having memory and one or more processors coupled to the memory:
measuring responses of the nervous system of the diseased organism to the targeted light using functional magnetic resonance imaging (fMRI), wherein measuring comprises:
acquiring fMRI image frames;
reconstructing the fMRI image frames using a graphics processor (GPU); and
motion correcting the reconstructed fMRI image frames using parallel processing operations of the GPU;
mapping for the diseased organism neural circuit activity locations and timings based on the measured responses of the nervous system;
obtaining neural mapping information from the one or more additional living organisms based on responses of the nervous systems of the one or more additional living organisms to the targeted light;
comparing the mapped neural circuit activity locations and timings with the obtained neural mapping information; and
profiling the particular disease based on the comparison of the identified neural circuit activity and locations with the obtained neural mapping information; and
determining based on the profile one or more therapeutics that combat the particular disease.

### Claim 2 (depends on 1)

The method of claim 1, wherein the particular disease profile defines disease sub-types based upon the measured responses.

### Claim 3 (depends on 1)

The method of claim 1, wherein the particular disease profile defines disease progression sub-types based upon timing of measurement acquisitions.

### Claim 4 (depends on 1)

The method of claim 1, wherein the particular disease profile is defined across a disease progression over time.

### Claim 5 (depends on 1)

The method of claim 1, further comprising:
applying a therapeutic of the one or more therapeutics to the diseased living organism; and
measuring a therapeutic efficacy of the applied therapeutic, wherein the therapeutic efficacy is measured across time during therapy-induced modifications.

### Claim 6 (depends on 1)

The method of claim 1, wherein the plurality of microbial light-responsive trans-membrane conductance regulators includes a first subset of light-responsive molecules responsive to a first wavelength of light and a second subset of the light-responsive molecules responsive to a second wavelength of light distinct from the first wavelength;
wherein delivering the targeted light includes delivering light having the first wavelength and delivering light having the second wavelength; and
wherein the response of the target cell population to the first wavelength of light is distinct from the response of the target cell population to the second wavelength of light.

### Claim 7 (depends on 6)

The method of claim 6, wherein the first wavelength of light comprises blue light of approximately 470 nm and the second wavelength of light comprises yellow light of approximately 580 nm.

### Claim 8 (depends on 6)

The method of claim 6, wherein the first subset of light-responsive trans-membrane conductance regulators includes Channelrhodopsin-2 (ChR2) and the second subset of light-responsive trans-membrane conductance regulators includes halorhodopsin (NpHR).

### Claim 9 (depends on 6)

The method of claim 6, wherein delivering the light having the first wavelength and delivering the light having the second wavelength comprises concurrently delivering the light having the first wavelength and the light having the second wavelength.

### Claim 10 (depends on 6)

The method of claim 6, wherein delivering the light having the first wavelength and delivering the light having the second wavelength comprises:
delivering the light having the first wavelength concurrently with the light having the second wavelength; and
delivering the light having the first wavelength without delivering the light having the second wavelength.

### Claim 11 (depends on 1)

The method of claim 1, wherein profiling the particular disease includes profiling the particular disease based at least in part on disease and therapeutic assessments.

### Claim 12 (depends on 1)

The method of claim 1, wherein delivering the targeted light to the target cell population comprises controlling a function of the target cell population, and the method further comprises:
applying at least one of the determined one or more therapeutics to the diseased living organism, wherein applying the at least one therapeutic includes applying a drug at least one of:
a time before control of the function of the target cell population,
a time during control of the function of the target cell population, and
a time after control of the function of the target cell population; and
assessing at least one of:
efficacy of the applied drug,
dose amount of the applied drug, and
timing of the application of the applied drug.

### Claim 13 (depends on 1)

The method of claim 1, wherein the one or more determined therapeutics include a neuromodulation; and
wherein at least one of the neuromodulation target cell type, location, frequency, and timing is determined based on the particular disease profile.

### Claim 14 (depends on 13)

The method of claim 13, wherein the neuromodulation is done by electrical stimulation, and wherein delivering the targeted light to the target cell population comprises controlling a function of the target cell population.

### Claim 15 (depends on 1)

The method of claim 1, wherein the one or more therapeutics includes at least one of cell therapy and gene therapy directed to a location identified by the particular disease profile.

### Claim 16 (depends on 1)

The method of claim 1, wherein the responses of the nervous system include seizures or epilepsy.

### Claim 17 (depends on 1)

The method of claim 1, further comprising:
expressing light-responsive molecules in excitatory neurons in a hippocampus of the diseased living organism; and
stimulating in at least one of the hippocampus and a thalamus.

### Claim 18 (depends on 1)

The method of claim 1, further comprising analyzing the measured responses for resting connectivity to interpret clinical resting state functional neuroimaging data.

### Claim 19 (depends on 1)

The method of claim 1, wherein the measuring is conducted in a parallel processing architecture, including a closed-loop control.

### Claim 20 (depends on 1)

The method of claim 1, wherein the measuring is conducted with a high-resolution using a parallel compressed sensing reconstruction.

### Claim 21 (depends on 1)

The method of claim 1, wherein measuring responses of the nervous system of the diseased organism to the targeted light comprises measuring responses of the nervous system of the diseased organism in real time using off-resonance steady-state free precession (SSFP) imaging.