# US 2014/0194726 A1 · Ultrasound Neuromodulation for Cognitive Enhancement

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- Number: US 2014/0194726 A1
- Document ID: US20140194726A1
- Status: Published application
- Kind: A1
- Application number: 13/734,216
- Filed: 2013-01-04
- Published: 2014-07-10
- Earliest claimed: 2013-01-04
- Assignees: Neurotrek, Inc.
- Applicants: Neurotrek, Inc.
- Inventors: David J. MISHELEVICH; Daniel Z. WETMORE; William J. TYLER; Tomo SATO
- Web page: https://patentgrep.com/patent/US20140194726A1

## CPC

- A61N 7/00: Ultrasound therapy (lithotripsy A61B17/22, A61B17/225; massage using supersonic vibration A61H23/00 {; using ultrasound for introducing media into the body A61M37/0092})
- A61B 5/0036: {including treatment, e.g., using an implantable medical device, ablating, ventilating}
- A61B 6/037: {Emission tomography}
- A61N 2/002: {in combination with another treatment}
- A61N 2/006: {for magnetic stimulation of nerve tissue}
- A61B 5/4064: {Evaluating the brain (for intracranial pressure A61B5/031; for cerebral blood gases A61B5/14553; using EEG A61B5/369)}
- A61B 5/4836: {Diagnosis combined with treatment in closed-loop systems or methods (A61B5/0036 takes precedence)}
- A61B 18/12: by passing a current through the tissue to be heated, e.g. high-frequency current
- A61B 2017/00154: {pulsed}
- A61B 2090/374: {NMR or MRI}
- A61B 2090/378: {using ultrasound}
- A61N 2007/0026: {Stimulation of nerve tissue}
- A61N 2007/0078: {with multiple treatment transducers}
- A61N 2007/0091: {with moving parts, e.g. transducers, lenses, reflectors}
- A61N 2007/027: {with multiple foci created simultaneously}
- 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)

## Abstract

Disclosed are methods and systems for non-invasive neuromodulation using ultrasound for cognitive enhancement. Cognitive enhancement can be used for mitigation of abnormal conditions such as Alzheimer's Disease, Parkinson's Disease or stroke, or for enhancement in a normal individual. The neuromodulation can produce acute or long-term effects. The latter occur through Long-Term Depression (LTD) and Long-Term Potentiation (LTP) via training. Included is control of direction of the energy emission, intensity, frequency, pulse duration, pulse pattern, mechanical perturbation, and phase/intensity relationships to targeting and accomplishing up regulation and/or down regulation.

## Claims

### Claim 1

A method of deep-brain neuromodulation of a subject with ultrasound stimulation, the method comprising:
focusing one or more ultrasound transducers at one or more neural targets related to cognitive enhancement;
applying pulsed power to the one or more ultrasound transducers to transmit ultrasound to the one or more neural targets; and
controlling the pulsed power to enhance a cognitive function of the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the one or more neural targets comprises one or more of a hippocampus, a cingulate cortex, a thalamus, a hypothalamus, a cerebellum, an amygdala, or a nucleus accumbens and wherein an acoustic ultrasound frequency is in a range from 0.3 MHz to 0.8 MHz.

### Claim 3 (depends on 1)

The method of claim 1, wherein:
a. the ultrasound is transmitted into a brain of the subject with the one or more ultrasound transducers targeting one or more brain regions related to an emotional state or a mood disorder;
b. an acoustic frequency of the ultrasound is greater than about 100 kHz and less than about 10 MHz;
c. a spatial-peak temporal-average (Ispta) intensity of an ultrasound waveform at a site of cells of the neural target to be modulated is less than about 1 W/cm2;
d. an ultrasound pulse length is less than about 5 seconds; and
e. the ultrasound induces an effect in the one or more brain regions comprising one or more of neuromodulation, brain activation, neuronal activation, neuronal inhibition, or a change in blood flow, and
f. the one or more neural targets is heated by no more than approximately 2 degrees Celsius for a period greater than about 5 seconds.

### Claim 4 (depends on 1)

The method of claim 1, wherein the neural target comprises one or more of,
a Somatosensory cortex, an Auditory cortex, a Temporal-parietal junction, a central sulcus, an intraparietal sulcus, an insular cortex, a primary visual cortex, an extrastriate visual cortex, a Piriform cortex, a Wernicke's area, a Broca's area, a Hippocampus, a parahippocampal formation, an entorhinal cortex, a perirhinal cortex, a Rostral anterior cingulate cortex, a Limbic system, an amygdale, a primary motor cortex, a supplementary motor cortex, a thalamus, a cerebellum, a basal ganglia, a substantia nigra, gamma rhythms, alpha rhythms, Brainstem nuclei, a hypothalamus, an amygdala, an anterior cingulated cortex, a prefrontal cortex, a ventromedial prefrontal cortex, a brain region involved in oxytocin and arginine vasopressin function, an inferior temporal gyms, a cingulated gyms, a subthalamic nucleus, an Amygdala, an insular cortex, an internal capsule, a nucleus accumbens, an anterior temporal gyms, brainstem nuclei, or Dorsolateral prefrontal cortex,
and wherein the cognitive function comprises one or more of
perception of touch, auditory perception, vestibular perception, visual perception, olfactory perception, language comprehension, language production, long-term memory, modulation of pain processing, emotion, motor control and movements, attention, relaxation, empathy, social interaction, mirth, laughter, fear, physiological arousal, sleep state, or modulation of risk taking.

### Claim 5 (depends on 1)

The method of claim 1 wherein the one or more neural targets responds to the ultrasound with one or more of an acute response, long-term potentiation, long-term depression, up-regulation, or down-regulation.

### Claim 6 (depends on 1)

The method of claim 1 wherein the treated cognitive function has been clinically diagnosed as abnormal and the subject has been diagnosed with a conditioned selected from the group consisting of: Alzheimer's Disease, Parkinson's disease, Creutzfeld-Jacob disease, Attention Deficit Hyperactivity Disorder, dementia, and stroke.

### Claim 7 (depends on 1)

The method of claim 1 wherein the ultrasound improves learning by a student studying for a test.

### Claim 8 (depends on 1)

The method of claim 1 wherein the one or more neural targets is selected from the group consisting of Orbito-Frontal Cortex (OFC), Anterior Temporal Lobe, Left Hippocampus, Left Frontal Cortex, Left Middle Temporal Lobe, Ventral Tegmentum, Hypothalamus, and the Central Thalamus.

### Claim 9 (depends on 1)

The method of claim 1 wherein acoustic energy is delivered by the one or more ultrasonic transducers such that beams intersect at one or more brain targets.

### Claim 10 (depends on 1)

The method of claim 1, wherein acoustic energy of the ultrasound has a frequency in a range between 100 kHz and 10 MHz.

### Claim 11 (depends on 1)

The method of claim 1 wherein a power of the ultrasound applied is at least 21 mW/cm2.

### Claim 12 (depends on 1)

The method of claim 1 wherein the power applied is greater than 21 mW/cm2 and less than a damage threshold of the one or more neural targets.

### Claim 13 (depends on 1)

The method of claim 1 wherein a stimulation frequency of lower than 500 Hz is applied for inhibition of neural activity.

### Claim 14 (depends on 12)

The method of claim 12 wherein a modulation frequency of lower than 500 Hz is divided into pulses having a duration within a range from 0.1 to 20 msec. repeated at frequencies of 2 Hz or lower for down regulation.

### Claim 15 (depends on 1)

The method of claim 1 wherein a stimulation frequency for excitation is in the range of 500 Hz to 0.25 MHz.

### Claim 16 (depends on 14)

The method of claim 14 wherein a modulation frequency of 500 Hz or higher is divided into a plurality of pulses, each pulse of the plurality having a duration of 0.1 to 20 msec. and wherein the plurality of pulses is repeated at frequencies higher than 2 Hz for up regulation.

### Claim 17 (depends on 1)

The method of claim 1, wherein a pulse length is within a range between 0.5 microsecond and 5 seconds.

### Claim 18 (depends on 1)

The method of claim 1, wherein a pulse repetition frequency is within a range between 50 Hz and 25 kHz.

### Claim 19 (depends on 1)

The method of claim 1 wherein mechanical perturbations are applied radially or axially to move the one or more ultrasound transducers.

### Claim 20 (depends on 1)

The method of claim 1 wherein a feedback mechanism is applied, wherein the feedback mechanism is selected from the group consisting of functional Magnetic Resonance Imaging (fMRI), Positive Emission Tomography (PET) imaging, video-electroencephalogram (V-EEG), acoustic monitoring, and thermal monitoring.

### Claim 21 (depends on 1)

The method of claim 1 wherein deep-brain neuromodulation is combined with one or more therapies selected from the group consisting of Transcranial Magnetic Stimulation (TMS), deep-brain stimulation (DBS), application of optogenetics, radiosurgery, Radio-Frequency (RF) therapy, behavioral therapy, and medications.

### Claim 22

A system for deep-brain neuromodulation of a subject with ultrasound stimulation, the system comprising:
one or more ultrasound transducers configured to focus at one or more neural targets related to cognitive enhancement; and
circuitry configured to apply pulsed power to the one or more ultrasound transducers and control the pulsed power to enhance a cognitive function of the subject.