JP5705223B2 - System and method for stimulating mechanosensory nerve endings - Google Patents

Description

(Cross-reference of related applications)
This patent application claims the benefit of US Provisional Patent Application No. 61/372111, filed Aug. 26, 2009, which is hereby incorporated by reference in its entirety. .

This invention was made with national treasury assistance based on NIH ROI DC003311, NIH P30 HD0258, and NIH P30 DC005803 awarded by the National Institutes of Health.
The US government has certain rights in the invention.

Adaptation is a dynamic process that is affected by reduced neurosensitivity due to repetitive sensory stimuli and can span a wide range of temporal scales that vary from millisecond to life of an organism.
Attenuation of sensory responses due to adaptation is a common mechanism in the sensory system (visual, auditory, olfactory, and somatosensory), and this common mechanism depends on factors such as stimulus intensity and stimulus frequency As such, this attenuation is inherent and this attenuation is generally more pronounced at the cortical level than at the subcortical level (Chung et al., 2002).
Since the sensory system has a definite number of outputs to represent sensory stimuli in a wide range of environments, adaptation dynamically creates a limited set of outputs to encode different ranges of stimuli. Reassignment is considered essential.
Accordingly, devices and systems that conduct research to monitor adaptation in the sensory system have been studied and developed.

The supply of current through the skin to activate sensory nerve endings has been studied, but current is an unnatural form of stimulation that activates fibers from deep and superficial receptors In between, peripheral mechanoreceptors may be bypassed (Willis & Coggeshall, 1991).
This stimulation approach could potentially result in altered afferent recruitment patterns due to spectral-based differences in nerve fiber electrical impedance and concomitant activation of efferent nerve fibers close to the stimulation site There is sex.
Furthermore, when biomagnetic techniques such as magnetoencephalogram (MEG) scanning are used to study cortical response adaptation, electrical stimulation creates a source of interference during magnetoencephalography recording.
In addition, piezoelectric transducers for applying vibrational stimuli have been investigated and have an excellent frequency response.
However, the piezoelectric transducer has a limited displacement amplitude and requires a large source current to operate the piezoelectric crystal.
As the MEG sensor array approaches these transducers, substantial electrical interference occurs.
Disk transducers (Kawahara et al., 2004 and Shirahashi et al., 2007) can provide vibrational stimuli, but operate at a single frequency, and to MRI and MEG for multiple noise sources (electrical, magnetic, acoustic) It is nonconforming.
Recently, pneumatic manifolds have been used to generate tactile stimuli using air puffs (Huang et al., 2007) and von Frey filaments (Dresel et al., 2008) in MRI scanners.
However, the time it takes to wear a device to a participant can limit dedication to the protocol, and movement of the face or limb during a stimulation session can change the site of stimulation.

  Accordingly, there is a continuing need for improved devices and systems for conducting research to monitor adaptation in the sensory system.

In one embodiment, an apparatus for stimulating mechanosensory nerve endings includes an internal chamber, a housing having a first opening and a second opening, covering the first opening of the housing, and a vibration mechanism. A sufficiently flexible membrane to receive and vibrate from a vibration stimulus and a coupling mechanism portion in a second opening configured to be fluidly coupled to the vibration mechanism portion, the device The whole is made of a magnetic non-responsive material.
The housing can be cylindrical or any polygonal shape.
The membrane can be integral with the housing or connected to the housing using, for example, an adhesive.
In some cases, the membrane can be removably coupled to the housing.

In one example, the device can include a lid having an aperture therethrough.
The lid can be configured to couple the membrane to the housing.
The lid and the housing can include corresponding fasteners so that the lid can be tightened to the housing.
Corresponding fasteners can include one or more of snap joints, tongues, corresponding threads, adhesives, or clips.

  In one example, the coupling mechanism that receives the vibrational stimulus can include a fluid coupling mechanism that fluidly couples the internal chamber to the vibration mechanism. For example, the joint mechanism can include a luer lock. In some cases, the joint mechanism can be located on the wall of the housing. In another option, the coupling mechanism can be located on the opposite side of the membrane with respect to the internal chamber.

In one example, the apparatus can include a tube that is coupled to the coupling mechanism and can be coupled to the vibration mechanism.
The tube has sufficient length to extend out of the magnetic field of the MRI or MEG so that the opposite end of the tube can be coupled to a component having a magnetically responsive component, Sexual components do not respond to magnetic fields.

In one embodiment, the membrane has a cross-sectional profile that corresponds to the cross-sectional profile of the housing.
In one aspect, the membrane is flexible elastic and / or stretchable.
In one aspect, the membrane is less than about 0.5 mm thick.
In another aspect, the membrane is about 0.127 mm, ie, less than about 0.0005 inches.
The thickness of the film can vary significantly.
The membrane is configured to vibrate sufficiently to activate the skin mechanoreceptor, which then carries nerve impulses along the primary somatosensory pathway and is encoded in the brain .
The membrane can have a positive vibration displacement of at least 1 mm.
Preferably, the vibration displacement is at least about 4 mm.

In one embodiment, the present invention can include a system for stimulating mechanosensory nerve endings.
Such a system includes a device described herein, a vibration mechanism configured to be fluidly coupled to a coupling mechanism portion of the device, and a magnetic configured to fluidly connect the device to the vibration mechanism portion. And non-responsive tubes.

In one embodiment, the vibration mechanism is configured to oscillate the fluid into and / or out of the chamber to oscillate the membrane or cause a pressure change in the fluid. The
In some cases, the vibration mechanism unit may include a servo motor.
In one aspect, the vibration mechanism is fluidly connected to a magnetic non-responsive tube that is fluidly connected to the joint mechanism.

In one example, the system can include a computing system that can be operatively coupled to the vibration mechanism.
In one aspect, the computing system is operatively coupled to the vibration mechanism.

  In one embodiment, the system includes an MRI system.

  In one embodiment, the system includes a MEG system.

In one example, the present invention can include a method of stimulating mechanosensory nerve endings.
Such a method comprises preparing an apparatus or system as described herein, placing a membrane on a subject's skin, and shaking the membrane on the skin. Can be included.

  In one example, the mechanosensory nerve endings are stimulated within the MRI.

  In one example, the mechanosensory nerve endings are stimulated within the MEG.

  In one example, the mechanosensory nerve endings are stimulated as part of physical therapy.

  In one example, the stimulation is for developmental sensorimotor impairment or motor rehabilitation of a patient with injury.

  During any test, the method can include monitoring the subject's brain during nerve terminal stimulation.

  The above embodiments and features of the present invention, as well as other embodiments and features, will become more fully apparent from the following description and accompanying drawings, or may be learned by practice of the invention as described below.

To make the above advantages and features of the present invention and other advantages and features more clear, a more detailed description of the invention is presented by reference to specific embodiments of the invention shown in the accompanying drawings. The
These drawings represent only illustrative embodiments of the invention and should not be considered as limiting the scope of the invention.
The invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

FIG. 2 includes brain MRI images (panels A and B) representing source reconstruction results for one subject, with the dipole localized on both sides in response to lip stimulation (panel A). FIG. 5 is shown in MRI slices, localized to the contralateral side to the right hand stimulus (panel B), with the dipole position and orientation orthogonal (axially and coronally). FIG. 4 is a graph containing tactile stimulus responses to frequency (panels AF) representing source reconstruction results for a single subject, with dipole position and orientation orthogonal (axially and coronally). The S1 dipole intensity with respect to time is shown for each stimulation rate on the right side of the panel. FIG. 6 is a graph showing a comparison of primary somatosensory skin (S1) peak dipole intensity at 2 Hz, 4 Hz and 8 Hz for lip stimulation. 2 is a graph showing a comparison of primary somatosensory skin (S1) peak dipole intensity at 2 Hz, 4 Hz and 8 Hz for hand stimulation. It is a graph which shows the comparison of S1 peak dipole intensity | strength delay time with respect to lip stimulation of 2 Hz, and hand stimulation. It is a graph which shows the comparison of S1 peak dipole intensity | strength delay time with respect to lip stimulation of 4 Hz, and hand stimulation. It is a graph which shows the comparison of S1 peak dipole intensity | strength delay time with respect to lip stimulation of 8 Hz, and hand stimulation. FIG. 2 shows an example of a TAC-Cell device representing a polyethylene cylinder, a 0.005 inch thick silicone membrane, and a Luer tube fitting that connects the cell to a servo controlled pneumatic pump. FIG. 6 is a diagram showing an example of a TAC-Cell device representing a polyethylene cylinder, a 0.005 inch thick silicone membrane, and a Luer tube fitting that connects the cell to a servo controlled pneumatic pump. It is the schematic of a TAC-Cell stimulus control system. FIG. 7 includes a graph showing a sample stimulation voltage pulse and the corresponding TAC-Cell displacement response, with a TAC-Cell mechanical response time (MRT) of 17 ms. It is a figure which shows the TAC-Cell apparatus fixed to the midline of the upper lip red lip part and the lower lip red lip part using the double-sided adhesive tape before the MEG recording session, It is the figure fixed also to other body parts, such as a hair skin surface layer (forefinger and middle finger), and the corner of a face. FIG. 7 shows a patterned stimulation train used as an input to a TAC-Cell air servo controller during a MEG session, with 125 pulse trains of 2 Hz, 4 Hz and 8 Hz in hand and in separate series. It is a figure which is applied to the hairless skin below the face and each pulse train is composed of six 50 ms pulses regardless of the train speed. FIG. 6 is a graph representing TAC-Cell displacement in millimeters versus time in seconds for 2 Hz. It is a graph showing a TAC-Cell displacement in millimeters with respect to time in seconds with respect to 4 Hz. FIG. 6 is a graph representing TAC-Cell displacement in millimeters versus time in seconds for 8 Hz. FIG. 6 is a graph representing facial stimulation at 2 Hz, 4 Hz and 8 Hz and a corresponding decrease in mean global field potential skin MEG response representing adaptation to the stimulation.

In general, the present invention responds to a train of synthetic air skin stimulation supplied by skin stimulation vibrations, such as the short-term of nervous system primary somatosensory skin S1 (eg, using stimulation vibrations of human hands and lips). In order to compare and characterize adaptive patterns, it relates to using the much higher temporal resolution of the MEG approach with millisecond skin stimulation oscillations.
It has been shown that the spatial resolution of MEG is sufficient to map the S1 representation of the human body including lips, lower, fingers and hands, but can be used for other body parts as well.
Previous studies have revealed that vibrotactile adaptation mechanisms exist in both the hand and face, but short-term adaptation of either the hand or face S1 to repeated point-like mechanical stimuli on a person Little is known about how it works.
Stimulation vibration can be induced using an MRI / MEG compatible haptic stimulation cell (TAC-Cell).
It is possible that repeated skin vibration stimulation can result in a frequency-dependent pattern of short-term adaptation that appears in the evoked magnetoencephalogram S1 response.
It is also possible that there may be significant differences between the spatiotemporal characteristics of the face-to-hand adaptation pattern due to the fundamental difference between mechanoreceptor neural responses and functions in motor responses.

The TAC-Cell device can non-invasively deliver patterned skin stimuli to the face and hands to study the magnetoencephalographic response adaptation pattern inside the primary somatosensory skin (S1).
Individual TAC-Cells are placed on the surface of the skin body such as the hairless surface layer of the right hand and the midline of the upper lip red lip and lower lip red lip as described herein. can do.
A 151 channel magnetoencephalogram (MEG) scanner can be used to record skin responses to tactile stimuli supplied by TAC-Cell, which are transmitted at three different frequencies through the TAC-Cell active membrane surface. It consists of a repetitive 6-pulse train that is sent out. Inducible activity within S1 (bilateral to hand stimulation and bilateral to lip stimulation) can be characterized from the best-fit dipole of the earliest prominent response component.
The S1 response revealed significant modulation and adaptation as a function of the frequency of the punctate air stimulation train and the stimulation site (hairless hands for hairless lips).

TAC-Cell may help activate human somatosensory brain pathways using pointy scalable stimuli in an MRI / MEG scanner environment.
TAC-Cell can be non-invasive and effective in neural stimulation applications.

Accordingly, the present invention includes devices, systems and methods that use TAC-Cell to stimulate mechanosensory nerve endings in the skin of the face and hands. The device is prepared from a non-magnetic responsive material (eg, a material that does not respond to magnetic fields such as antiferromagnetic, non-ferrimagnetic, non-diamagnetic, or other similar materials).
Such stimuli can be used in brain imaging devices such as magnetic resonance imaging (MRI) and magnetoencephalogram (MEG) brain sensors.
In use, the device stimulates nerves, which allows imaging of brain responses during peripheral nerve stimulation.

The device may include a container having one open end into which the micromembrane is fitted over the opening and having an apertured cap that fits over the membrane and remains in the cylinder.
The container further has another opening with a fitting to receive fluid (eg, hydraulic liquid or pneumatic gas such as air) that enters and exits the interior of the container, and the pressure movement The change in pressure in response to the vibration causes the micromembrane to vibrate like a drum.
The opening and fitting can be configured to couple to a pressure source capable of supplying a fluid, such as air, and vibrate by rapidly rocking the fluid into and out of the chamber. cause.
The TAC-Cell can be used as a neurotherapeutic interventional device with considerable potential in movement disorders in adults and children.
The TAC-Cell can have another configuration for providing vibrational stimulation as described herein and can operate to conform to MR1 and / or MEG.

TAC-Cell can be used to stimulate mechanosensory nerve endings in the face and hand skin or other body parts for human brain imaging and potential motor rehabilitation applications .
TAC-Cell can be used in clinical research settings for motor rehabilitation of (1) patients with developmental sensorimotor disorders and (2) adults with persistent cerebrovascular attacks. Other uses of TAC-Cell are further envisaged, such as monitoring brain activity in physical therapy, during a brain scan, or in combination with an electroencephalogram.

The TAC-Cell can be configured as a small diameter pneumatic actuator having a membrane configured to vibrate in response to changes in air pressure resulting from the pneumatic device.
The TAC-Cell is compatible with MRI / MEG, is non-invasive, and can be configured to be suitable for both adults and children with or without nerve damage / disease.
In one example, the TAC-Cell can be prepared from a cylindrical (eg, 19.3 mm diameter) chamber (eg, polyethylene bottle) prepared from a material that is not magnetically responsive, and the vibrating membrane is contained within the cylindrical chamber. A vibrating membrane (eg, a 0.005 inch silicone membrane sheet) attached to the opening of the cylindrical chamber can be included so that it can vibrate in response to fluid pressure changes.
For example, the vibrating membrane can be installed between the lip portion of the cylindrical chamber and the retaining ring.
However, other connection structures can be used to connect the vibrating membrane to the cylindrical chamber, such as by bonding the membrane to the chamber.
These size parameters vary to about 0.5 mm, 1 mm, 1.5 mm, 2 mm, 3 mm, 5 mm, or even larger, up to 2 cm, up to 5 cm and as large as possible (or the cross-sectional dimension of the sheet). be able to.
Also, the TAC-Cell chamber and / or film material may vary as long as it is non-magnetic.
That is, the TAC-Cell material is not magnetically responsive.
Thus, the chamber can be prepared from various polymers and ceramics, and the membrane is prepared from a polymer and some rubber.
Material variations can be achieved using a myriad of materials as long as the magnetic non-responsive properties are maintained.

The TAC-Cell can be included in a TAC-Cell system that includes other components such as a pneumatic device that supplies a vibrating fluid that vibrates the membrane.
The TAC-Cell system can also include MRI and / or MEG systems or other scanners.
One example includes a 151 channel CTF MEG scanner configured to record cutaneous neuromagnetic responses to pneumatic tactile stimuli generated by TAC-Cell.
The pneumatic device is a vibration stimulus including a repetitive 6-pulse train (50 ms pulse width, train interval = 5 s, 125 repetitions / train speed, train speed [2 Hz, 4 Hz and 8 Hz, see FIG. 8)] in the TAC-Cell Although it can be configured for delivery, other variations and patterns of pneumatic tactile stimulation can be performed.

The TAC-Cell device / system can include a fastener that secures the TAC-Cell to the subject on the skin.
One example of such a fastener is an adhesive, strapping, clamp, adhesive collar, double-sided adhesive color tape, or adhesive, clip, wrapping, bandage, etc. that can be used to attach a TAC cell to a subject. Including other types of iron-free attachments.
Fasteners secure the TAC-Cell at various locations on the skin, such as the face, hands, fingers, fingertips, palms, feet, soles, arms, legs, torso, or any other location It can be constituted as follows.
For example, a fastener can be configured to hold the TAC-Cell in some skin locations, such as the hairless surface (index / middle finger) of the right hand and the upper lip red lip and lower A midline with the lip and red lip can be included.

  A single TAC-Cell can be attached to any part of the subject's skin. Alternatively, the array of TAC-Cell devices can be attached to one or more portions of the subject's skin.

In addition, the present invention provides a multi-channel TAC-Cell array (e.g., multiple arrays) that can be used to simulate a sensory experience associated with apparent movement and direction in the face and hands, or other parts of the body. TAC-Cell device).
A TAC-Cell array consists of several TAC-s installed in a spatial pattern that can be activated sequentially (eg, with a short delay, such as 10 ms from one adjacent TAC-Cell to another TAC-Cell). Cell may be included.
Alternatively, the installation and activation can be random or pre-designed.
The TAC-Cell array induces and accelerates the mechanisms of brain plasticity and brain regeneration in patients with acute cerebrovascular attacks that affect facial movements (speech, swallowing, gestures) and hand movements (manipulation) It can be used as a new type of neurotherapeutic stimulus (intervention).

The TAC-Cell can take the form of other variations and examples. For example, a TAC-Cell consists of a “dome-shaped” membrane, a textured membrane, a membrane integrated into the TAC-Cell body (eg without a retainer collar), a pneumatic servo controller and a high-speed pneumatic switch (valve). Can be realized when miniaturization is available, can have micro-servo or integrated rocking function to move membranes such as pumps, and various other features can be modified .
The TAC-Cell can potentially be driven by servo electronics.

  Similarly, a TAC-Cell can be driven by a magnetically responsive pneumatic device located remotely from the TAC-Cell device, and a magnetic non-responsive tube can fluidly connect the TAC-Cell with the pneumatic device. .

The TAC-Cell membrane can be swung by pneumatic servo control of a pneumatic device to generate a vibration stimulus on the skin.
A fluid conduit prepared from a magnetic non-responsive material can send a vibrating fluid to the TAC-Cell to vibrate the membrane.
The active “pulsating” surface of the TAC-Cell can be used to generate a point-like mechanical input to the skin (eg, vibrations are 4.25 mm displacement with a 25 ms rise / fall time). The rise time and swing may vary depending on the fluid swing and the cross-sectional profile and size of the membrane.
However, all of the dimensional parameters, rocking parameters, material parameters, or other parameters can be varied within reasonable limits.

As shown in FIGS. 4A-4B, one embodiment of the TAC-Cell device 400 includes a housing 402 with an internal chamber 402a and a membrane 403 that covers one opening 404 of the chamber 402a. And configured to vibrate in response to the vibration mechanism.
As shown, a selectable annular ring 405 is used to connect the membrane 403 to the housing 402 and cover the opening 404.
The TAC-Cell device 400 can include a neck 406 that is coupled to the housing 402, and the neck 406 can have an internal lumen 408 that extends from the chamber 402 a to the opening 412.
The neck 406 can further include a joint component 410 at the opening 412 that can be coupled to a pneumatic device, for example, via a tube.
The coupling component 410 can be configured as a luer fitting, for example.

  In one embodiment, the housing 402, the membrane 403, the ring lid 404 (including the aperture if the membrane is not integral with the housing), the neck 406, and the coupling component are also magnetically responsive. Unless otherwise specified, plastic, polymer, rubber, silicone, polyethylene, polypropylene, ceramic and the like may be used.

FIG. 5 shows an embodiment of the TAC-Cell system.
As shown, the TAC-Cell is fluidly connected to a servo motor via a pneumatic line.
The servo motor may include a position sensor that is operatively coupled to the servo motor controller.
The servo motor controller can also receive input from a central processing unit (CPU) such as with a 16-bit ADC / DAC.
Further, the servo motor controller can be operatively coupled to an amplifier that can amplify the signal from the servo motor controller before being supplied to the servo motor.
Thus, the TAC-Cell is controllable and can receive hydro-pneumatic vibrations from a remote servo motor via a magnetic non-responsive pneumatic line.

As a result, the TAC-Cell 402 can have a fluid coupling with the chamber 402a that can be connected to an external vibration mechanism (for example, a servo motor) for generating a swing motion.
The servo may be a high performance servo system that regulates and generates pressure to drive the membrane 403.
The servo or other vibration mechanism can be located very far from the housing 402 and the membrane 403 so that the metal component or other magnetic responsive component associated with the housing 402 and membrane 403 is This is not present and allows for use in a brain scanner.

In one embodiment, the housing may resemble a standard bottle such as a specimen bottle or a chemical bottle.
The bottle lid portion has an opening (aperture) formed in the lid portion, and a membrane (for example, a 1/5000 inch thick silicone membrane) covers the bottle lid portion and can vibrate through the opening portion of the cap. Can be processed as follows.
The housing can be configured to include a fluid coupling mechanism, such as a luer fitting.
The fluid coupling mechanism may be located at the bottom of the housing or at some other location within the housing.
The fluid coupling (e.g., luer lock fitting) can accept a silicon tube or other magnetic non-responsive tube that is fluidly connected to the vibration mechanism at the other end.

The vibration mechanism unit may be of a computer control type (e.g., CPU) because the pressure inside the TAC-Cell is controlled and controlled very accurately.
The vibration mechanism can drive the TAC-Cell and the membrane is moved very rapidly so that the membrane is raised or sucked into the cylinder and has a 10/90% rise / fall time May be on the order of 25 ms.
In 1/5000 second, the membrane can move 3.6 mm, or other dimensions, depending on the size of the membrane, which gives a very robust irritation to the surface of the skin. This stimulation, in turn, drives somatosensory nerves in the skin.

Traditionally, providing stimulation in MRI or MEG has been difficult due to problems associated with stimulating the somatosensory system in a magnetic environment such as MRI or MEG.
Magnetic non-responsive TAC-Cell can provide skin stimulation or tactile stimulation without being damaged by a magnetic field.
This makes it possible to feel pressure changes on the skin and allows medical professionals to know what is happening inside the brain of a subject undergoing pressure changes on the skin.
TAC-Cell can provide a way to objectively test the entire pathway of the human nervous system using two scanner approaches, MRI and MEG.
The TAC-Cell sensation is similar to tapping on the skin because the stimulation comes in very fast and intermittently.
The membrane stimulator has an excellent frequency response up to about 30 Hz.
The examples herein show 2 Hz, 4 Hz and 8 Hz.
TAC-Cell can vibrate the surface of the skin and activate thousands of sensory nerve endings in the skin, which are then passed through the spinal cord or brainstem, and finally, It reaches the thalamus and sends a nerve fire (signal) transmitted to the somatosensory cortex.

As a result, TAC-Cell provides a pneumatic tactile stimulation cell membrane for somatosensory stimulators that are MRI compatible and MEG compatible and can be used for human neuromagnetic skin reaction stimulation.
TAC-Cell can also be used with any animal such as fish, birds, reptiles, mammals and the like.

  TAC-Cell is specifically the integrity of the trigeminal-thalamic cortical (facial) somatosensory pathway and medial hairband-thalamus-cortical (hand-fore / foot-hindlimb) somatosensory pathway in the human brain, It can be used for basic neurological evaluation of brain function using MRI and MEG scanning techniques to map the characteristics of neuroadaptation.

TAC-Cell can be used to study animals using a MEG scanner to map brain responses to TAC-Cell vibration stimuli.
TAC-Cell can be used for activation of somatosensory pathways in the human brain.

FIG. 10 shows in the figure a servo-controlled stimulation waveform that is useful for driving a pneumatic pump, which in turn modulates the pressure in the TAC-Cell.
Servo-controlled stimulus waveforms are discrete, rapid pulses that have a duration of only a few milliseconds.
The waveform in the lower trace shows the cranial nerve magnetic field response.
As shown for facial stimulation, the brain is excited within about 50 ms after each stimulation pulse.

TAC-Cell can stimulate the brain to be a highly recognizable stimulus in a brain scan (see FIG. 1A).
The TAC-Cell device is useful for mapping and diagnosing lesions in detail and can be used to determine whether a nerve signal pathway is blocked.
In addition, the TAC-Cell device can identify whether a patient is damaged during a stroke.
TAC-Cell can also be used for rehabilitation of damaged brain.
Thus, TAC-Cell can be used as a therapeutic stimulus that activates the nervous system and helps rewire the brain after it has been damaged.

In physical therapy, TAC-Cell can be used to replace electrical stimulators.
One drawback with electrical stimulators is that they reverse the order in which neurons are restored.
Another drawback is that electrical stimulation does not distinguish between sensory fiber activation and motor fiber activation.
When current is introduced into the skin, neurons with the lowest threshold for current stimulation are first excited and may be accompanied by mixed activation of sensory and / or motor neurons.
TAC-Cell eliminates this problem and selectively activates mechanosensitive afferent neurons and does not stimulate motor neurons directly.
Under natural forms of skin stimulation (i.e. tactile, pressure, vibration, not current use), normal recovery order and neuron type are preserved.
TAC-Cell is found in the skin and encodes the tactile, vibration, texture and skin stretches of the AR primary afferents associated with fast adaptation type I (FA I) and type II (FA II) It is particularly well suited for selectively stimulating slow-adapted (SA I and SA II) sensory nerve fibers.
Thus, TAC-Cell is superior to electrical stimulation in these respects.

A single TAC-Cell or TAC-Cell array can be used for all types of methods for various stimulation studies.
This can include right half body studies, left half body studies, bilateral stimulation, and hemispheric lateralization.

In one embodiment of the array, five TAC-Cells can be installed in place and each TAC-Cell is individually controlled by a separate fluid line.
When TAC-Cells are placed in a straight line and then turn on individual cells with some time delay, such as a 10 ms time delay, between each TAC-Cell, the brain will see this as an apparent movement or movement. Interpret perception.
This provides a virtual experience for the brain being treated and the perception and experience of movement that will actually help the damaged neuron and cortex rewire and form connections be able to. This is part of brain plasticity.

The TAC-Cell device can be used for either lip or hand stimulation with the same patterned stimulation and may be efficient to induce short-term adaptation of S1.
The difference in the short-term adaptation pattern between the hand and the lips may be a function of the difference in mechanoreceptor typing between the skin and subcutaneous areas, as well as between facial and limbic muscle tissue. May be due to the difference.
In addition, there may be differences with respect to other parts of the body.
The magnitude of the attenuation of the Si response depends on the stimulation frequency and pulse index, with attenuation being most pronounced at 8 Hz for both hand and lip stimulation and less pronounced at 2 Hz.
The significant difference between the waiting time of the hand and lip peak dipole intensity S1 is due to the difference between the axon length and the distance from the lip and hand mechanosensory nerve endings to their central target in S1. It is thought that.

TAC-Cell is specifically the integrity of the trigeminal-thalamic cortical (face) somatosensory pathway and the spinal column-inner hair band-thalamus-cortex (hand-forelimb / foot-hindlimb) somatosensory pathway in the human brain. Can be used for basic neurological evaluation of brain function using MRI and MEG scanning techniques.
The comparison of spatiotemporal adaptation patterns between normal healthy adults and various clinical populations such as adults with autistic children, traumatic brain injury, or cerebrovascular attacks is fundamental It may give new insights into sensory processes.

For example, repeated tactile stimulation to autistic children resulted in hypersensitivity and improvement but a slower adaptive response.
Suppressed GABAergic suppression mechanisms due to the reduction of proteins utilized to synthesize GABA are thought to be responsible for these abnormal response characteristics.

Another example may include patterned somatosensory stimulation for motor rehabilitation using TAC-Cell or TAC-Cell arrays.
Sustained somatosensory stimulation can increase motor cortex excitability and is closely related to motor learning and functional recovery after cortical injury.
Thus, in addition to functional mapping of somatosensory pathways, TAC-Cell may find use as a new neurotherapeutic interventional device for rehabilitation of adult and pediatric motor disorders.

Healthy women (mean age = 24.8 years [standard deviation = 2.9]) with no history of neurological disease participated in this study.
The TAC-Cell used was a c-custom, small diameter pneumatic actuator (Cole-Parmer, part number R-08936-00) based on a 5 ml round glass bottle with a snap-type cap.
The polyethylene cap was processed to create an internal lumen 408 with a diameter of 19.3 mm.
A 0.005 inch silicone membrane (AAA-ACME Rubber) was held securely between the edge of the glass bottle and the modified snap cap.
When pneumatically filled, the TAC-Cell active silicone membrane surface produced a peak displacement of 4.25 mm with a rise / fall time of 27 ms (based on a gradient intercept of 10% to 90%).

Custom non-rectifying servo motor coupled to a custom Airpel® glass cylinder (Airpot, 2K4444P series) operating under position feedback (Biocommunications Electronics, LLC, model 511 servo controller) and computer control (H2W Technologies, NCM 100-2LB) was used to drive the TAC-Cell using pneumatic pulses.
The computer was equipped with a 16-bit multifunction card (PCI-6052E, National Instruments).
Stimulation control signals were custom programmed in the laboratory using LabVIEW® software (version 8.0, National Instruments).
These signals served as inputs to the servo controller and were further used to trigger data acquisition by the MEG scanner.
This hardware configuration realized synchronization between stimulus generation and MEG data acquisition.
A 15 foot long silicone tube (0.125 inch ID, 0.250 inch outside diameter, 0.063 inch wall thickness) from the servo motor to the TAC-Cell installed above the participants in the MEG scanner Used to guide pneumatic stimulation pulses.
The machine response time (MRT), defined as the delay between the leading edge of the pulse train voltage waveform and the start of the corresponding TAC stimulus displacement, was a constant 17 ms for all stimulus rates (FIG. 6). The reported peak dipole strength latency value reflects a correction to the TAC-Cell MRT.

As shown in FIG. 7, the double-sided adhesive tape collar 450 has a hairless surface layer (forefinger / middle finger) (not shown) of the right hand and a midline (shown) between the upper lip red lip and lower lip red lip. Were used to secure separate TAC-Cell 400 to two skin locations of subject 460.
Installation at each skin site was completed within 1 minute.

A pneumatic servo control was used to generate a pulse train [pulse train interval 5s, repetition rate 125 per pulse train].
Each pulse train was composed of six single-phase pulses [pulse width 50 ms] (FIG. 8).
Short-term adaptation of the cortical neuromagnetic response to TAC-Cell patterned input was evaluated using a random block design with three pulse train rates of 2 Hz, 4 Hz and 8 Hz at each skin site.
The 2 Hz stimulation block lasted approximately 16 minutes, the 4 Hz stimulation block lasted approximately 14 minutes, and the 8 Hz stimulation block lasted approximately 12 minutes.
The order of stimulation frequency and stimulation site conditions was randomized among subjects.

FIG. 7 shows a subject being analyzed using a full-head MEG system 440 (CTF omega) with 151 axial gradiometer sensors and used to record cortical responses to TAC-Cell input. 460 is further shown.
A magnetic non-responsive tube 420 is connected to the joint mechanism 410.
Local coils 430, 436 were installed at three locations including the nose root point and the left and right auricular front points to determine the head position relative to the sensor coil.
Two bipolar electrodes 432 were used to record an electrooculogram (EGG), which was used to identify trials affected by eye movement artifacts and blinking.
Alignment landmarks were placed at the same three locations used to position the local coil.
Following the MEG recording session, the TAC-Cell was removed from the skin site and the participants were immediately housed inside an MRI scanner at an adjacent location to image brain tissue.

MEG data was digitally bandpass filtered between 1.5 Hz and 50 Hz using a bi-directional quaternary Butterworth filter. Trials corresponding to 1 second before and after the pulse train stimulation were observed for artifacts, and trials containing motion artifacts or blinking artifacts were excluded.
The remaining trials for each experimental condition were averaged and the DC component was offset using the pre-stimulation period as the baseline.
Over 90 trials per subject in each experimental condition were used for averaging.

CURRY ™ (COMPUMEDICS NeuroScan) is specialized signal processing software used to parse data obtained from MEG records.
CURRY can further be used to map anatomical MRI images with MEG data to map biomagnetic dipole sources.
Thus, reconstruction of the biomagnetic dipole source was performed in CURRY using a spherically symmetric volume conductor model that fits closely to each subject skull segmented from MRI data.
The biomagnetic dipole source space was defined as a regular grid of points throughout the brain volume (the average distance between the points was 4 mm).
A current density analysis is applied to the first response in the pulse train (ie, characterized by the best signal-to-noise ratio (SNR)) to identify the spatial peak of activity corresponding to S1 activity This was performed using the norm least squares method (MNLS).
Location-constrained dipole analysis (dipole position set to the spatial maxima retrieved by MNLS) shows dipole direction and peak intensity (μAmm = microamperes) for S1 activity following each pulse in the train Was subsequently used to estimate -mm).
Peak dipole peak intensity and latency is significantly different between stimulation site (lips and hands), frequency (2, 4 and 8 Hz) and pulse index in pulse train using 3 way ANOVA Compared.
For each lip and hand stimulus, the difference in the corresponding dipole position in the left hemisphere was tested for statistical significance using 1-way ANOVA.
SPSS software (version 17, SPSS) was used for statistical analysis.

For finger stimulation, the earliest prominent response component observed consistently across the subject peaked at 74.3 ± 6.7 ms following each skin reaction pulse.
For the lip stimulation, the earliest component had a peak at 50.3 ± 5.8 ms throughout the subject.
For both stimulation sites, these early components were followed by several delayed components with different temporal forms and spatial patterns of the magnetic field.

For the earliest component of the response, the distribution of the magnetic field induced across the sensor array indicates the presence of a biomagnetic dipole source in the contralateral S1 for hand stimulation conditions and the bilateral S1 for lip stimulation. Was consistent with.
This was confirmed by the results of the reconstruction of the biomagnetic dipole source demonstrated in FIG. 1A.
In FIG. 1A, the marked areas are 100 (dipole activation of facial expression in primary somatosensory cortex), 102 (dipole activation of facial expression in primary somatosensory cortex), and 104 ( Dipole activation of the contralateral hand representation in the primary somatosensory cortex).
The dipole source is consistently localized within the left S1 hand representation (hand stimulation) and on both sides within the S1 facial representation (lip stimulation).

The average dipole position for the lip and hand SI response is reported in Table 1.
A comparison between the dipole position in the left hemisphere for lip stimulation and the dipole position in the left hemisphere for hand stimulation using one-way ANOVA for each of three orthogonal coordinates is lateral (p <0. 001), significantly different SI sources along all three directions, forward (P = 0.008) and downward (P <0.001).
These results show that the somatic function localization of the primary somatosensory cortex in which the lips S1 are expressed from the hand S1 toward the center of the back of the center, that is, more laterally, forwardly and downwardly. (Penfield and Rasmussen, 1968).

Peak dipole intensity was used to quantify the magnitude of the cortical response as a function of stimulation rate and serial position within the train.
The SI response latency was determined from the peak dipole intensity and the machine response time (MRT) was modified.
A 3-way ANOVA with a dipole intensity peak is statistically significant between frequency (p <0.001) and pulse index (p <0.001), along with stimulation factors, stimulation frequency, and index factors within the stimulation train. The main effect was clarified.
The interaction between the stimulation site and frequency (p = 0.016) and between the frequency and pulse index (p = 0.003) was also statistically significant.

The peak dipole intensity of the S1 response (FIGS. 2A-2B) reveals a gradual decay with the serial position of the stimulus in the train.
The sharp attenuation of the neuromagnetic response that appeared for the 8 Hz stimulation condition prevented the analysis of latency over the third dipole intensity peak for both lip and hand stimulation conditions.
The magnitude of S1 adaptation is slightly higher in the hand than in the lips between the three test frequencies, indicating differences in mechanoreceptor expression and central integration along the bandage and thalamic cortex And can be explained in part by the mechanism.

The 3-way ANOVA with S1 peak latency revealed that the main factor of the stimulation site (p <0.001) was statistically significant, along with the factors of stimulation site, stimulation frequency and pulse index within the train.
There is no significant interaction in this example.
The lack of interaction means that the TAC-Cell induced S1 response peak latency is significantly different between the hand and lips at all three stimulation frequencies (FIGS. 3A-3C), which is shorter in the trigeminal pathway It is clarified that it is consistent with the conduction time.

The present invention may be embodied in other specific forms without departing from the spirit or basic characteristics of the invention.
The described embodiments are to be considered in all respects only as illustrative and not restrictive.
The scope of the invention is, therefore, indicated by the claims rather than by the foregoing description.
All changes that come within the meaning and range of equivalency of the claims are to be embraced within the scope of the invention.

-Dipole positions for lips (contralateral and ipsilateral hemisphere) and hand (contralateral hemisphere) S2 are associated with TAC-Cell stimuli of 2 Hz, 4 Hz and 8 Hz. Mean ± standard deviation over the entire subject is expressed in an orthogonal coordinate system based on external landmarks on the scalp.
The x-axis goes from left to right through the anterior point of the pinna, the y-axis goes from the back of the head to the nasal root point, and the z-axis points towards the head apex.

Claims (14)

A system for stimulating mechanosensory nerve endings,
A housing including an internal chamber, a first housing end including a first housing opening and configured to be coupled to a subject; and a second housing opening;
A pipe joint mechanism connected to the second housing opening;
A first pipe end connected to the pipe joint mechanism, and a magnetic non-responsive pipe having a sufficient pipe length to extend the second pipe end outside the magnetic field of MRI or MEG, A device array comprising a plurality of devices made of magnetic non-responsive material;
It is connected to the second tube end of each tube of each device so as to be fluidly connected to the internal chamber of the housing of each device, and the fluid is pneumatically vibrated with the internal chamber of each device to A vibration mechanism including a pneumatic device configured to change the pressure of the fluid;
A controller for controlling the vibration mechanism unit to individually control the pneumatic fluid vibration of the internal chamber of each device;
An adhesive collar for each device configured to connect the first housing end to the subject's skin to apply a pressure change to the skin. The second housing opening is at a second housing end opposite to the first housing end;
The system according to claim 1, wherein the pipe joint mechanism includes an elbow between the second housing end and the pipe.   3. A system according to claim 1 or claim 2, wherein the tube length is at least 15 feet.   4. The system according to any one of claims 1 to 3, comprising a computing system configured to be operably coupled to the controller.   5. The apparatus according to claim 1, wherein the fluid is oscillated in a pneumatic manner in order into and / or out of the chamber of each device of the device array. The system according to one. A method of stimulating mechanosensory nerve endings,
Providing the system according to any one of claims 1 to 5 including the vibration mechanism disposed outside a magnetic field;
Placing the subject in the magnetic field;
Adhering the first housing end of each device to the skin of the subject;
Oscillating fluid between the vibration mechanism and the internal chamber of the housing of each device to stimulate the subject's nerve endings in a pattern and / or sequence by point air stimulation. A method characterized by being.   The method of claim 6, comprising monitoring the subject's brain activity during nerve ending stimulation provided by the system.   8. A method according to claim 6 or claim 7, comprising the step of adhering the device to the skin of the subject's face and / or the skin of the hand with the adhesive collar. Magnetically scanning the subject's brain during nerve ending stimulation provided by the system;
9. A method according to any one of claims 6 to 8, comprising imaging a brain response to a nerve ending stimulus provided by the system.   10. A method according to any one of claims 6 to 9, comprising the step of pneumatically oscillating fluid into and / or out of the chamber of each device of the device array in turn. The method described.   The method of claim 10, wherein the order is pre-designed.   12. The method of any one of claims 6 to 11, comprising mapping somatic sensory pathways and / or regions of the subject's brain to nerve ending stimuli provided by the system. the method of. Adhering the device to the subject in a row;
13. The method of any one of claims 6 to 12, comprising: oscillating fluid in pneumatic sequence in and out of the chamber of the device pneumatically. The method described. The method according to claim 6, wherein the magnetic field is provided by an MRI apparatus or an MEG apparatus.

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