AU2019100370A4 - A method of reducing fear memory by using magnetic resonance imaging-navigated transcranial magnetic stimulation(TMS) - Google Patents

A method of reducing fear memory by using magnetic resonance imaging-navigated transcranial magnetic stimulation(TMS) Download PDF

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AU2019100370A4
AU2019100370A4 AU2019100370A AU2019100370A AU2019100370A4 AU 2019100370 A4 AU2019100370 A4 AU 2019100370A4 AU 2019100370 A AU2019100370 A AU 2019100370A AU 2019100370 A AU2019100370 A AU 2019100370A AU 2019100370 A4 AU2019100370 A4 AU 2019100370A4
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Ming Chen
Yue Jiang
Likui Ju
Dan YAN
Yihe Yuan
Yiran Zhuo
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    • A61N2/00—Magnetotherapy
    • A61N2/004—Magnetotherapy specially adapted for a specific therapy
    • A61N2/006—Magnetotherapy specially adapted for a specific therapy for magnetic stimulation of nerve tissue
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    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
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    • A61N2/02—Magnetotherapy using magnetic fields produced by coils, including single turn loops or electromagnets
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
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    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/389—Electromyography [EMG]
    • A61B5/395—Details of stimulation, e.g. nerve stimulation to elicit EMG response

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Abstract

The present application relates to a method of reducing fear memory by using magnetic resonance imaging-navigated transcranial magnetic stimulation. Using of magnetic resonance imaging-navigated transcranial magnetic stimulation(TMS) could reduce fear memory. We completed experiments which consisted of four steps(habituation, acquisition, extinction and recall).In acquisition state, electrical stimulation was applied with the appearance of two faces while rTMS stimulation was applied in specific brain area during extinction state.The skin electric response was recorded in both of the states.In the end, we got the result that, compared with the natural extinction as well as irrelevant brain area, the fear was reduced in the subjects influenced by rTMS in specific brain area,which is related to vmPFC. According to the result and some researches, we can use this method as a therapy to treat patients with PTSD and phobia,etc. We can also use it after catastrophes to reduce fear memory of residents. Browse the form Brainsight Setthe 5etthe Treat skin calibrating instrument cabratthe TMsa Iandmarks cordinates targr coordinates Measuring Motor Thregold Measurement of pain voltage extremun epRun the habituation prograni mau voltage habituation program magnetic edup Setup Run the acquisition program Adjusting SCR acquisit on programellr look for tarrey Ciba ki dat a ptsiz Adjusting the paramet rs coordinate lcation f TM Setup the Run the Extinction prga Extinction program i nidi 124h Setup the Reci Run the Recall program Figure supraliminal stimulus Behavior change magnetic field 0 Intracellular activity electric field deoaizto Presynaptic and postsynaptic activity Cortical inhibition and facilition subliminal stimulus Figure4

Description

TITLE
A method of reducing fear memory by using magnetic resonance imaging-navigated transcranial magnetic stimulation(TMS)
FIELD OF THE INVENTION
In humans, brief rTMS trains(20 Hz, 300ms duration, seven pulses per train, 100% resting motor threshold(rMT),4 totally ) are delivered to a location in the left posterior middle prefrontal cortex, which has been showed robust connectivity with the left vmPFC projecting to the amygdala. This method can be used to reduce fear memory efficiently, compare with traditionally behaviral exposure approach.
BACKGROUND OF THE INVENTION
People with extreme stressors such as getting wounded in combat, being a victim or experiencing a crime could cause trauma that can last a lifetime. It is characterized by intense fear,helplessness or horror, intrusive recollections of the traumatic event avoidance and numbing. Some groups, like military personnel, are at highly probable risk for exposure to fearful events, therefore they have higher prevalence rates compared to ordinary people, thus giving rise to a high demand for rehabilitation assistance. The compulsive medications (such as alpha-1 blocker prazosin or Beta-blockers) cannot completely meet the different
2019100370 05 Apr 2019 conditions of patients,but these agents must be administered shortly after the trauma before Post-Traumatic Stress Disorder(PTSD) has been established,which brings up complex ethical issues.PTSD is also treated with antidepressant and atypical antipsychotic medications and psychotherapies,such as cognitive behavioral therapy or eye movement desensitization and reprocessing therapy. Existing behavior therapies for fear, like extinction and blockade of reconsolidation, also fail to achieve a high level of cure.
Transcranial magnetic stimulation (TMS) is an accurate rehabilitation technology with limited restrictions, which imposes a strong magnetic field on a part of the brain cortex, temporarily inactivates or excites neurons in the magnetic field, and can noninvasively regulate the activity of the brain region, revealing the causal relationship with behaviors. To navigate TMS to the intended targets, each subject underwent structural 3T magnetic resonance imaging (MRI), and the individual MRI scans were used in a TMS navigation system, a functional correlation between a region and a behavior can be established.TMS is currently effective in treating Refractory Depression.
In animal models,fear and extinction memories can be manipulated by interfering with prefrontal cortex(PFC) or amygdala activity.ln rats, previous studies have shown that brief electrical stimulation
2019100370 05 Apr 2019 (approximately 300-ms high-frequency stimulation)within the infralimbic cortex(IL)100ms after on set of a fear-conditioned tone significantly reduced freezing tested during extinction recall.These latencies appear to translate well to humans.The human ventromedial prefrontal cortex(vmPFC) is considered to be a functional homologue of the rat IL.
In humans,a research has shown that spatiotemporally focused TMS may enhance extinction learning and/or consolidation of extinction memory so that the cue paired with TMS to left prefrontal cortex (MNI coordinate: [-56,2,40]) ,which is showed robust connectivity with the left vmPFC, may help to reduce fear.Due to the limited effect of the natural extinction as well as treatments,we suggest using rTMS as a therapy to reduce fear.
SUMMARY OF THE INVENTION
What is TMS?
The TMS contains three stimulation modes according to different stimulation pulses: single-pulse TMS (sTMS), double-pulse TMS (pTMS) and repetitive TMS (rTMS). In this experiment, 20Hz rTMS is used, so before using it, potential safety hazards should be investigated: 1. Whether there are metal materials near the stimulus coil in the brain of the subjects. 2. Is there a pacemaker? 3. Whether there are
2019100370 05 Apr 2019 craniocerebral diseases, trauma, specific epilepsy, recent use of tricyclic drugs to reduce the threshold of epileptic seizures, alcoholism, the use of neuroexcitatory drugs.
According to the principle of electromagnetic induction, TMS discharges rapidly from the energy storage capacitor to the stimulus coil.The static magnetic field or the slowly changing magnetic field cannot excite the nerve tissue. Only the high speed transient motion magnetic field can induce the induced electromotive force and current in the skull and then generate the nerve stimulation.The induced electromotive force is proportional to the rate of change of the magnetic field.Magnetic fields do not attenuate the strength of magnetic fields through high-impedance tissues (such as the skin, skull, and dura mater), nor do they affect the induced electromotive force generated in brain tissues.The induced current is proportional to the electrical conductivity of the tissue. The impedance of the skin, fat or bone is high, and the induced current is low, so the pain receptors are hardly excited. Thus, transcranial magnetic stimulation technology is a lossless and painless nerve stimulation technology.According to the principle of electromagnetic induction, the intracranial cerebral cortex under the coil generates reverse induction current and changes the cell membrane potential. When the intensity of the induction current exceeds the excitation threshold of the nerve tissue, it will cause the depolarization
2019100370 05 Apr 2019 of local brain neurons, cause excitatory action potential and produce a series of physiological and biochemical reactions.
What is BrainSight Software?
Brainsight software, the hardware part of the current popular navigation system is mainly infrared ray emission and camera and camera device, infrared ray tracking pointer, tracker fixed in the stimulation coil and on the head of subject.The tracking pointer and tracker are equipped with three infrared reflective light balls for tracking and positioning.2. On a fixed chair or lounge chair, try to fix the head of the person receiving TMS stimulation in a comfortable position, put on an elastic EEG cap and a tracker for head positioning, turn on the MRI navigation system, calibrate these registration points with a tracker pen at the mark of the same marker pen, and then move the positioning pen on the whole head surface,obtain more registration points of the external contour of the skull and store them as 3d digital signals on the skull surface.
Principle procedure and results
1.Principle
l)There is a classical research paradigm in fear memory : acquisition-* extinction-* formation of extinction memory/ extinction recall.
2019100370 05 Apr 2019
2) There is also an Extraction-Regression Model based on Pavlovian Conditioned Reflectance::
3) The ways to recover from fear include spontaneous recovery and re-reinforcement.
2.Procedure
The experiment phase consist of four steps, including habituation , acquisition, extinction and recall. We use four similar programs for experiments.Firstly, subjects need to enter any number to determine that two faces (CS+)will appear electrical stimuli and another won’ t(CS-).(CS conditioned stimulus:Can cause the stimulation of subject unconditioned reflex, also call unconditional stimulation.For example, dogs salivate when they eat food. Food is an unconditioned stimulus that causes saliva to flow;UCS,unconditioned stimulus:Can cause the stimulation of subject unconditioned reflex, also call unconditional stimulation.For example, dogs salivate when they eat food. Food is an unconditioned stimulus that causes saliva to flow.)
The subjects will be asked to enter an arbitrary number to determine which two faces will be posed electric stimulation and which one won’ t.The method is to divide the selected number by 3 to find the remainder.lf the remainder is 1, then [l,l,0]will be chosen. If the
2019100370 05 Apr 2019 remainder is 2, then [0,l,l]will be chosen, if the remainder is 3, then [1,0,1]will be chosen. Num. 1 means electrical stimulation will be applied with faces while Num. 0 means electrical stimulation won ’ t be applied.Participants need to enter name, age, sex,then duration 12s,each face appears between 10 and 20 s,50% probability for electrical stimulation.Press the space bar to start the experiment.Three different faces with calm emotion will appear at random intervals, expressed in facel face2 face3, which appear and disappear automatically. “ — ” and will also appear on the computer screen and subjects need to press the corresponding key in order to maintain concentration.
In the process of habituation, subjects have to randomly input the number to get the corresponding remainder, and then enter the name, age, sex and the corresponding parameters. At this time, the subjects do not need to connect any instruments, but are familiar with the experimental process. After pressing the space bar, the faces and arrowheads appear randomly within a certain time interval, the subjects only need to follow the experimental requirements to operate.
In acquisition, subjects repeated the input of the number and other parameters.After cleaning, attach positive and negative electrodes to the medial front of subjecs’ right arm and connect an instrument for electrical stimulation to him.Attach positive and negative electrodes to
2019100370 05 Apr 2019 left index finger, middle finger,then connect skin electrical response monitor, which needs to be calibrated in the air before using.Gradually increase the intensity of electrical stimulation until it can cause enough voltage intensity of annoying but not pain and it will be used as the intensity of electrical stimulation during the experiment.Then the experiment officially began.Two faces will have a 50% probability of electrical stimulation, and participants gradually developed a fear memory to these faces. After electrical stimulation, the skin electrical response will be significantly increased. After the acquisition of fear, the skin electrical response increased even without electrical stimulation.
In extinction, we use TMS to interfere with the extinction of fear memories formed in one of the faces, the other won ’ t be interfered and extinct naturally.The face without electrical stimulation won’ t appear.At the very beginning, we need to test and find out the rMT. of the subjects.Make sure the exact stimulation point with reference of target navigation,the power intensity of rTMS is adjusted at 80% initially.According to the magnitude of the absolute value of the distance between the troughs and crests of the single pulse of the EMG signal, it was determined that half or more of the EMG signal with a intensity of about 50 was generated in 10 stimuli, and 100% of the intensity was set as rMT of the subject.The coordinates of the corresponding brain region will be ] determined according to the position of target 1 or target 2 of
2019100370 05 Apr 2019 the standard brain,and the position as well as angle of the rTMS octahedral coil should be adjusted properly.Then enter the name, age, sex, and corresponding parameters ,and then connect the skin electrical response monitor with subjects. There is no electrical stimulation at this time.The results of skin electrical reaction is unnecessary to be analyzed when rTMS was applied.
In the extinction recall, the instrument that applied the electrical stimulation as well as the skin electrical response monitor will be attached to subjects. Then the name, age, sex and corresponding parameters of the subjects will be input. The effect of fear extinction will be analyzed and judged by the changes of skin electrical response.
DESCRIPTION OF DRAWINGS
Figure 1 illustrates an Extraction-Regression Model based on Pavlovian Conditioned Reflectance.
Figure 2 illustrates the circuit diagram.
Figure 3 illustrates total step flow chart.
Figure 4 illustrates the principle of TMS.
Figure 5 illustrates the working principle of TMS.
2019100370 05 Apr 2019
Figure 6 illustrates the specific position of the initial three landmarks(Nasion, LPA,RPA included) in Brainsight.
Figure 7 illustrates the specific position of the initial three landmarks(Nasion, LPA,RPA included) in Brainsight.
Figure 8 illustrates the specific points in the directions of Χ,Υ,Ζ axis (Back,Top, Front included).
Figure 9 illustrates the skin conductance response monitor.
Figure 10 illustrates the electromyography (EMG) sensor and electric stimulator.
Figure 11 illustrates the type of electromyography (EMG) sensor.
Figure 12 illustrates the position of target 1 and monitoring of electromyographic response.
Figure 13 illustrates the position of target 1 and monitoring of electromyographic response.
Figure 14 illustrates the monitoring of electromyographic response.
Figure 15 illustrates the total flow chart of the program.
Figure 16 illustrates the habituation state of flow chart in the program.
io
2019100370 05 Apr 2019
Figure 17 illustrates the acquisition state of flow chart in the program.
Figure 18 illustrates the extinction state of flow chart in the program.
Figure 19 illustrates the recall state of flow chart in the program.
Figure 20 illustrates the match the position of specific brain to the subject's brain and adjust the intensity of magnetic stimulation to rMT. of subjects.
Figure 21 illustrates the bar charts and line charts of skin conductance responses for target 1 in two separate time windows.
Figure 22 illustrates the bar charts and line charts of skin conductance responses for target 2 in two separate time windows.
DESCRIPTION OF PREFERRED EMBODIMENT
Step 1.Preparation
1, The experimenter introduces the experimental process to the subject.And the subjects browsed the informed consent form.
2. MNI152 brain(standard brain) and the subject’ s brain matching and measuring rMT.
2019100370 05 Apr 2019
1) The calibration of TMS navigation.
2) Target coordinate setting and landmarks positioning. ©Positioning Target 1 [-56,2,40] and Target 2 [-46,23,43] in Brainsight. ©The standard brain was matched with the subjects’ brains by adjusting the specific position of the initial three landmarks(Nasion, LPA,RPA included) in Brainsight in order to establish the model of the subject and proofread it.Make the error of the front side of the brain and the back side of the brain less than 3mm.Except the three initial coordinates,adding the specific point in the directions of Χ,Υ,Ζ axis to improve the accuracy(Back,Top, Front included) in order to improve the matching rate between the standard brain and subject’ s brain.
3) The subjects were connected to the Electromyography (EMG) sensor. In conductive scrub and 75% alcohol processing subjects right thenar eminence and little finger abductor muscle.The cuticle was removed to monitor the EMG response.The electromyogram (EMG) sensor was connected with positive and negative electrodes on the thenar eminence to detect the electromyogram response generated by rTMS to the corresponding areas of the cerebral motor cortex.The little finger abductor muscle was attached to the ground electrode, and the subjects were asked to grasp and observe whether the EMG signal on the BrianSight was normal.
2019100370 05 Apr 2019
4)Measure resting motor threshold(rMT)
Make sure the exact stimulation point with reference of target navigation,the power intensity of rTMS is adjusted at 80% initiaIly.According to the magnitude of the absolute value of the distance between the troughs and crests of the single pulse of the EMG signal, it was determined that half or more of the EMG signal with a intensity of about 50 was generated in 10 stimuli, and 100% of the intensity was set as rMT of the subject
Step 2. experiment
Firstly,the experimenter needs to start the program, input the subject's personal information and relevant parameters.When the program runs, there will be three different faces with calm emotion, “<-”and“->” on the computer screen.Faces will automatically appear and disappear but the subjects need to press the corresponding key in order to maintain concentration.During acquisition phase,two faces will be given electrical stimulation to the subjects at a 50% probability.After electrical stimulation, the skin conductance response (SCR) of subjects' will increase and recorded by a machine.During extinction phase,one of the two faces stimulated by electric will be stimulated by rTMS.
2019100370 05 Apr 2019
1. Habituation
The subjects were used to the experimental process,which did not require electrical stimulation or rTMS stimulation.
2. Acquisition
1) After cleaning, attach positive and negative electrodes to the medial front of subjecs' right arm and connect an instrument for electrical stimulation to him.Attach positive and negative electrodes to left index finger, middle finger,then connect skin electrical response monitor, which needs to be calibrated in the air before using.
2) After input of relevant information and parameters, the experiment begins.In the course of this experiment, two faces will be given electrical stimulation with a 50% probability (CS+), causing fear in subjects while another won't(CS-).
3. Extinction
l)Within lOmin after the previous experiment, the experimenter will ensure stimulus coordinates (targetl or target2; where target 1 is a region related to vmPFC and target2 is a region not related to vmPFC)according to the standard brain.Determine the position and angle of rTMS stimulation and adjust the intensity of magnetic stimulation to
2019100370 05 Apr 2019 rMT. of subjects.
2)After entering the relevant information and parameters, the experiment begins.Apply rTMS stimulation with one of the previous faces given electrical stimulation to make the memory of fear subsided naturally.
4.Recall
The subjects repeated the experimental steps of acquisition. In this stage, we connect the dermatoelectric monitor and electrical stimulation apparatus to subjects, but do not apply electrical stimulation. After input of relevant information and parameters, the experiment begins.
Step.3 Analysis
Bar charts and line charts showing skin conductance responses for target in two separate time windows. The Recall line chart demonstrates the difference between extinction effects with and without TMS stimulation in contrast to the proximity of Acquisition lines (in conditioned response [CR] time courses [0-12seconds], which are showed in 3-second bins). The bar charts show similar results with line charts (in unconditioned response [UCR] time courses [12-18seconds]).
Bar charts and line charts showing skin conductance responses for target
2019100370 05 Apr 2019 in two separate time windows. No distinct difference exists between the group using TMS stimulation during extinction and the group healed naturally. The results demonstrated in bar charts in unconditioned response (UCR) time courses (12-18seconds) closely resemble the results in line charts in conditioned response (CR) time courses (0-12seconds).
CASE 1.
Bar charts and line charts showing skin conductance responses for target 1 in two separate time windows. The Recall line chart demonstrates the difference between extinction effects with and without TMS stimulation in contrast to the proximity of Acquisition lines (in conditioned response [CR] time courses [0-12seconds], which are showed in 3-second bins). The bar charts show similar results with line charts (in unconditioned response [UCR] time courses [12-18seconds]).
In this experiment, an acquisition task was completed first. In this task, the right wrist of the participant was connected to the electrode. The task required the participant to watch three different neutral faces. Each face was presented randomly for 8 times, with two of them had a 50% probability of triggering electrical stimulation. After completing the acquisition task, the participant will have a 10-minute break, during
2019100370 05 Apr 2019 which we could use the TMS navigation system to locate the target area. In this case, we selected targetl, which is in the left posterior PFC showing strong connectivity with the vmPFC, to be stimulated later with TMS. The next phase began after finishing the break. In the second phase, we tried to subside the participant' s fear. One of the two neutral faces that the participant had acquired fear before matched the TMS stimulation, the other mismatched stimulus (natural extinction). All of the three faces were presented randomly as in the first phase. At the same time the next day, the participant came to the laboratory again to complete the recall task in the third phase. The task presented three faces randomly, and no stimulation was matched this time so that we can observe the effect of fear distinction under different conditions. It is worth mentioning that, although there is no electrical stimulation in the second and third phases, the right wrist of the participant is always connected with the electrical stimulation trigger instrument to ensure the validity of the experimental results during the whole process of the experiment.
The experiment' s results showed in Fig. 23. In the acquisition phase, we calculate averages of participant's skin conductance data every 3 seconds in all trials we need. As a result, we found that no evident difference exists in these
2019100370 05 Apr 2019 trials, the results are similar in conditioned response window (when the neutral face appears) and unconditioned response window(when the neutral face disappears, and then electronic stimulation occurs).In the recall phase, the data display the results after distinction. An obvious separation occurs between TMS trials and no TMS trials. When the participant watched the faces with TMS distinction, the fear arousal decreased apparently. However, when the participant watched the faces with natural distinction, there seems no apparent data tendency. The results prove that adding TMS stimulation in Targetl area in extinction phase can make the participant reach a better level of fear extinction.
CASE 2.
Bar charts and line charts showing skin conductance responses for target 2 in two separate time windows. No distinct difference exists between the group using TMS stimulation during extinction and the group healed naturally. The results demonstrated in bar charts in unconditioned response (UCR) time courses (12-18seconds) closely resemble the results in line charts in conditioned response (CR) time courses (0-12seconds).
In this experiment, we implement the same process as described in case
1. The only difference between 2 cases is about the target areas. In this
2019100370 05 Apr 2019 case, we chose target2, a nearby PFC area with poor functional connectivity with the vmPFC. The experiment' s results showed in Fig. 24. Both in the acquisition phase and recall phase, we calculate the averages of data every 3 seconds. As a result, we dicin' t find any evident difference between TMS extinction trials and natural extinction trials, which confirmed our hypothesis that extinction with TMS can be effective while the TMS stimulates the functional connected area of vmPFC. It is the stimulation areas that count, thus TMS can be used effectively to cause the responses in correct areas in processes of fear extinction.
2019100370 05 Apr 2019

Claims (3)

1. A method of reducing fear memory by using magnetic resonance imaging-navigated transcranial magnetic stimulation, is characterized in that rTMS are combined together with navigation positioning system to fix position of brain area,and then rTMS are applied during extinction state after the subject acquire fear memory.
2. The method according to claim 1, wherein experiments are designed to compare the effect of natural extiction and applying rTMS during extiction ,and got the result that we definitely found using rTMS to the specific brain area related to vmPFC could help to reduce fear memory, there is still no therapy like this method to treat mental disorders like PTSD,phobia etc.
3. The method according to claim 1, wherein three faces with calm emotion are used as material to acquire and extinct fear memory, two faces serve as conditioned stimulation(CS+) and appear with electrical stimulation while another face serves as unconditioned stimulation(CS-) combining with nothing; rTMS is applied to one of the CS+ in order to compare the effect of natural extiction and applying rTMS during extiction.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111202908A (en) * 2020-01-16 2020-05-29 电子科技大学 Palm electrical stimulation control system based on elbow motion driving

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111202908A (en) * 2020-01-16 2020-05-29 电子科技大学 Palm electrical stimulation control system based on elbow motion driving
CN111202908B (en) * 2020-01-16 2023-03-14 电子科技大学 Palm electrical stimulation control system based on elbow motion driving

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