Guidelines for ethics-related problems with “non-invasive research on human brain function”

4. Ethical characteristics and testing guidelines for each non-invasive research method

D.Functional Magnetic Resonance Imaging (fMRI)

1) Overview
Functional Magnetic Resonance Imaging (fMRI) is a research method that uses a magnetic resonance imaging device to estimate the localized brain activation by measuring the changes in blood flow through the blood vessels (blood flow volume) as well as in oxygen metabolism, which is triggered by neural activity. Two methods are primarily used: one that measures the concentration of deoxygenated hemoglobin in the blood (blood-oxygenation-level dependent (BOLD) method), and the other that directly measures the blood flow volume.

2) Effectiveness
With fMRI, it is possible to measure the spatial distribution of neural activity with high spatial resolution. Compared to PET, it has the advantage of allowing measurements to be taken repeatedly on the same individual subject, and of having a high spatial as well as temporal resolution; however it also has the disadvantage of being prone to generate artifacts when the test subject moves, and to show signal reduction and distorted images in the areas surrounding the aural and nasal cavity. The test subject must remain still inside the magnet when the measurement is being taken. Compared to MEG or EEG, fMRI has a high spatial resolution but a lower temporal resolution.

3) Problematic points (risks involved during testing)
Problematic points associated with fMRI measurement are essentially common to those associated with MRI measurement. Here, these points are divided into three categories: 1. Impact of MRI measurement itself on the test subject’s health; 2. Risks of accidents specific to MRI-environment; 3. Others. 1 and 2 are based on Japanese Industrial Standards (JIS) specifications (JIS Z4951) 2004, which provides a translation, with supplements, of the International Electrotechnical Commission (IEC) Specifications (IEC 6060-2-33) 2002.

  1. Impact of MRI measurement itself on the test subject’s health IEC/JIS specifications focus on three aspects. The “operation mode,” which is important to ensure safety, is defined by the following limit values [details are given in Section 1 under 4) Testing guidelines].
    i) Intensity of the magnetic field
    Moving one’s head in the magnetic field can cause dizziness, nausea, or taste abnormality. The stronger the magnetic field, the more people experience symptoms. In addition to this, various studies have examined the adverse biological effects of strong magnetic fields, but IEC/JIS specifications have concluded that these effects lack foundation for fields of up to 7T.
    ii) Time variation of the intensity of the gradient magnetic field (dB/dt)
    When the time variation of the intensity of the gradient magnetic field becomes greater, peripheral nerves are stimulated by the electric current triggered by the change in the magnetic field, causing an uncomfortable twitching sensation. When the time variation becomes even greater, there is a possibility that the cardiac muscle might get stimulated directly.
    iii) Radio Frequency (RF) Energy (specific absorption rate (SAR))
    Since a high-frequency RF magnetic pulse, which excites and flips the spin, conducts heat to the tissues, it has the potential to cause adverse changes in body temperature or burn injuries.
  2. Risks of accidents specific to MRI-environment
    There are risks of accidents that are specific to MRI-environment, which might result from the negligence of those performing or undergoing the test, or by natural disasters.

    i) Propulsion of magnetic substances caused by a strong magnetic field
    Magnetic research or medical equipments can be drawn to a strong magnetic field, and collide with those conducting or undergoing the test, causing physical injury. There have been reports of fatalities. It is also possible that in case of emergencies, members of the emergency medical service or the fire department might enter the scanner room with their magnetic equipment, triggering a secondary accident.
    ii) Effects of the magnetic field on medical devices implanted in the body of the test subject
    When the test subject has any magnetic parts or medical devices with an electronic circuit implanted inside or on the surface of the body, the magnetic field has the risk of causing physical tissue damages or improper operation of the electronic circuit. The most common magnetic parts implanted inside the body include artificial cardiac valves, artificial joints, or stents for blood vessels; the most common electronic implants are cardiac pacemakers. Even when there is a distance between the subject and the MRI scanner, there are possible adverse effects due to leakage of the magnetic field.
    iii) RF energy generated by hard-wiring, body loop, and magnetic substances inside the body or on the surface of the body
    There is a possibility that the test subject might incur burn injuries inside the body or on the surface of the body because of an unexpected generation of energy: when the hard-wiring of research or measuring equipment forms a loop on the surface of the body; when the test subject’s body itself forms a loop because of the contact of body parts; when the RF coil itself is adjacent to the body; when there are magnetic substances (such as bullets or pieces of iron) inside the body; when there are magnetic substances (such tattoos, cosmetics, accessories, medical patches, contact lenses that contain metal) on the surface of the body.
    iv) Sounds generated during imaging
    There is a risk that persons performing or undergoing the test might develop auditory disorders due to the extremely loud sounds generated during the MRI procedure.
    v) Quenching
    In general, liquid helium is used to cool down the superconductive electromagnet that maintains the strong magnetic field of the MRI machine. There are rare cases where something causes this liquid helium to evaporate and to rapidly and drastically expand its volume (in an explosion). This is called “quenching” the magnet. Usually, this triggers initiation of a double safety device, but when this fails, there is a possibility that the test subject might experience frostbite or asphyxiation due to helium leakage.
    vi) Claustrophobia
    The space inside the MRI scanner (the bore), where the test subject is placed, is extremely narrow, and it is not uncommon to dim the lights when conducting the test. These conditions might trigger panic when the test subject has claustrophobia or nyctophobia.
    vii) Lack of awareness of abnormal conditions inside the scanner
    After starting the scanning procedure, there might be various abnormal conditions, including those stated above, which are noticed only by the test subject. However, because it is normally not easy to observe the subject from the operating room, and because the subject’s voice disappears among the sounds generated by the machine, the persons performing the test might not notice the subject’s attempt to communicate through body language or voice.
  3. Other risks
    i) Incidental findings
    In rare events, MRI results obtained for experimentation purposes show structural abnormalities which may indicate the presence of tumors. In principle, diagnosis is not part of the basic research purpose of fMRI experimentation. However, to forgo the chance of treating the test subject when withholding treatment may be fatal is problematic from a humanitarian point of view. There is the potential for lawsuits to be raised against research institutions that withhold this information. On the other hand, if the test subject is informed of these incidental findings, and if further detailed tests elucidate no signs of abnormality, there is a risk of being sued by the test subject for causing unnecessary psychological damage.
    ii) Rumors
    Incidental occurrences of ischemic heart disease or epileptic seizure during fMRI testing are possible, even when there is no actual causal relation between the scan and the medical condition. Furthermore, when the magnetic field is strong, it is not uncommon for test subjects to experience dizziness, nausea, or taste disturbances due to movement of the head. Because of these incidences, when explanations given to test subjects are insufficient, or when there is little trust between the subject and the persons performing the experimentation, rumors about health hazard of MRI might develop to produce an unwanted prejudice in society against the entire field of fMRI experimentation.

4) Testing guidelines
Explanations of these guidelines are given in five categories: 1. MRI equipment and operation protocol; 2. Safety management at the testing site; 3. Manuals and training to handle an emergency situation; 4. Prior screening of test subjects and persons conducting the test; 5. Other. Contents stated in Section 1 through 4 are based on IEC/JIS specifications. It is advisable that persons performing the test look through the latest IEC/JIS specifications.

  1. MRI equipment and operation protocol
    IEC/JIS specifications define three modes of operation based on the level of risks incurred by the test subject during MRI procedures. Each mode has different restrictions across three parameters of the MRI scan: the intensity of the magnetic field, time variation of the intensity of the gradient magnetic field, and RF Energy (SAR). Each mode also has different safety measures which should be in place (such as the need to have a doctor monitoring, contents that require approval of the institutional review board).

    i) Normal operation mode
    This is the safest mode of operation. The intensity of the magnetic field is restricted to 2T or lower. Based on currently known physiological mechanisms and numerous research findings, the three MRI parameters, mentioned above, are set and limited to values which are considered to be incapable of causing physiological stress on the test subject. MRI devices configured for this operation mode do not allow imaging parameters to be set at values higher than these limits. However, even when the intensity of the magnetic field is 2T or lower, there are people who experience dizziness or nausea because of the movement the head.
    ii) First level controlled operation mode
    This mode recommends that the operation be monitored by a doctor. The limit of magnetic field is set at 4T or lower. The limits set for time variation of the intensity of the gradient magnetic field and SAR are even higher. Although biological impact is considered to be extremely low in a magnetic field of 4T or lower, when these higher intensities of the magnetic field are used, more people experience dizziness, nausea, or taste disturbances because of movement of the head. Even within restricted ranges, when the time variation of the intensity of the gradient magnetic field is greater there is a possibility of stimulating the peripheral nerves. If the test subject has a weaker capability of adjusting body temperature (such as is seen in patients suffering from febrile disorders, cardiac disorders or sweating disorders), a medical doctor must monitor the effects of the RF energy. MRI devices configured for this operation mode do not allow imaging parameters to be set at values higher than the established limits. They also have the capability of indicating the time variation of the intensity of the gradient magnetic field and the value of SAR on the operating monitor.
    iii) Second level controlled operation mode
    This mode of operation requires reviews that follow national regulations (national approval), and applies in cases where the value of any one of the three aspects mentioned above exceeds the value set under the first level controlled operation mode. There is a possibility that the magnetic field might have biological impact, that the time variation of the intensity of the gradient magnetic field might stimulate the cardiac muscles, or that RF energy might trigger adverse changes in body temperature or burn injuries.
    It is necessary for the persons conducting the test to clarify which of the three modes of operation listed above will be used for their experimentation. First level controlled operation mode applies to general research. It is advisable that the operation mode be listed in research application forms, which are reviewed by institutional review boards. IEC/JIS specifications require MRI machine manufacturers to implement safety settings in MRI devices in order to ensure that values for time variation of the intensity of the gradient magnetic field and SAR do not mistakenly come to be within the range of values for a higher level mode of operation.

    ※The upper-limit values indicated above in the sections explaining normal and first level controlled operation mode are based on IEC specifications 2002 (JIS specifications 2004), and might be altered in future revised versions. Persons conducting the test need to refer to the latest IEC/JIS specifications.

  2. Safety management and considerations at the testing site
    MRI testing sites require the following:

    i) Restricted areas
    Areas with a magnetic field of 0.5mT or higher need to be clearly indicated as restricted areas and differentiated from surrounding areas (e.g. with floor and wall markings). It is necessary to have signs in place to prevent anyone carrying improper magnetic substances, or anyone with implanted magnetic medical devices or cardiac pacemakers, from entering these areas. Although there is no clear evidence for the impact of magnetic fields on fetuses, it is recommended that pregnant women should not enter a restricted areas unless necessary.
    Even while fully understanding that magnetic substances, which have the danger of being propelled by the magnetic field, or electronic devices, which have the potential of getting damaged (watches, cell phones, and magnetic cards), are not allowed in restricted areas, persons conducting or undergoing the test might accidentally enter the restricted areas wearing their watches or accessories, or keeping their keys, coins, cell phones, and wallets in their pockets, when habitually conducting scans. Persons conducting the test must systematically check themselves and their pockets on each occasion before entering the magnet room and restricted areas; they also need to visually examine the test subjects and inspect them with the use of checklists or metal detectors each time these areas are to be entered.
    ii) Avoiding accidents occurring to test subjects during testing
    In order to avoid burn injuries from RF energy, persons conducting the test need to visually examine the test subjects, or inspect them with the use of checklists or metal detectors immediately before each test to ensure that there are no magnetic substances (cosmetics, hair dye, contact lenses, accessories, or clothing that contains metal) on the surface of their body. Also, when the test subject has been placed inside the scanner for testing, the hard-wiring or the subject’s body should not in any arrangement form a loop. The RF coil itself should not be adjacent to the body.
    In order to avoid damage to the auditory system due to the sounds generated by the MRI device, test subjects should wear earplugs or headphones during testing. As a further precaution, persons conducting the test must confirm whether the sounds have been sufficiently lowered beforehand. Also, other measures can be implemented, such as preparation of a checklist, so that those conducting the experiment always remember to instruct the subject to wear earplugs or headphones.
    A means of communication between operators and subjects should be established so that the test subject can ask for the procedures to be stopped at any time during testing. It is common to establish a system that sets off a loud alarm sound in the operating room when the test subject squeezes a valve in his or her hand.
    Finally, the test subject should be monitored at all times during testing through a window or with a video monitor. During the time intervals between sections of the protocol, frequent communication with the subject should be made verbally, and when necessary, the imaging room can be entered to check the subject’s condition.
  3. Manuals and training for handling an emergency situation
    The person responsible for the MRI facility must meet with MRI manufacturers or related parties (hospitals or the fire department etc.) to discuss the following emergency measures and prepare a manual as necessary. The person must also ensure that persons conducting the test are thoroughly familiar with the manual, and have completed a training session if necessary. Persons conducting the test must check with the safety manager of the facility about the following emergency measures and be prepared to carry them out if circumstances arise.

    i) Emergency medical measures
    Arrangements should be made so that swift measures can be taken when an injury or a medical problem occurs during testing. In case of emergency, the scanning procedure should be aborted immediately and the injured party evacuated from the scan room. The individual can then be delivered to the appropriate department within the hospital or, if appropriate, an ambulance called. If possible, it is advisable to establish a system whereby those present may be able to administer first-aid or life-saving measure in cases such as a cardio-pulmonary arrest. It is also advisable to seek the consent of a specific hospital in advance to be the destination of ambulance patients.
    ii) Emergency shut-down of magnetic field
    When the test subject or the person conducting the test gets caught between the scanner and a foreign magnetic object or when it is anticipated that members of the emergency medical crew or the fire department will enter the scanner room because of natural disasters, it is necessary to perform an emergency procedure that shuts down the magnetic field of the MRI machine. Persons conducting the test need to familiarize themselves with this procedure.
    iii) Measures against fire or earthquake
    Arrangements should be made so that necessary measures can also be swiftly taken in case of fire or earthquake.
    iv) Measures for quenching
    Arrangements should be made so that appropriate measures can be taken in the case of quenching the magnet or faulty operation of safety devices. Quenching is evidenced by white smoke (visually detectable) or a decrease of oxygen concentration (measured using an oximeter).
  4. Prior screening of test subjects and persons conducting the test
    The person responsible for the safety of the MRI facility and experimentation needs to establish a system where prior screening of candidates who may be conducting or undergoing the test is performed to assess the risks involved for that individual in entering restricted areas or participating in MRI testing, as stated below.

    i) The following persons are prohibited from conducting or undergoing MRI testing (i.e. they are prohibited from entering restricted areas).
    ・Persons who have implants, inside the body or on the surface of the body, containing magnetic substances or medical devices containing an electric circuit (artificial cardiac valves, artificial joints, stents for blood vessels, cardiac pacemakers, etc.).
    ii) The following persons cannot be test subjects unless there is a specific legitimate reason.
    ・Persons who have magnetic substances that are within the body (bullets or pieces of iron, etc.) or on the body surface (tattoos etc.) and that cannot be removed.
    ・Pregnant women
    iii) It is advisable that following persons are kept from becoming test subjects, unless there is a specific legitimate reason. When the person does become a test subject, the experimentation needs to be carried out under a doctor’s supervision.
    ・Persons who may experience an episode due to a medical disorder (e.g. ischemic heart disease or epilepsy) that might be triggered during testing.
    ・Persons with claustrophobia or nyctophobia.
    ・Persons with conditions which make it difficult to secure a means of communication during MRI testing.
    ・Persons with a weakened capability to adjust body temperature (patients suffering from febrile disorders, cardiac disorders or sweating disorders etc.).
    iv) It is recommended that the following persons avoid entering restricted areas.
    ・Pregnant women
  5. Others
    i) In case of incidental findings
    When explaining the experimentation to the test subject, it should be made clear that the experimentation is solely for research purposes and that brain imagining is not precise enough for medical diagnosis. Also, when the test subject agrees to participate in the experimentation, it is advisable to have the subject write down whether or not he/she wishes to be notified in case of incidental findings. The responsibility of ultimately deciding whether or not to notify the subject should fall on the person responsible for the experimentation, regardless of the subject’s wishes. The person responsible for the experimentation needs to make prior decisions about procedures for handling incidental findings and about methods of notification, and to ensure that members of the research team are thoroughly familiar with these procedures and methods. When it is decided that the findings require detailed testing, the basic measure is to recommend the test subject to consult a healthcare provider. In actuality, decisions waver over whether or not the findings are abnormal (and whether or not to notify the test subject) in many instances. It is advisable to seek the informative opinion of an expert who specializes in diagnosis on the basis of brain imaging data.

5) Explanatory documents for test subjects
As a general rule, follow the contents indicated in Section 6 of current guidelines.

<Acknowledgement>
These guidelines were created with the help of Toshiharu Nakai.

References
Medical electrical equipment -Part 2-33: Particular requirements for the safety of magnetic resonance equipment for medical diagnosis, IEC 60601-2-33, Edition 2.2, April 2008, International Electrotechnical Commission
Japanese Industrial Standards:Magnetic resonance tomography imaging diagnostic device-safety,JIS Z 4951:2004,July 2004, Japanese Industrial Standards Committee