(revised on February 3, 2009 and December 4, 2009; words and phrases revised in January and March, 2010; revised in November, 2019)
The Japan Neuroscience Society
Ethics and COI Committee
(Chairperson: Norihiro Sadato)
In the past, localized functions of the human brain have been conjectured by closely observing the clinical signs in patients who incurred insults to parts of the brain as a result of trauma or cerebrovascular disorders. These clinical signs include neurological deficits (negative signs) such as motor paralysis, sensory disturbance, aphasia, and memory deficit, as well as positive signs (e.g. convulsions), which can be observed as partial signs of epileptic seizures. Localization of brain function has also been conjectured by examining the phenomena triggered by electrostimulation applied to the surface of the cerebral cortex during surgical treatments for patients with intractable epilepsy. However, while comparing these clinical signs and lesion areas has made it possible to speculate upon how a certain area of the brain plays an important part in a given function, it has been difficult to determine the actual functional connections or network mechanisms that exist among the different structures inside the brain. In particular, it has been extremely difficult to carry out research on the mechanisms of recovery from neurological deficits by relying solely on clinical observations, despite the fact that clinically this is the most critical issue.
Thanks to the development of various new technologies in the past 30 years, it has become possible to conduct research with methods that make human brain function visible to the eye. These methods include: electrophysiological methods, whereby brain potentials are detected from the scalp by electroencephalograpy (EEG) or magnetoencephalography (MEG), allowing for analysis of the cortical electrical activities that are triggered by various brain functions; transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), whose use has been expanding recently; positron emission tomography (PET) and single-photon emission computed tomography (SPECT), which use radioactive isotopes; functional magnetic resonance imaging (fMRI), which has lately become especially popular; and optical imaging, which uses near infrared spectroscopy. These research methods are more or less minimally invasive to research participants1, and are therefore termed non-invasive methodologies. Each of these testing methods has unique characteristics. In particular, electrophysiological methods, including magnetic stimulation methods, provide relatively detailed temporal information of brain function; other imaging methods provide relatively precise spatial information.
It has been 10 years since the previous revision of the guidelines. Since then, “Ethical Guidelines for Medical and Health Research Involving Human Participants” (2014, the Ministry of Education, Culture, Sports, Science and Technology [MEXT] and the Ministry of Health, Labour and Welfare [MHLW], partially revised on February 28, 2017) have been developed, which combine “Ethical Guidelines Concerning Epidemiological Research” (Notification No. 1 from MEXT and MHLW in 2007) and “Ethical Guidelines Concerning Clinical Research” (Notification No. 415 from MHLW in 2008). The new guidelines specify the rules that should be followed by all parties involved in medical research conducted in humans. Moreover, the Clinical Trial Act, promulgated in 2017, stipulates the procedures and information disclosure systems of clinical trials, defining such trials as research to clarify the efficacy or safety of pharmaceuticals by using these pharmaceuticals in humans. Because the law stipulates only the basic principles regarding various forms of medical research, the establishment of specific and appropriate guides based on these principles is desired for each field. As neuroscience advances, non-invasive research on human brain function overlaps more often with medical research, as seen in the research on neurofeedback and the brain-machine interface. Since the development of guidelines and regulations reflect Japan’s drive to move forward with brain science research, it has become necessary to clarify management systems for non-invasive research on human brain function at each facility for gaining social understanding. Furthermore, the Act on the Protection of Personal Information was significantly revised in 2015, and the revision took effect in 2017. Under these circumstances, we have decided to revise the current guidelines.
The purpose of non-invasive research methodologies, which are covered under the current guidelines, is to shed light on the mechanism of the brain in healthy individuals. For take memory, which is one of the most important high-level brain functions, our purpose would be to clarify the ways in which information obtained from the external world gets stored and retrieved as necessary. To be able to gain new knowledge about the function of the brain, which has been considered complex and obscure in the past, is, of course, extremely important in itself from a scientific point of view; yet this is also crucial because we thoroughly believe that it will lead us to be able to recognize signs and symptoms triggered by various brain disorders, unravel their pathogenic mechanism, and develop more effective treatment methods. In other words, to use the example of memory, if a patient who has suffered a lesion to a certain area of the brain incurs memory impairment, it would be possible to determine the stage in the memory process where the damage has occurred based on the knowledge obtained by studying the neurological networks associated with memory in healthy participants. Another example is use of the resting state functional connectivity that is calculated based on MRI images, as well as the neurological network data obtained by diffusion tractography, it might be possible to determine which regions contain the information transduction pathways that are affected by the disease; this would in turn make it possible to plan treatments and measure their effects. Moreover, if details of the neurotransmitters and their receptors, which are necessary for information transmission in the given neural pathways, could be elucidated by using neurotransmission imaging methods with PET, there is a high possibility of developing therapeutic agents. In addition, TMS and tDCS, which have recently become popular, may be applied to the relevant neural network to yield information that is useful for establishing policies regarding functional recovery and rehabilitation. If the physiological adjustment mechanisms relevant to the recovery of impaired brain function can be elucidated, there is a high possibility that this will lead to the development of effective drugs or rehabilitation training. In particular, these avenues of research carry huge social significance in the 21st century, where an increase in the number of patients with dementia or mobility impairment is undoubtedly expected as a result of an aging society.
However the gain of new knowledge of brain function, as mentioned above, increases the danger of proliferation of inaccurate or over-interpreted information to the general public, creating superstitions that are not scientifically proven, or generating suspicions about the reliability of neuroscience. The basis of development and progress in neuroscience requires the firm trust from society, starting with research participants and various related parties, and more general recognition of the social effectiveness and significance of research. Moreover, since non-invasive research involves examination of also covers areas of the “mind”, that is directly linked to human dignity, it entails special care so as not to trigger social concerns that lack scientific bases, such as “Are they going to manipulate my mind?” or “Are they going to read my mind?” Precautions must be taken in order to ensure that results of non-invasive research on brain functions are not used to discriminate or ostracize certain people, and thereby cause an invasion of human rights.
With recent advancements in artificial intelligence and autonomous systems, including robots and neurotechnologies, ethical aspects of brain science are being increasingly debated worldwide.1,2) There is growing concern regarding the potential erosion of self-identity (physical and mental integrity), diminishment of agency (ability to choose one’s own behavior), and invasion of individual privacy, which are basic human rights. For this reason, the provision of informed consent prior to participation in experiments is emphasized more now than in the past, as a means of protecting the basic human rights of research participants. Sufficient attention should also be paid to possible changes in societal norms and new forms of discrimination related to novel neurotechnologies for the extension of specific abilities.
As stated in the previous section, brain/neuroscience research currently receives substantial financial support from the government. In such circumstances, it is sought that research results be used in return for the benefit of society. To achieve this, efforts at publicizing research results through the media, such as the press and documents, or through outreach activities, such as public lectures and science cafes, are being encouraged. Yet, in order to ensure that research results are communicated accurately without generation of any pseudo-brain/neuro-science or so-called “neuro-myths” as mentioned above, it is necessary to present research results after considering how they would be perceived by society and verifying how these achievements would ultimately be disseminated by the media. For this, it is advisable to be familiar with the characteristics of the media and society, and as well as to actively facilitate mutual communication with these two parties.
Since non-invasive testing methods, except for those involving radionuclide methods, have the advantage that they can be repeated multiple times, they have been widely used to examine brain function in healthy participants. However, application of these methods also has the danger of being misused because of their convenience; each of these methods also has different ethical issues.
As stated in the previous section, neuroscience research also covers areas of the human mind. It therefore requires knowledge and application of ethical standards pertaining to research on human participants; special attention must also be paid to its influence on society. Therefore, in neuroscience research, consideration for the welfare of research participants and related parties must take precedence over scientific and social benefits. Researchers must respect the sanctity of research participants and related parties and abide by the general principles protecting their human rights. Researchers are also required to draw up a research plan which takes ample consideration of ethical, legal and social issues, and to carry out their research accordingly. Under these circumstances, it has become important and necessary for our Society to set out guidelines, particularly those regarding such ethical issues, and to establish practical policies relating to such research.
It should be noted that these guidelines are only sample guidelines set out by our Society and that they do not limit individual research conducted at various research institutes and facilities. Each research project should be carried out by following the regulations established at each research institute and facility based on the national law and policy applicable to each research area listed below, and by obtaining approval of their institutional review board.[Clinical trial] 2
A. Magnetoencephalography (MEG)1) Overview
Magnetoencephalography (MEG) is an imaging technique that uses a measuring device to record changes in the magnetic field produced by the brain. Electroencephalography (EEG), which is used widely, and MEG both directly rely on the electrical activity generated by the brain. When areas of pyramidal cells in the cerebral cortex which have dendritic protrusions at the pointed extremity are stimulated, they produce a depolarization, which generates electric currents inside and outside the cells. While EEG records electric currents that flow outside the cells, MEG records the magnetic field that becomes generated by the electric currents inside the cells. Thus the underlying source of the signal for both EEG and MEG recordings is identical, and since neither technique entails application of stress or direct stimulation to the brain, these methods are considered highly safe.
Compared to EEG, MEG’s greatest strength is its high spatial resolution. The space between the brain and scalp is made up of three layers – cerebrospinal fluid, skull and skin – and each has a significantly different electric conductivity. Because of this, these layers have a great impact on the electric field generated by the brain, making it difficult to accurately measure the active area in the cortex from the electrodes placed on the scalp, unless a special estimation method (such as the dipole tracing method) is used. However, magnetic fields are not affected by electric conductivity, and thus when recording conditions are favorable, MEG can be used to image active areas with 1mm precision. Compared to PET and fMRI, MEG has the advantage of being completely non-invasive; it records the cells’ electric activities themselves rather than the changes that occur in localized cerebral blood flow; and, like EEG, it has a high temporal resolution of 1 msec. However, the biggest problem with MEG is that, as with EEG, when estimating localized brain function, its location must be estimated based on the recorded distribution of the magnetic field (i.e. the inverse problem must be solved). In other words, compared to fMRI or PET, it inevitably yields an indirect estimate of the location. MEG also has four more disadvantages: (1) it cannot record activities of the cerebral white matter (because their source is located in the pyramidal cells of the cortex); (2) it is difficult to record activities that are generated in the deep part of the cerebrum (because the spatial attenuation is large due to the distance of the magnetic field signal); (3) it is difficult to record activities in the cerebral gyrus parallel to the surface of the head (due to technical problems associated with measuring magnetic fields); (4) it is difficult to accurately estimate the location of activities when they are occurring simultaneously in multiple areas (because the algorithm of the analysis software becomes extremely complicated when estimating activities in multiple areas).
3) Problematic points (Risks involved in testing)
Essentially, it can be claimed that MEG does not involve any risks. So far, there have been no articles or reports concerning safety considerations when using MEG. If accidents were to occur, potential causes might include design errors in the MEG measurement equipment or installation device, or their deterioration; equipment might also get damaged or fall down due to natural disasters such as earthquakes. Yet manufacturing companies take extreme precautions against these possibilities; they also carry out frequent and regular inspections. Thus far, such accidents, including small-scale accidents, have not been reported. Rather, the problem with MEG concerns the pain that research participants experience at the time of actual testing. Firstly, in order to achieve high spatial resolution, research participants must try, as much as possible, not to move their head during the test. This condition can cause pain when the test lasts for long periods of time. Secondly, since the test is conducted in a sealed room, there is a sense of being isolated and trapped, which can become distressing to research participants who have tendencies to experience “claustrophobia.” Thirdly, when recording functional responses to stimuli, which may be tactile, visual, or auditory, (induced magnetic encephalography), experiment protocols can cause discomfort for some research participants. However, these problematic points are not only associated with MEG but are also common to tests that use EEG, fMRI and PET.
A higher risk, beyond the three points mentioned above, is posed by participation of epilepsy patients in these brain imaging procedures. During MEG testing the measuring device completely covers the entire head of the test participant, and in the event of the patient having a convulsive seizure there is the possibility that that the head and neck areas of the patient might get severely damaged (though there have been no reports of such incidents so far). In order to take precautions against this possibility, it is crucial to be familiar with the patient’s medical history and current condition before conducting the test, especially when applying visual stimuli to an epilepsy patient.
4) Testing guidelines
5) Explanatory documents for research participants
As a general rule, follow the content stated in Section 6 of the current guidelines. Below, we provide some examples of information which can be provided specific to the characteristics of MEG testing, which can be used in explanatory documents.
These guidelines were created with the help of: Kohnan Hospital; Faculty of Medicine, The University of Tokyo; Faculty of Medicine, Kyoto University; Faculty of Medicine, Osaka University; Helsinki University of Technology; Faculty of Medicine, University of Heidelberg; The Hospital for Sick Children, Toronto.
Supplementary remarks concerning electroencephalography (EEG)
Electroencephalography (EEG) is obtained by recording the electrical potential of the brain from the scalp using metal electrodes. Since there is no need to apply any stimulation or stress directly to the brain, the procedure is extremely safe and is widely used, including in the field of psychology. In recent years, EEG has been increasingly used for various commercial purposes in daily life, which has heightened the need for accurate communication of results. Neuromarketing is expected to enable the collection of information regarding consumers’ reactions to products in a way not possible with questionnaire-based surveys in the past. Even when EEG is used solely for investigative purposes, attention should be paid to the fact that the general public may interpret it as being related to such commercial applications. For details on its technical aspects, follow “Revised clinical electroencephalography tests standards 2002,”1) which are the most recent guidelines outlined by its specialist organization, the Japanese Society of Clinical Neurophysiology.
2) Problematic points (risks involved during the test)
While measuring EEG has been used widely, including neuropsychological studies (see later), there have been no reports of severe accidents specific to EEG. Since skin allergies can be triggered in reaction to procedures on the scalp or electrode paste, which are applied in preparation for the test, it is advised to inquire the past medical history of drug allergy before testing.
3) Test guidelines
Follow the guidelines set out for MEG. Since a sealed room is not required for measuring EEG, the procedure is less stressful for the examined research participant. Also, because of its minimally invasive nature, the test might be conducted continuously, and might last for a week or longer, depending on its purpose (e.g. research on sleep or epilepsy).
3) Explanatory documents for research participants undergoing the test
In principle, follow Section 6 of the current guidelines.
Transcranial magnetic stimulation (TMS) is a method that stimulates the cortex of a person by placing a coil on the outside of the skull. It was developed by Barker et al in 1985.1) Because the skull has high electric resistance, the brain, which is located inside the skull, cannot be easily stimulated by applying an electric current from outside. TMS uses the magnetic field, which is not weakened by the skull. A varying magnetic field is generated by applying a time-varying electric current to a coil placed on the scalp, and this magnetic field reaches the brain tissues beneath the skull without weakening. This time-varying magnetic field in the brain tissue induces an eddy-current, which electrically stimulates the neural circuits in the brain. Since the method involves stimulating a human brain, there were initially quite a few debates concerning its safety. Experiences to date show that its safety standards have become clearer, at least with regards to single pulse stimulation.
Because human brain can be stimulated externally, TMS has been used for physiological research on healthy participants as well as for tests on patients. While TMS can stimulate many parts of the cerebral cortex and has been reportedly used for stimulation of the cerebellum or brainstem, this method has been used most frequently to stimulate the motor cortex, where stimulation results can be assessed more easily. Types of stimulation methods include single magnetic stimulation and repetitive magnetic stimulation. Use of the latter requires careful consideration of safety. Moreover, repetitive magnetic stimulation has already been used for healthcare purposes, specifically for the treatment of neuropsychiatric diseases such as depression.2) With both single and repetitive magnetic stimulation, it is advisable that all tests follow the guidelines set out by the Japanese Society of Clinical Neurophysiology, which is an academic organization specializing in research methods used in clinical neurophysiology, including TMS.5,6) At the same time, it is desirable that tests involving repetitive magnetic stimulation follow international guidelines.3, 4) Furthermore, tests conducted mainly for the purpose of diagnosing or treating disorders are required to follow the “Ethical Guidelines Concerning Clinical Research.” When the purpose is performing primary or supplemental diagnosis of diseases, the “Ethical Guidelines for Medical and Health Research Involving Human Participants” must be followed. In cases of “specified clinical trials,” defined in the “Clinical Trials Act” as those which involve therapeutic intervention, the “Clinical Trials Act” must be followed.
Studies involving healthy participants require particular attention to close adherence to safety standards, as there are no benefits, including treatment effects, for the research participants. Moreover, repetitive magnetic stimulation should not be used without preparing for the possibility of seizure, which are a significant adverse reaction.
As stated above, TMS is characterized by its ability to stimulate human brain without pain. Therefore, its greatest scientific contribution is in the investigation of the physiological functions of healthy participants. In particular, it has the advantage of a high temporal resolution of 1 msec. By combining it with other imaging technology that has high spatial resolution, it becomes possible to analyze which part of the human brain functions during which time interval. A second advantage concerns its use as a diagnostic device. Currently, TMS is especially useful in assessing lesions in the pyramidal tract as well as in identifying the location of such lesions. It is also used to assess disorders of motor control from the cerebellum and basal ganglia. A third advantage concerns its use as a treatment device. It has attracted attention for the treatment of mental disorders including depression, and neurological disorders such as Parkinson’s disease. A medical device used for TMS treatment of depression was approved in September 2017 in Japan. The Japanese Society of Psychiatry and Neurology developed relevant guidelines.13) However, since applications in those fields are currently in the research stage, it is premature to set any fixed protocols or safety guidelines applicable to the diverse fields of neuroscience.
3) Problematic points (risks involved during the test)
When considering the risks involved with TMS, it is necessary to divide the methods used into repetitive high frequency magnetic stimulation and single or paired magnetic stimulation, and to consider the risks involved with each. For descriptive purposes, repetitive high frequency magnetic stimulation is defined as the repetitive application of stimuli at a frequency exceeding 1 Hz, and includes patterned repetitive magnetic stimulation, including theta-burst stimulation protocols and quadro-pulse stimulation (QPS), which have lately become widely used. The stimulation parameters of repetitive high frequency magnetic stimulation and patterned repetitive magnetic stimulation should be specified in accordance with the latest guidelines developed by Japanese Society of Clinical Neurophysiology6) and Rossi et al.’s report on international standards.7)
Risks that are common to both single magnetic stimulation and repetitive magnetic stimulation are listed first; problems with each type of method are then indicated.
Based on clinical use to date and assessments of animal and human participants, single and paired pulse stimulation can be considered to be without major risks, unless these approaches are contraindicated. Initially, epilepsy patients as well as children were excluded from TMS testing, and stimulation to the cervical region was not applied to patients suffering from cervical spondylosis. However, since then, studies have been conducted with these types of patients at several facilities, and based on considerable experience in Germany and other countries, the indications have been expanded. Although it is likely that single and paired pulse stimulation are safe for patients with epilepsy (e.g. no possibility of worsening epilepsy), it is still possible that incidental convulsive seizures might occur during or immediately after the stimulation. It is therefore necessary to explain this possibility to patients in advance, to carefully monitor for convulsions, and to prepare for their occurrence. Additionally, special precaution should be taken when stimulating epilepsy foci and when reducing antiepileptic doses. Indeed, even with healthy participants, since there is a chance that the participant happens to have undeveloped epilepsy, it is necessary to carefully and thoroughly inquire whether the participant has any previous history of febrile convulsion, head injuries, or brain surgery, family history of epilepsy, and any metal devices placed inside the body.
The use of repetitive high frequency magnetic stimulation has been reported for therapeutic purposes, for example the treatment of neuropsychiatric diseases, as well as for psychobehavioral tests in healthy participants. However, since some reports have indicated that even healthy participants can develop seizures during stimulation, safety and non-invasiveness have to be carefully considered. Prior to treating patients or conducting research with repetitive high frequency magnetic stimulation, approval of the applicable institutional review board at each research institution or facility must be obtained unless such use is considered to be established medical practice. The stimulation parameters should be within the ranges specified in the latest international safety standards.3,4,6) Regarding the total number of stimulations, the recommendation by the Japanese Society of Clinical Neurophysiology can be referred to as follows. In the “Guidelines on Safety of Magnetic Stimulation Method (2019 version)”,6) it is stated that stimulation at a frequency up to 10 Hz with a strength up to 1.2 times the resting threshold in the motor area can safely be repeated up to 15,000 times per week. Among the stimulation methods with an irregular rhythm, it is stated in the guidelines that theta-burst stimulation with a strength not exceeding the resting threshold can safely be repeated up to 3,000 times per week, and QPS with a strength not exceeding the resting threshold is safe up to 2,880 times per week. However, tests conducted for the purpose of treatment are not necessarily restricted by these standards. For example, in psychiatric patients who have already been receiving electroconvulsive therapy (ECT), it might be possible to apply a level of stimulation that is higher than the limit set by the standards. It is recommended that repetitive high frequency magnetic stimulation be performed under physician supervision and responsibility, and that physicians be involved in the decisions on the treatment protocol and parameters.6) In principle, stimulation should be implemented by physicians with sufficient knowledge of the applicable device, while healthcare professionals who have sufficient knowledge of the device, who can respond to emergency situations, and who have participated in training sessions organized by academic societies or other organizations, can carry out the monitoring during stimulation. It is essential to perform the stimulation under circumstances where the recipient can be transferred to a general hospital in case of convulsion or other events.
4) Precautions for use
Young individuals aged less than 18 years and patients with clear dementia require caution.
The above are merely general precautions. Researchers must be responsible for the implementation of the procedures in each research study, and they (or research groups) need to take responsibility for matters such as ethical review of the research protocol at each institute or facility and acquisition of informed consent.
5) Explanatory documents for research participants
As a general rule, follow contents stated in Section 6 of current guidelines. In particular with TMS, since there is a wide variety of purposes and testing methods, it is impossible to create one template. It is therefore preferable that these documents be prepared by the researchers themselves according to their individual research.
B-2. NBS using electricity
1) Overview and efficacy
NBS methods using electricity are collectively called “transcranial electrical stimulation” (tES). For tES, direct current, alternating current, or random electric stimulation is used.
When direct current is used, tES is called “transcranial direct current stimulation” (tDCS). It has been known that when using direct current to stimulate the brain, the firing frequency of neurons sometimes changes according to the polarity of the stimulation. In applying this principle non-invasively, a method that alters brain function by applying a weak direct electric stimulation from the scalp has been introduced since the latter half of the 1990s.1) This method has come to be used for neuroscientific research as well as for the treatment of neuropsychiatric disorders.
Unlike TMS, this method does not stimulate the brain as a way to induce firing in the neural cells themselves, and is relatively safe. There have been no reports of significant accidents, as long as the electrodes are placed on the head. However, risks can occur in cases where electric current is intentionally directed toward the heart with the use of an inappropriate method of stimulation.
When tES uses alternating current, it is called “transcranial alternating current stimulation” (tACS). In this method, alternating current modifies cerebral cortex activity by inducing synchronization of rhythmic brain activities.2) Transcranial random noise stimulation (tRNS) is a method based on tACS, and is implemented by randomly changing the frequency or strength of alternating current stimulation.3)
2) Problematic points (risks involved in testing)
Existing reports from Europe and the United States concerning the risks involved with tDCS4,5) (including the phase I trial in the United States) indicate that there were no serious adverse events with stimulation parameters up to 2 mA of electrical current and 20 minutes of duration. The latest report in 2016 did not include any serious accidents or adverse reactions.6) There have been no reports of convulsive seizures with tDCS, although convulsion of unknown cause was reported 4 hours after tDCS in a patient with a history of epilepsy.7)
Adverse reactions experienced by research participants in response to tDCS include symptoms such as itching and headache during stimulation. However, these symptoms were also observed in sham stimulation and are therefore not likely to be directly related to electric stimulation.8) With daily tDCS, minor skin injuries have been reported.9) As high resistance in the skin is speculated to be a factor underlying skin injuries, electrode placement should achieve an even distribution of electric current, and the sponge needs to be wetted thoroughly.8) It is desirable to use physiological saline to wet the sponge; tap water is not suitable.8, 9) Attention should be paid to sponge deterioration, as it may also cause skin injuries.8) Evaluation of risks associated with tACS did not show serious adverse reactions up to the following stimulation parameters: 5000 Hz, 1 mA, and 10-minute duration (stimulation site, primary motor cortex).10)
Previously reported adverse reactions to tACS include phosphenes with stimulation of the motor area11) and dizziness with stimulation of the parietal region.12) Increase in seizure frequency was also reported in tACS in patients with generalized epilepsy.13)
Because tES transiently improves brain function or enhances the effect of training, depending on stimulation parameters, an expert stated the need to discuss ethical issues surrounding the possible use of tES as a method for neuroenhancement.14) On the other hand, there has been low reproducibility of related research due to individual differences in efficacy.15) The relationship between neuroenhancement and tES should be discussed further from both technical and ethical perspectives in the future.
3) Test guidelines
Regarding tES, there exist both internationally acknowledged guidelines8,15) and the recommendations of the Committee on Brain Stimulation Methods of Japanese Society of Clinical Neurophysiology.16,17) It is therefore desirable to use tES within the range specified in these guidelines and recommendations. However, stimulation parameters can vary, and tES has not been completely established as a method for neuroenhancement. Discussions on ethics are currently underway. Against this background, even research protocols using stimulation parameters that have not been reported are not uniformly prohibited at present, provided that approval is obtained from the institutional review board of the relevant research institution or facility.
4) Explanatory documents for research participants
As a general rule, refer to contents listed in Section 6 of current guidelines.
These guidelines were created with the help of Kazumasa Uehara (RIKEN), Satoshi Tanaka (Hamamatsu University School of Medicine), Tatsuya Mima (Ritsumeikan University), and the Committee on Brain Stimulation Methods of Japanese Society of Clinical Neurophysiology.
Both PET and SPECT are methods that administer a diagnostic agent labeled with a radioactive nuclide into the body and reveal its mode of aggregation as a tomographic image. Their characteristic is that they allow various kinds of information relating to brain function, such as blood flow, metabolism, and neural transmission and function, to be derived from the distribution and behavior of the administered indicator agent inside the brain. However, their usage has limitations, since they require the use of radioactive nuclides, and there are problems concerning its management and radiation exposure to research participants participating in the research and the persons engaged in the research.
PET uses radioactive agents that are tagged using a positron-emitting radionuclide with an extremely short life-span, such as carbon-11 (half-life 20 min), oxygen-15 (half-life 20min), nitrogen-13 (half-life 10 min) and-fluorine (half-life 110 min). It is characterized by its ability to qualitatively measure metabolism or function within an organism, which cannot be measured through other testing methods. Because using these nuclides with an extremely short life-span requires setting up a small-scale cyclotron at the test site facility to produce the positron indicator agent, PET entails a large amount of expense and manpower for installation and operation.
By contrast, SPECT testing uses gamma ray-emitting radionuclides, which have a relatively long life-span, such as technetium-99m (half-life 6 hrs) and iodine-123 (half-life 13 hrs). While the quality of qualitative measurement obtained from SPECT is inferior to that obtained from PET, it has the advantage of using radioactive agents that are used daily in clinical nuclear medicine tests. In addition, because it uses nuclides that have a longer life-span than those used in PET, this method allows their dynamic states to be traced for long hours, and is useful for imaging synaptic receptors and transporters.
Since PET and SPECT allow qualitative measurement of metabolism or function within an organism, they are useful for assessing brain function of healthy individuals, ascertaining the clinical condition of individuals with various disorders, performing early diagnostics, and determining treatment effects. These methods are used in brain science research for measuring blood circulation and metabolism in the brain, testing brain activation, as indicated by the cerebral blood flow, and imaging neural transmission and function.
Because it is thought that changes in cerebral blood flow and glucose metabolism occur in parallel to localized neural activity, it is possible to measure changes in localized brain activity by measuring the changes in localized cerebral blood flow and metabolism. The testing of brain activity, which is indicated by cerebral blood flow, is a method that compares cerebral blood flow during completion of a task with the cerebral blood flow during a control state, to detect the areas where changes in cerebral blood flow have occurred. Assuming that the area with a significant increase in blood flow plays some part in completing the given task, it is possible to identify the locations where changes in neural activity related to this task have occurred. As a method for measuring cerebral blood flow and metabolism when conducting a test of brain activity, a system that uses oxygen-15 labeled water and PET has been employed frequently as it allows repeated measurements and has good spatial resolution. Even today when tests of brain activation using MRI have become popular, because PET/SPECT allow easy physical access to the research participant during testing, various electrical measurements, comprehension of physiological states, and assessment of task achievements can be performed with precision. They also allow easy access to the deep structures of the brain and act as methods that provide standards for qualitative measurement of cerebral blood flow.
In addition, imaging of various functions associated with neurotransmission becomes possible by administering radioactive labeling agents that uniquely bind to specific receptors and by using PET or SPECT to trace the dynamic state of distribution inside the brain. While mapping of receptors and transporters that exist at neural synapses is being widely practiced, other attempts are also being made, such as using agents to measure the percentage of areas occupied by the receptor, assessing enzyme reactions associated with synthesis and resolution of specific neurotransmitters, and imaging information transmission functions inside neural cells.
For PET visualization of abnormal proteins that have accumulated in the brains of patients with neurodegenerative diseases, radiolabeled agents that bind to amyloid β-protein have been developed. This visualization is currently widely used for the diagnosis of Alzheimer’s disease. Radiolabeled agents that bind to tau protein have also been developed and are being evaluated. These agents will be used to diagnose and evaluate treatments of not only Alzheimer’s disease, but also other neurodegenerative diseases associated with accumulation of tau protein, including progressive supranuclear palsy and corticobasal degeneration.
3) Problematic points (risks involved during testing)
For tests using PET or SPECT, it is necessary to consider radiation exposure to research participants participating in the research as well as persons engaged in the research. As a fundamental principle for radiological protection, the International Commission on Radiological Protection (ICRP) issues recommended dose constraints for individuals. ICRP adopts a stance of justification: “Any activities that involve radiation exposure cannot be employed unless they yield benefits that sufficiently cancel out the radioactive damages that are incurred by exposed individuals or societies as a result of such activities.”1) With radiation exposure, dose constraint is set for three types of exposure: public exposure, work place exposure, and medical exposure. For persons in charge of the test, radiation exposure incurred during testing procedures is handled under the category of work place exposure. As far as the tests are conducted as a medical practice, taking the patients’ benefits into account, radiation exposure incurred by the patients falls under the category of medical exposure. By contrast, ICRP issues additional recommendations for healthy volunteers or patients who agree to participate in clinical research even though they do not receive any direct medical benefits.2) In our country, a regulatory body’s standpoint on this issue is indicated only in the guidance by the Ministry of Health, Labor and Welfare on “micro-dose clinical trial” which are carried out under the Pharmaceutical Affairs Act. ICRP recommendations, which define three tiers of benefit that research brings to society, allow research participants who do not directly receive benefits themselves to be exposed to 10 mSv of radiation in a situation that yields the “substantial” benefit to society. MHLW does not indicate dose constraints and requires that effective dose on human should be estimated based on the results obtained from animal testing. Since research participants undergo tests voluntarily, it may be thought that their radiation exposure requires standards that are different from those set for public radiation exposure. Yet taking into account that these research participants do not receive direct benefits, considerations should be made: for the institutional review board at each research institute and facility to set the ceiling of radiation dose constraints; to establish a mechanism that prevents research participants from participating in multiple studies at the same time or without appropriate intervals between tests; to draw up research plans that accommodate the scientific needs of individual research projects while minimizing radiation exposure; for the institutional review board to make thorough assessments and to make arrangements at the planning and implementation stage to minimize radiation exposure to research participants and persons engaged in the research. Safety issues pertaining to radioactive agents used must be reviewed carefully at each facility. Depending on their type and amount, some agents require precautions as they might have pharmacological effects. Therefore, it is necessary for decisions about the composition, quality control, and dose administration of indicator agents to be made under the supervision of a doctor and pharmacist with specialist knowledge.
Since the research participant is asked not to move his or her cephalic region during testing, measurements that last for a long time can cause discomfort or pain. Therefore, pay thorough attention should be paid to the research participant’s condition to ensure that the pain is kept to an absolute minimum. In addition, when taking qualitative measurements of functions, there are cases when it is necessary to collect a sample of arterial blood to obtain the input function from the blood to the brain. While taking appropriate measures can lower the chances of developing complications occurring, these cases should be dealt with by a medical doctor who is experienced in appropriate well-versed in such techniques.
4) Testing guidelines
All procedures, from the composing of radioactive label agents to measurements using PET or SPECT, should be carried out in radiation controlled areas. Since radiological protection laws apply when setting up a small-scale cyclotron to produce positron-emitting nuclides and creating a composite of radioactive agents for labeling, it is necessary to seek the approval of the Ministry of Education, Culture, Sports, Science and Technology.
For quality control of radioactive labeling agents used, each research institute and facility must establish and follow its own standards by referring to the guidelines set by the Japanese Society for Nuclear Medicine or by Cyclotron Nuclear Medicine Usage Special Committee under the Division of Medicine and Pharmacology at Japan Radioisotope Association.2-4) Current standards regulate the following aspects of the agents: manufacturing method, properties, confirmation (radioactive nuclides, labeling compound), purity (inclusion of foreign radioactive substances, foreign radioactive nuclides, or other materials), and full weight; and when necessary, its compatibility for thermogenic material testing, aseptic condition, pH, and specific activity.
For SPECT testing, when using agents that have been provided by pharmaceutical companies as radioactive medical products, each agent’s usage standards should be followed. When using labeling agents that have been developed uniquely at each research institute or facility, they should be handled as other labeling agents made of positron nuclides.
When developing a research protocol, considerations should be made to ensure that radiation exposure to research participants is kept to an essential minimum. The sensitivity and performance of the measuring device used should be taken into account. For the ceiling of dose constraints for radiation exposure to research participants, ICRP recommendations1) can be referred to, as well as Japanese regulations relating to radiological protection. 2-4) Approval from the institutional review board at each research institute and facility should then be secured. Selection procedures for research participants should be reviewed, taking into account such factors as their health condition, current medical symptoms, age, gender, and capacity to give consent. As a general rule, the individual becomes a research participant when voluntary consent has been obtained from the test participant him or herself. However, when consent, which is necessary to carry out the test, cannot be obtained from the research participant, consent can be gained from the participant’s family or a representative who can give consent on behalf of the research participant. As a general rule, pregnant women are excluded as participants. All female participants should indicate whether or not they are pregnant. Although children are, in principle, excluded from testing, in cases where there is clinical merit, approval should be obtained from the institutional review board at each research institute and facility. Research evaluating the efficacy or safety of PET agents meets the definition of clinical trials in the Clinical Trials Act, while research on unapproved PET agents or on the usage, effects, and performance of approved PET agents used outside the approved range meets the definition of “specified clinical trials” in the Act;8 these clinical trials require review by certified review boards. In contrast, research whose intent is not to evaluate the efficacy or safety of PET agents but rather to monitor the disease state based on the accumulation of PET drugs does not meet the definition of clinical trials in the Clinical Trials Act. In such cases, however, even the secondary endpoints are assumed not to include evaluation of the safety or efficacy of PET agents.
5) Explanatory documents for research participants
As a general rule, Section 6 of the current guidelines should be followed. The research participant should be provided with thorough explanations about the purpose, content, and method of the test, its possible side-effects and radiation exposure. The research participant’s understanding of the protocol should be sought, and his or her consent obtained. For matters regarding the amount of radiation exposure, concrete descriptions should be provided by making a comparison with tests that are more generally familiar.
Functional magnetic resonance imaging (fMRI) is a technique that uses MRI to estimate the localized brain activity by measuring changes in blood flow (cerebral blood flow) and oxygen metabolism in blood vessels. 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.
With fMRI, the spatial distribution of neural activity can be measured with high spatial resolution. Compared with PET, fMRI has advantages such as the ability to repeat measurements on the same participant, and high spatial and temporal resolution. However, it has disadvantages such as the tendency to produce artifacts due to the movement of the participants, and the reduction of signals and image distortion around the ear and nasal cavities. The research participants need to stay still in a magnet during measurement. Compared with MEG or EEG, fMRI has a high spatial resolution but a lower temporal resolution.
3) Problematic points (risks involved during testing)
The problems of fMRI measurement are basically the same as those of MRI measurement in general. Here, these points are classified into three categories: 1. Effects on the health of the research participants, 2. Accident risks specific to the MRI measurement environment, and 3. Others. 1 and 2 are based on the 2017 version of the Japanese Industrial Standard (JIS) specifications (JIS Z4951), translated and supplemented from the 2015 version of the International Electronic Industries Association (IEC) standard (IEC 60601-33-2, Amd2).
i) Strength of the magnetic field
Moving the head in a static magnetic field can cause dizziness, nausea, and taste disturbance. Depending on increasing of static magnetic filed strength, the more people experience these symptoms. In addition, although various studies have been conducted on the adverse biological effects of high static magnetic field strength, however IEC/JIS specifications have concluded that these effects lack foundation for fields of up to 8 T.
ii) Temporal changes in gradient field strength (dB/dt)
As an increase in the gradient magnetic field strength over time, peripheral nerves are stimulated by the electric current that accompanies the change in the field, causing an unpleasant twitching sensation. A greater temporal variation in magnetic field strength may directly stimulate the myocardium.
iii) Radio Frequency (RF) heating (specific absorption rate (SAR))
High frequency RF pulses, which excite and invert spins, provide heat to tissues, it has the potential to cause adverse changes in body temperature or burn injuries.
i) Propulsion of magnetic substances caused by a strong magnetic field
Research or medical equipment made of magnetic materials are attracted to a strong magnetic field and collide with the research partcipants and experimenters, causing physical injury. Fatal accidents have also been reported. In the event of an emergency, rescue and firefighters may enter the scanner room and cause a secondary accident due to magnetic material.
ii) Effects of the magnetic field on medical devices implanted in the body of the research participant
In the case of medical devices containing magnetic components or electronic circuits embedded in the body or surface of a research participants, the magnetic field may cause physical tissue damage or malfunction of electronic circuits. Typical implanted magnetic components are artificial heart valves, stents for blood vessels, artificial joints and electronic components are cardiac pacemakers. Even when away from the MRI scanner, there may be adverse effects due to leakage of the magnetic field.
iii) RF energy generated by lead wire, body loop, and magnetic substances inside the body or on the surface of the body
When the wires of the experiment/measurement equipment form a loop on the body surface, if the body of the research participants forms a loop due to contact with a body part, if the RF coil itself is in close proximity to the body, if there is a magnetic substance (Bullets and pieces of iron) buried in the body, or if there is a magnetic substance (Tattoos, cosmetics, ornaments, chemical patches, contact lenses containing metal, etc.) on the body surface, unexpected heat generation may cause burns on the body and the body surface of the research participants.
iv) Sounds generated during imaging
The sound of an MRI scan is so loud that it can cause hearing impairment in a research participants or experimenters.
Generally, superconducting magnets that maintain the strong static magnetic field of MRI are cooled by liquid helium. In rare cases, the liquid helium vaporizes for some reason and causes a rapid volume expansion (explosion), which is called quenching. Double safety devices usually operate, but when this fails, it could lead to frostbite and asphyxiation of the research participants due to helium gas leaks.
The space inside the MRI scanner (the bore), where the research participants is placed, is very narrow, and the lights are often dimmed during experiments. These conditions might trigger panic when the research participants has claustrophobia or nyctophobia.
vii) Oversight of abnormal conditions inside the scanner
After starting MRI scan, only the research participants may notice various abnormal situations including those stated above. However, in general, it is not easy to observe the research participants from the operating room, and even if the participant utters a voice, it is drowned out by the imaging sound and cannot be heard, so the experimenters may not notice the body or voice message from the research participants.
i) Incidental findings
Tumors or other findings may rarely be found in images taken for experimental purposes. In principle, diagnosis is not part of the basic research conducting fMRI experiment. however it is a humanitarian problem to neglect these incidental findings and to give up the opportunity to treat or save the research participants, and there is a possibility of being held liable in a lawsuit. On the other hand, if these incidental findings are reported to the research participantss and the results of the examination are normal, there is a possibility that the research participantss will bear the risk of lawsuits for unnecessary mental damage.
Even if there is no actual causal relationship, it is possible for the study participants to accidentally develop ischemic heart disease or seizures during an fMRI experiment. When the static magnetic field strength is high, many research participants experience dizziness, nausea and dysgeusia due to head movements. If the explanation of the experimenters and the relationship of trust with the research participants are insufficient, reputations about health hazard of MRI might develop to produce an unwanted prejudice in society against the entire field of fMRI research.
Explanations of these guidelines are given in five categories: 1. MRI equipment and operating mode, 2. Safety management and consideration in the experiment, 3. Emergency response manual and training, 4. Prior screening of research participants and experimenters, 5. Other 5. 1 ~ 4 is based on the IEC/JIS standard, and it is recommended that the experimenters read the latest IEC/JIS standard.
In the IEC/JIS standard, three operating modes are defined based on the degree of risks incurred by the research participants during MRI measurements. Each mode of MRI operation has different restrictions across three parameters: the strength of the static magnetic field, time variation of gradient field strength, and RF heating (SAR). Each mode also has different safety measures which should be in place (such as the need to have a medical doctor monitoring, contents that require approval of the institutional review board).
i) Normal operating mode
This is the safest mode of operation. The strength of the static magnetic field is restricted to 3T or lower. Based on the physiological mechanisms currently known and the results of 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 research participants. MRI scanner configured for this operation mode do not allow imaging parameters to be set at values higher than these limits. However, even when the strength of the static magnetic field is 3T or lower, there are people who experience dizziness or nausea because of the movement the head.
ii) First level controlled operating mode
This mode recommends that the operation to be monitored by a medical doctor. The static magnetic field strength is up to 8 T, and the time variation of the gradient field strength and the SAR limit are higher. A static magnetic field strength of 8 T or less is thought to have only minor biological effects, but as the field strength increases the number of people who experience dizziness, nausea, or dysgeusia due to head movement increases. There is the possibility of the peripheral nerve stimulation, when the time variation of the gradient magnetic field strength is sufficiently intense even within the limit value. For the latter, medical doctors’ monitoring of the effects of RF heating is essential in the case of research participants with decreased thermoregulatory ability (Patients with febrile diseases, heart diseases, dyshidrosis, etc.). In the MRI systems set in this operation mode, it is not allowed to set the imaging parameters exceeding these limits, and further, the time variation of the gradient magnetic field intensity and the SAR value can be displayed on the operation console.
iii) Second level controlled operating mode
This mode requires approval by the ethics committee of each facility in accordance with domestic laws and regulations, and is used only for research. This operating mode is entered when the value of any of the three elements exceeds the first level controlled operating mode. There is potential biological effects of static magnetic field strength, myocardial stimulation associated with temporal changes in gradient field strength, and adverse temperature changes and burns associated with RF heating.
It is necessary for the persons conducting experiments to clarify which of the three operating modes will be conducted in. In general, it is used under the first level controlled operating mode. The operating mode should also be included in research applications reviewed by the institutional review boards. The IEC/JIS standard requires MRI manufacturers to make safety settings on MRI scanner to prevent accidentally entering the upper operating mode, which allows higher temporal changes in gradient field strength and SAR.
※The static magnetic field strength limit values for the normal and 1st level controlled operating modes described above are based on IEC Standard 2015 (JIS Standard 2017) and may be changed in future revisions. The experimenters should refer to the latest IEC/JIS standard.
MRI scanner sites require the following:
i) Restricted areas
Areas with a static magnetic field strength of 0.5 mT or more should be clearly separated from surrounding areas (e.g. By marking, etc.) as off-limits areas. And markings or other measures should be used to prevent the inadvertent introduction of magnetic materials or the entry of persons implanted with magnetic medical devices or cardiac pacemakers. Although there is no clear evidence for the effects of static magnetic fields on the fetus, it is recommended that pregnant women refrain from unnecessary access.
Even experimenters and research participants who fully understand the prohibition of bringing in magnetic materials that may be adsorbed by a static magnetic field, or electronic equipment (clocks, mobile phones, magnetic cards, etc.) that may be broken, who habitually conducting scans, may enter the restricted area wearing watches or accessories, or with keys, coins, mobile phones, wallets, etc. in their pockets. Persons conducting the scan must systematically check themselves and their pockets on each occasion before entering the magnet room and restricted areas; they also need to visually inspect the research participants and the use of checklists or metal detectors each time.
ii) Avoiding accidents occurring to research participants during testing
In order to avoid burn injuries from RF heating, it is necessary for the experimenters to check every time before measurement whether or not there is any magnetic materials (cosmetics, hair dyes, contact lenses, ornaments, clothing containing metals) on the body surface of the research participants using a visual check list or a metal detector. Also, when the research participants has been placed inside the scanner for measurement, make sure that the lead wire or the research participant’s body should not in any arrangement form a loop, and that the RF coil itself should not close to the body.
In order to prevent hearing impairment due to scanner noise, research participants must wear earplugs or headphones during measurement. In these cases, the experimenters checks whether the reduction of the scanner noise is sufficient. In addition, measures such as a checklist should be taken so that research participants do not forget to wear earplugs or headphones.
A means of communication between operators and research participants should be established so that the research participants can ask for the procedures to be stopped at any time during measurements. It is a general system that a loud alarm sounds in an operation room when a research participant squeezes a valve in his/her hand.
In addition, it is necessary to constantly monitor the state of the research participants through a window or a video monitor during measurement, and to communicate with the research participants frequently between measurements, and to enter the imaging room and confirm their condition as necessary.
The person responsible for the MRI facility must meet with the MRI manufacturer and relevant departments (Hospitals, fire stations, etc.) as necessary to prepare a manual for the following emergency response: The experimenters must be familiar with this procedure and trained if necessary. The experimenters must verify the following emergency response with the facility’s safety manager and be prepared to actually perform it.
i) Emergency medical procedure
When an accident resulting in injury or a feeling unwellness occur during an experiment, scan should be aborted immediately, and the research participants or the experimenters should be quickly removed from the scanner room, transported to the hospital or called an ambulance. If possible, it is desirable to establish a system that enables first-aid treatment and primary life support in the event of cardiopulmonary arrest. In addition, it is desirable to obtain approval from specific hospitals to accept patients to be transported by ambulance.
ii) Emergency shut-down of magnetic field
When a research participant or experimenter is caught between a scanner and a magnetic object and cannot escape, or when an emergency crew or a fire fighter is expected to enter the scanner room due to a disaster, etc., it is necessary to urgently shut down the static magnetic field of the MRI. The experimenters should be familiar with this operation.
iii) Measures against fire or earthquake
Preparation should be made for taking the immediate steps necessary in the event of a fire or earthquake.
iv) Measures for quenching
In the case of a quench or a malfunction of the safety device, the experimenters should recognize these events by visual observation of white smoke or a decrease in oxygen concentration using an oxygen concentration meter, and take necessary measures.
The person responsible for the safety of the MRI facility and experiments need to establish a screening system in place in which operators and potential research participants are to be entered into restricted areas who are at risk from MRI measurements, as stated below.
i) The following persons are prohibited from conducting or undergoing MRI examination (i.e. they are prohibited from entering restricted areas).
・Persons who have medical devices (Artificial heart valves, artificial joints, vascular stents, cardiac pacemakers, etc.) containing magnetic components or electronic circuits implanted in the body or its surface.
ii) The following persons cannot be research participants unless there are particularly reasonable grounds.
・Persons who is buried magnetic substance that cannot be removed in the body (Bullets and pieces of iron) or the body surface (tattoos, etc.)
iii) It is recommended that the following persons not be included in the research participants unless there are particularly reasonable reasons. When these persons are made to be a research participants, it is necessary to carry out the experiment under the supervision of the medical doctor.
・Persons who may experience an attack due to a medical disorder (e.g. ischemic heart disease or epilepsy) during measurement.
・Persons with claustrophobia or nyctophobia.
・Persons who have difficulty in securing a means of communication during MRI measurements.
・Persons with an impaired thermoregulation (Patients with febrile diseases, heart diseases, dyshidrosis, etc.).
iv) It is recommended that the following persons avoid entering restricted areas.
i) Preparing for incidental findings
When explaining the experiment to research participants, it should be made clear that the MRI scan is solely for research purposes and this brain imagining is not precise enough for diagnosis purposes. In addition, it is desirable to have the applicant indicate in writing whether or not he/she wishes to be informed of any incidental findings when he/she agrees to participate in the experiment.
Regardless of the existence of participant’s declaration, person in charge of the experiment should have the final responsibility should have final responsibility for disclosing the medical notification.
He/She should decide in advance about procedures for handling incidental findings and about methods of notification, and to ensure that all members of the research team are fully informed.
If the findings are determined to require close examination, the basic response is to recommend that the research partcipant to consult a medical care.
There are many cases in which it is difficult to decide whether it is actually an abnormal finding (and whether or not to notify the research participants), and it is desirable to consult an expert who is specialized in diagnosis on brain imaging.
5) Instructions for the research participants
As a general rule, follow the contents indicated in Section 6 of current guidelines.
6) For the establishment of MRI safety management systems at facilities, refer to the following guideline:
Guidelines for MRI in human participants for basic research 2018 (Joint Working Group for Examination of Guidelines for MR Imaging Related to Basic Research of the Japan Neuroscience Society and Japanese Society for Magnetic Resonance in Medicine).
These guidelines were created with the help of Toshiharu Nakai.
Medical electrical equipment -Part 2-33: Particular requirements for the safety of magnetic resonance equipment for medical diagnosis, IEC 60601-2-33, Amd. 2, 2015, International Electrotechnical Commission
Japanese Industrial Standards：Magnetic resonance tomography imaging diagnostic device-safety, JIS Z 4951: 2017, 2017, Japanese Industrial Standards Committee
Near-infrared spectroscopy uses near infrared which has a high permeability for living organisms. It was developed so that changes in the concentration of hemoglobin and blood flow, which are triggered by activity in the cerebral cortex, could be mapped along the surface of the brain. For measurement, two wavelengths of near infrared (of around 800nm wavelength) are exposed to the surface of the head and the scattered light emitted from inside the brain is then examined from a point that is a few centimeters away. The exposed light is absorbed by the blood inside the living organism; the main absorbing component is the hemoglobin in the red blood cells. There are two types of hemoglobin: oxygenated hemoglobin and deoxygenated hemoglobin. Since each has a different absorption spectrum, changes in concentration of each type of hemoglobin as well as in blood flow can be measured using a method of spectral measurement that calibrates two wavelengths. For this procedure, the research participant wears a cap consisting of numerous optical fibers.
In near infrared spectroscopy, the average value of localized neural activity is estimated by measuring the concentration of oxygenated and deoxygenated hemoglobin in the blood, which reflect the changes in blood flow and oxygen metabolism triggered by neural activities. Near infrared spectroscopy thus works by a similar principle to fMRI, yet each uses a different method for image reconstruction. MRI is based on three-dimensional image reconstruction using the nuclear magnetic resonance of the proton inside a living organism, enabling to delineate the anatomical structure. fMRI utilizes the difference in magnetic property between oxygenated hemoglobin and deoxygenated hemoglobin. Change in brain activity causes localized changes in deoxygenated hemoglobin concentration which in turn fluctuate the MRI signal. By combining these time-oriented fluctuating signals with an anatomical structure, regional task-related activation can be elucidated. By contrast, unlike MRI, it is difficult to achieve image reconstruction with near infrared spectroscopy. This is because the light scattering property of a living organism is uneven. Therefore, near infrared spectroscopy gathers averaged signals that are generated in areas of a few centimeters in diameter which are formed between optical fibers that emit light and optical fibers that receive light. The most common method of image reconstruction is called the Back Projection method, which generates an image by interpolating the average value of each area. Yet in the past few years, another method has been proposed, which statistically calculates the signals in each area and maps them onto a brain surface image. This image may be obtained by conducting an additional MRI scanning or by employing a method that estimates parts of a standard brain from the location of the scalp. In particular, the latter method is often employed when testing infants and children. The spatial resolution of the image obtained is a few centimeters.
Compared to MEG or fMRI, the greatest advantages of near infrared spectroscopy include its less restrictive nature of the experiment and the lack of safety issues associated with the experimental equipment. This method is considered lower-risks because there is no need to isolate the research participant in a sealed room or inside a magnet, and it does not employ substances like liquid helium. Within the field of brain science, near infrared spectroscopy is characterized by the fact that it produces less noise than fMRI and that it enables natural brain function to be measured within an everyday environment. These characteristics make it possible to measure brain function of a wide variety of people, from infants to the elderly. Compared to EEG, near infrared spectroscopy has the advantage that it does not require paste or gel for impedance matching, and that in principle, it is easy to estimate the active parts in the cerebral cortex.
3) Problematic points (risks involved in testing)
1. Risks involved in using low-power lasers
Equipment has been approved by the Pharmaceutical Affairs Act as a general method of clinical testing, and there are no known safety issues. Near infrared spectroscopy equipment manufactured by Hitachi comprises of a class 1M low-laser product as specified in C-6802 under JIS specifications (equivalent to class 1M as specified in IEC60825-1 Edition 1.2). When the research facility in question has regulations in place regarding allowable exposure to lasers, equipment should be used in accordance with these regulations. Notably, low-power lasers do not cause damage to skin or brain tissues. Some equipment, such as Hitachi’s ETG series, have been approved for medical use as defined by the Pharmaceutical Affairs Act. In addition to public regulations, studies concerning the safety of near infrared spectroscopy have reported an estimated internal temperature by measuring the temperature inside a living organism and by simulating light diffusion.1, 2)
2. Pain experienced by the research participant at the time of actual measurement
In addition to the “pain” caused by wearing a headgear with multiple fiber poles that connect to the optical fibers, the research participant needs to make an effort not to move his or her head as much as possible during testing, because recordings fluctuate if the pole is shifted from its original location. Remaining still can cause discomfort or pain when the test lasts for long periods of time.
4) Testing guidelines
5) Explanatory documents for research participants
As a general rule, follow the contents indicated in Section 6 of current guidelines. Below, we provide some examples of information which can be provided specific to near infrared spectroscopy, which can be used in explanatory documents.
Guidelines were created with the cooperation of Maki Atsushi, Hitachi Advanced Research Laboratory, Hitachi, Inc.
It can be expected that in the future, methods used in neuropsychological studies will be combined with non-invasive measurement methods, such as fMRI, PET, MEG, EEG, TMS, and near infrared spectroscopy for researching high-order functions of the cerebrum. In anticipation of this, it is necessary to carefully consider the ethical aspects of neuropsychological research methods.
Neuropsychological studies have been conducted for some time. Their objective is to investigate patients who have spontaneously developed organic or functional disorders of the brain, such as diseases or injuries, by investigating their cognitive processing using questionnaires or by observing their reactions to various tasks. In addition to verbal and behavioral data, data of brain measurements and physiological indices are collected.
Neuropsychological studies can effectively explore the internal processes (i.e. cognitive processing) of patients or research participants with disorders, which enables inference regarding normal cognitive processing. However, impaired sites and functions cannot be controlled, and therefore variation among research participants tends to be significant.
3) Problematic points (risks involved in testing)
Neuropsychological tests are associated with the risk of placing psychological stress on research participants. Sufficient attention needs to be paid to this point.
4) Testing guidelines
5) Explanatory documents for research participants
As a general rule, follow the contents indicated in Section 6 of the present guidelines, except for the tests performed as a part of treatment.
Guidelines were created with the cooperation of Masami Yamaguchi (Chuo University) and Akira Midorikawa (Chuo University).
A Brain Machine Interface (BMI) is a neural engineering technology that enables communication between the brain and a device outside the body by measuring brain activities and performing computer analysis (decoding) of brain information such as motion intention. In other words, the BMI allows the brain to bypass the body and directly connect with the outside environment. BMIs are classified according to the technique by which brain information is recorded: non-invasive, which involves collection of brain information by methods such as scalp electroencephalography and fMRI, and invasive, which employs recording probes surgically placed in the central nervous system. Ethical issues associated with invasive BMIs are beyond the scope of the present guidelines and are therefore not discussed here. For non-invasive BMIs, it is desirable to follow each section of the present guidelines according to the method by which brain activities are measured. Moreover, unique ethical issues have been acknowledged among researchers even regarding only non-invasive BMIs, and have mostly arisen due to the development of new technologies for decoding or modifying brain information.
The efficacy of BMIs that directly connect brain and machines is generally assessed according to whether the BMI is used as a neural prosthesis or for neural modulation. A neural prosthesis is a technology for accessing the central nervous system to compensate for functional impairment of the sensory and/or motor systems. The narrow definition of a BMI is a neural prosthesis for a motor system, such as a robotic prosthesis driven by brain-derived information. On the other hand, neural modulation by a BMI involves intervention in the central nervous system by using brain activities as clues for the purpose of inhibiting abnormal neural activities or stimulating functionally impaired neural or compensatory circuits to enhance neurological function. One example of neural modulation by a BMI is closed-loop deep brain stimulation (DBS). Closed loop DBS is based on BMI technology and is used for neuro-rehabilitation or the treatment of Parkinson disease. In closed-loop DBS, DBS is driven by neural activities. Another example of neural modulation by BMI technology is neurofeedback. Neurofeedback is an experiment system in which a signal that reflects a certain neural process is measured and decoded by online fMRI or other methods; this signal is then presented to a research participant who manipulates this signal by changing the state of his or her own brain.
3) Ethical problems
At this point, risks associated with BMIs are speculated to be roughly equivalent to those associated with the measurement methods involved. However, ethical problems unique to the principles of BMIs have begun to be pointed out. It would be extremely convenient if information could be easily exchanged between the brain and the outer environment by BMI technologies in the future. BMIs are currently considered to still be in an investigative stage, and direct exchange of information between the brain and outer environment is deemed possible, but extremely limited. If, in the future, BMI technologies are applied in society, ethical problems on how to secure the privacy and autonomy of individuals may arise. Moreover, excessive expectations or misconceptions regarding the application of BMI technologies may spread in society faster than our understanding of these technologies. Some experts have proposed that discussion on ethical issues should be started in anticipation of future advancements of BMI technologies, even though there are no problems at present.1) Discussion of ethics, specifically concerning neurofeedback, should also be started in consideration of the potential societal impact of treatment of psychiatric disorders2) and neuroenhancement3).
4) Testing guidelines
The guidelines for each measurement method should be followed. Research on BMI/neurofeedback in human participants for the purpose of developing treatment methods of psychiatric and neurological disorders largely differs from research on treatment methods involving application of energy from outside the body, such as in DBS, but all types of research should follow related guidelines, rules, and regulations, including the Ethical Guidelines for Medical and Health Research Involving Human Participants and Clinical Trials Act. In cases of other basic research on BMIs, it is desirable to explain the following points to research participants and obtain their consent: 1) the range of investigative use of measured signals, 2) the information security of measured signals and their analysis results, 3) the possible extent and duration of the effects of BMIs and neurofeedback on brain functions, and 4) device safety mechanisms in cases of control of external devices by BMI. If prior explanation of these points is difficult because the investigator does not want research participants to have preconceptions about the study, debriefing after the research is recommended.
5) Explanatory documents for research participants
In principle, Section 6 of the present guidelines should be followed.
Guidelines were created with the cooperation of Junichi Ushiba (Keio University) and Hiroshi Imamizu (ATR, The University of Tokyo).
Genome analysis or genetic analysis is a method that identifies genetic factors (genome sequences) associated with a disorder or physiological trait. This method is currently established as an extremely powerful research method through the development of various DNA markers, the deciphering of the human genome reference sequence through the Human Genome Project, and the HapMap Project. Moreover, it technically became possible to routinely decode an individual’s whole genome sequence. This method can be applied to investigate not only the deciphering of genetic causes and molecular mechanisms of disorders but also the genetic or molecular basis, of various physiological traits. Studies that combine this method with physiological analysis or imaging have been conducted frequently, contributing to deciphering of the brain nervous system.
Typical methods of genome or genetic analysis include an approach that is based on linkage analysis of family samples, and one that is based on association analysis, which compares a group with disorders or specific features against a control group without such disorders or features. While there are various DNA markers, a system of analysis is currently being established that uses a DNA chip equipped with single nucleotide polymorphism (SNP) markers, which cover the entire genome. This makes it relatively easy to carry out a genomic or genetic analysis from a technical point of view.
In practice, studies that include analysis of the human genome or genetic analysis must be planned in accordance with the guidelines established by related ministries and agencies, including the ethical guidelines concerning research involving the human genome and genetic analysis and the ethical guidelines and laws regarding research involving human participants. The research plans must be reviewed and approved by the institutional review board or other appropriate committee on human genome and genetic analysis research established at each research institute.
Approaches to ethics review differ among applicable laws, regulations, and guidelines.9 In this section, the general responsibilities of institutional review boards stipulated in “Ethical Guidelines for Medical and Health Research Involving Human Participants” (hereinafter referred to as “guidelines for medical and health research”) are discussed.10 These guidelines for medical and health research can be referred to in cases of research other than “medical and health research involving human participants.”11 Institutional review boards whose operation does not currently fulfill the requirements in these guidelines must develop rules referring to and thoroughly considering these requirements for future operation.
An institutional review board is an advisory body for the head of the research institution. When the head of the research institutions asks the institutional review board for opinions regarding whether or not it is appropriate to conduct certain research, it is the responsibility of the board to review the research, including information regarding conflicts of interest of the research institute and researchers, in a fair and unbiased manner and from both ethical and scientific perspectives, and to communicate its opinions in writing. An institutional review board can make suggestions to the head of the research institution regarding modification of approved research protocols and discontinuation of research.
Researchers must appropriately conduct their research in conformance with laws, regulations, guidelines, and other rules according to the research protocol reviewed by the institutional review board and approved by the head of the research institution.12
A. Establishment of institutional review boards
The founder of an institutional review board must determine the rules regarding the organization and operation of the board, and ensure that the members of the board and persons responsible for clerical work carry out their tasks in accordance with these rules. Other responsibilities of the founder include storage of records, disclosure of the status of board meetings and board reviews,13 and implementation of measures for the education and training of members.
It used to be mandatory to establish an institutional review board at each research institution. This was changed, and the requirement to found a board at each institution was removed from national laws, regulations, and guidelines. In cases of multi-institution joint research, a single review per research protocol is considered sufficient. A research collaborator is allowed to request review by the institutional review board of the institution to which the chief researcher belongs, instead of requesting the board of his or her own institution.
Additionally, a research institution without its own institutional review board is allowed to request that the board at another institution perform research reviews. When the head of a research institution requests review by the institutional review board of a research institution other than his or her own, that board must conduct the review and express its opinions only after it fully understands the research implementation system at the institution that makes the request, which requires sharing of necessary information. The head of the research institution that requests the review is not allowed to participate in the review or in the process by which the board forms its opinions. However, this individual can attend the meetings of the institutional review board with the prior consent of the board if his or her attendance is necessary, in order to gain an understanding of the content of the review.
B. Composition and operation of institutional review boards
The following requirements for the composition of institutional review boards were established to ensure appropriate implementation of the reviews of research protocols and other tasks; all the requirements must be met. A single board member cannot fulfill more than one requirement from 1) to 3). The same requirements are applicable to holding meetings.
1) One or more persons knowledgeable in natural science, such as experts in medicine or healthcare, must be included.
2) One or more persons knowledgeable in humanities or social science, such as experts in ethics or law, must be included.
3) One or more persons who are able to express opinions from the perspective of the general public, including research participants, must be included.
4) Two or more members not affiliated with the institution of the founder of the institutional review board must be included.
5) Members must consist of both men and women.
6) There must be at least five members.
It is desirable for research conducted by any members of the Japan Neuroscience Society to include individuals with knowledge regarding the content, methods, and devices of neurological research, who fulfill the requirements in 1), and to ensure diversity of expertise and gender to the greatest extent possible. Institutional review boards can ask the opinions of other experts if this is necessary given the research they evaluate and the research participants. In reviewing and providing opinions on the protocols of research to be conducted in research participants who require special consideration, it is strongly recommended that when necessary, the institutional review boards ask the opinions of individuals who have insights regarding these participants.
Researchers to be involved in the research under review are not allowed to attend meetings where the relevant research is reviewed or where opinions regarding the research are formed. However, they can attend such meetings to explain the relevant research at the request of the institutional review board.
Institutional review boards must make every effort to form their opinions unanimously.
To ensure that a high level of review is implemented, researchers are required to prepare and submit appropriate research protocols before conducting the research.14 The guidelines for medical and health research include the principles regarding which matters should be described in the research protocols to be reviewed by institutional review boards. Please refer to these guidelines as necessary. 15
14 Refer to “Part 5 Obligations of Principal Investigator 1. Preparation of research protocol and compliance of investigators, etc.”.
15 Refer to “Part 8 Contents of Research Protocol”.
A. Informed consent procedures
Before researchers conduct research, and before relevant parties provide existing samples or information, they must obtain informed consent, in principle, in accordance with the research protocols approved by the heads of the research institutions. In the guidelines for medical and health research, procedures of informed consent in the following four cases are discussed: 1) when research is to be conducted by obtaining new samples and information, 2) when research is to be conducted using existing samples and information stored at the research institution of the researchers, 3) when existing samples and information are to be provided to another research institution, and 4) when research is to be conducted by receiving existing samples and information that become available based on the procedure in 3).16
The guidelines for medical and health research specify principles regarding which matters should be explained to research participants or other parties when obtaining informed consent. Please refer to these guidelines.17 Furthermore, for the research conducted by the members of the Japan Neuroscience Society, explanatory documents should address the length of time that research participants will be involved in the research, photos and an overview of the devices to be used, levels of physical or mental discomfort, and an arrangement to reduce such discomfort.
While the format of informed consent documents may differ between research institutes or facilities, or by research methodology, it is generally advisable to use a written document and to consider the points listed below as common elements, and to include them in the explanatory documents given to research participants.
Attention should be paid to the fact that for the use, provision, and receipt of samples and information, the procedures differ in terms of objectives or the level of anonymization, and preparation and storage of records are required.
Informed consent provided by proxy consenters needs to be discussed by the applicable institutional review board in the following cases: 1) when the research participant is a minor, 2) when the research participant is an adult but is objectively judged to be unable to give informed consent, and 3) when the research participant is deceased.19
B. Withdrawal of consent
When research participants or other parties withdraw all or part of their consent to begin or continue participating in the research, or reject the conduct or continuation of all or part of the research based on certain notifications or disclosures regarding information on the research, researchers must immediately take measures (discontinuation of experiments, discontinuation of use and disposal of already-obtained samples and information, suspension of provision of samples and information to another facility, etc.) according to the content of this withdrawal or rejection, and explain the measures to the research participants or other parties concerned. However, these requirements are not applicable in cases where these measures are difficult to implement and the head of the research facility decides to exempt researchers from these measures based on the opinions of the institutional review committee.20
C. Necessity of post-hoc explanation in cases where not all information can be disclosed in advance21
In principle, when not all the information regarding the content of the research can be disclosed to research participants in advance, for reasons related to the planning of the research, the reason and the methods for post-hoc information disclosure need to be explained to and approved by the institutional review board or other parties. If there is approval to refrain from disclosing some information, researchers need to disclose the information afterwards, thoroughly explain the reason for no disclosure, and sincerely apologize to the research participants. Researchers also need to answer all questions posed by the research participants to avoid any misunderstanding.
D. For research participants affiliated with the same organization as the persons conducting the research
The above principles regarding informed consent must be followed even for research participants affiliated with the same organization as the persons conducting the research.
16 Refer to “Part 12 Procedures for Obtaining Informed Consent, etc. 1.”.
17 Refer to “Part 12 Procedures for Obtaining Informed Consent, etc. 3.”.
19 Refer to “Part 13 Procedures, etc. for Obtaining Informed Consent from Legally Acceptable Representatives, etc.”.
20 Refer to “Part 12 Procedures for Obtaining Informed Consent, etc. 8.”.
21 Refer to page 11 of “Code of Ethics and Conduct” of the Japanese Psychological Association (https://psych.or.jp/wp-content/uploads/2017/09/rinri_kitei.pdf).
A. Definition of personal information
Personal information is defined as that which pertains to living individuals and which meets either of the following criteria.
1 ) Individuals can be identified based on any combination of the items included in the information concerned (excluding the personal identification code and including items that can be cross-checked with other information and that become personally identifiable when cross-checked), such as those mentioned in the name, date of birth, or other descriptions, or recorded or expressed in sounds, gestures, or other forms.
2) The information concerned includes the personal identification code (the code is considered to be personal information in and of itself).
B. Responsibilities of researchers regarding personal information
When conducting research, those involved must not obtain personal information by deceit or other illicit means. In principle, they also must not deal with personal or other information, obtained in association with the conduct of the research, that lies beyond the scope of the consent provided by the research participants in advance.22 Moreover, they must appropriately handle all personal and other information obtained in association with the conduct of the research that is retained at their research organization (including cases where storage is outsourced), in order to prevent the leak, loss, or damage of the information or to manage its security in other ways.23 For this purpose, personal information of research participants, including correspondence tables, needs to be anonymized and strictly managed.
If it is impossible to completely prevent the direct identification of research participants or if research participants may possibly be identified, an explanation to that effect must be given to the research participants and their consent must be obtained in advance.
Please appropriately refer to the Act on the Protection of Personal Information, Act on the Protection of Personal Information Held by Incorporated Administrative Agencies, etc., and Act on the Protection of Personal Information Held by Administrative Organs. They differ from each other and are reflected in the guidelines for medical and health research as well as other ethical guidelines for research.
22 Refer to “Part 14 Basic Obligations about Personal Information, etc.”.
23 Refer to “Part 15 Security Control Measures”.
When research results are published, research participants and their communities (such as regions and groups they belong to) must be kept unidentifiable, in principle. When using photos or videos of research participants, it is necessary to make sufficient effort not to identify the participants. Moreover, in order not to disadvantage the research participants and their communities by causing misunderstanding of the research results, expressions used in publications must be selected carefully.
In some cases, audio or visual records are used to accurately report behavioral or language characteristics. When there is a possibility that these records will be used in public, for example in a study group, and participants may be identified, an explanation to that effect must be given to the participants and their informed consent must be obtained in advance. In the presentation of the research results, it must be clearly stated that the consent of the research participants was obtained.
Presentation of research results at academic conferences and in journals is discussed above. When information related to the results is disseminated via non-specialized media, including general newspapers, magazines, television, and radio, it is desirable to handle personal information in the same way as described above.
In drawing up these guidelines, we received advice from Professor Akira Akabayashi, Department of Biomedical Ethics, School of Public Health, Graduate School of Medicine, The University of Tokyo, and Mr. Chohei Hashimoto, Kyoto Bar Association. For the present revision, we received advice from Professor Kaori Muto, Department of Public Policy, Human Genome Center, the Institute of Medical Science, The University of Tokyo, and Eisuke Nakazawa, Lecturer at Department of Biomedical Ethics, School of Public Health, Graduate School of Medicine, The University of Tokyo.