Incidental Findings in Magnetic Resonance Imaging (MRI) Brain Research

Magnetic resonance imaging (MRI) is a non- invasive imaging tool that utilizes a strong Mmagnetic field and radio frequency waves to visualize in great detail organs, soft tissue, and bone. Unlike conventional x-rays (including computed tomography [CT]), there is no exposure to ionizing radiation and at most field strengths (generally below 7 Tesla) the procedure is considered safe for nearly every age group. Because it is non-invasive (i.e., does not break the skin or harm the body) and possesses excellent spatial resolution (down to millimeters), the use of MRI as a research tool has increased exponentially over the past decade. Uses have ranged from add-ons to a clinical study (e.g., after scanning a child who has fallen from a bicycle, the radiologist might do an extra sequence to explore ways of obtaining higher resolution images) to studies of brain development in typically developing children. In addition, a major effort has been made in recent years to use MRI to study brain function (so-called “functional MRI” [fMRI]). Because the clinical utility of fMRI has not yet been realized, fMRI is still considered highly exploratory, and we cannot yet identify incidental findings of a functional (as opposed to structural) nature. Before discussing the issue of incidental findings (IFs) in MRI brain research, it is worthwhile to review some of the more common uses of MRI in studying both typical and atypical brain structure in children and adults. One such use has been to explore typical brain development across the first two decades of life. For example, the National Institutes of Health (NIH) has supported a contract issued to approximately seven institutions in North America to collect structural data on 0–18-year-olds; the goal of this project is to develop an atlas of the developing brain.1 Similar work is being performed by individual investigators as well. For example, John Gillmore and colleagues at the University of North Carolina have conducted groundbreaking work on infants between zero and one year of age,2 and Jay Giedd and colleagues at the NIH have conducted similar work on children age four and above.3 Perhaps most common has been the use of structural (anatomical) MRI to ground fMRI data; that is, all fMRI investigations require that structural data be obtained as well. In order to know precisely which regions of the brain are activated in a particular task, one must overlay the functional data on the structural (anatomic) data. For example, if the investigator wishes to determine whether the hippocampus is active during memory encoding, it is essential to know precisely where in the brain the hippocampus lies. As a result of this need to acquire structural data, large numbers of structural scans are performed. Despite its high costs (approximately $1500 for a clinical scan and $500 to $600 for a research scan), MRI has become very popular among those interested in brain development, primarily because it can provide such detailed images of the brain and because the exact same procedure can be used across the entire lifespan to illuminate brain development. Unfortunately, however, relatively little attention has been paid to the issue of IFs, where “an incidental finding is a finding concerning an individual research participant that has potential health or reproductive importance and is discovered in the course of conducting research but is beyond the aims of the study.”4 Although there are now reasonably accurate estimates of the incidence of IFs among adults — more than five percent of scans performed on adults show IFs5 — there are no comparable figures for children among developmental and pediatric investigators. Personal communication with the author among such investigators, however, places the estimate between five and ten percent.6 Of course, clinical intuition and personal anecdote are no substitute for real data, and thus, it would seem imperative for the field to acquire accurate estimates of IFs among children (assuming the figures that are in place for adults are accurate). Tremendous variation exists among investigators and laboratory sites in their approach to handling IFs. For example, some Institutional Review Boards (IRBs) require a discussion of IFs in their consent form, whereas others do not.7 In addition, some sites and IRBs require that all research scans undergo a clinical read to ascertain whether IFs are present in an individual child, although not all sites do and among those that do, not all are read by a board-certified neuroradiologist. The urgent need for systematic oversight of IFs can be illustrated by the following case study. The investigators discussed the matter with the university IRB, and were told that they had been in full compliance with procedures then in force, and that this was not an adverse event. Nevertheless, based on the surgeon’s read of the experimental MRI scan, it is not unreasonable to think that if this scan had been read by a neuroradiologist, the tumor would have been spotted earlier. The tumor would still have required removal, but the earlier warning might have been useful, as the student’s unexpected seizure could have been dangerous if she been driving at the time, for example. This case study illustrates the challenges faced by MRI investigators. Although some IRBs and the NIH now require that all MRI scans be read by a neuroradiologist,8 investigators and sites may still have differing procedures. For example, in some cases the scans are read informally and no report is issued; in others, the scans are formally read and a formal report is prepared and submitted to the principal investigator. In still others, the investigators — often Ph.D.s with no clinical training — read the scans themselves and only refer the scan to a neuroradiologist if something suspicious is detected. Even among sites where all scans are read clinically, there is variability in who reads the scans and when the scans are read. For example, in queries the author has made to colleagues from around the United States, it appears to be the case that at some sites, scans are batched and read “en masse” at some later point in time, so there might be a delay of weeks or months between when the scan was performed and when it was read. In addition to whether and when scans are read clinically, there are a number of other issues that must be considered in the context of MRI IFs. First, there has been a proliferation of higher-field scanners; for example, 3 Tesla scanners have, in many places, replaced 1.5 Tesla scanners, and 4 and 7 Tesla scanners are now much more common than they once were. With higher field strength come greater sensitivity and thus, greater likelihood of false positives — that is, detecting a problem when one does not actually exist. Second, many university and research sites use experimental pulse sequences (i.e., different algorithms that permit one to obtain higher resolution data) that may similarly lead to an increase in false positives. Third, as the use of MRI continues to proliferate, and the number of scans being performed increases, it is difficult to predict what the true incidence of IFs will be. Fourth, at many sites, the primary or principal investigator is often a Ph.D. student, postdoctoral fellow, or faculty member with no clinical training in neuroradiology and, very likely, relatively little training in neuroanatomy. If such individuals are the ones to read a scan, the possibility of missing an incidental finding will likely increase. Fifth, in the context of studying brain development, we thus far have only a rudimentary understanding of what typical development looks like. As a result, we do not have a template for what normal brain structure looks like at different ages, which increases the risk of both false positives and false negatives. Sixth, because of the costs involved in having a neuroradiologist read each scan, there is a financial disincentive to having such experts read each scan. In the early to mid 1990s, a student at a major research university volunteered as an MRI study participant. The study involved being scanned by what was at the time a relatively high-field scanner, 4 Tesla. Because few such scanners existed at that time, the work was considered experimental; in addition, the scan sequence was also exploratory (an example of the structural data obtained at 4 Tesla can be seen in Figure 1). As a result, and because it was not required by the IRB, the investigators did not have the scans read clinically. (In prior consultation with a neuroradiologist, the investigators learned that such scans were far from clinical grade, which would have increased the uncertainty of a clinical read.) Figure 1 Anatomic Image Obtained from a 13-Year-Old Boy, Scanned at 4 Tesla The study itself was unsuccessful, and the findings were never published. A few years later the student experienced an epileptic seizure and was brought by ambulance to a local emergency room. The patient underwent a neurological and neurosurgical evaluation, whereupon a brain tumor was found. The student was admitted to the hospital and surgery was scheduled. The student showed the surgeon a copy of the MRI scan he/she was given by the investigators from a few years earlier. The neurosurgeon studied the MRI scan and identified the tumor, surmising it had likely been present since birth.