The Inconvenient Truth About MRI in Psychiatric Research

At the turn of the 20th century, there was considerable debate among psychiatrists about whether mental illnesses were actually brain disorders—a debate that continues even today. In the hope of identifying anatomical differences associated with these conditions, researchers spent decades performing microscopic examinations of postmortem brains. Many findings were reported, but none withstood the test of time and more critical analyses of the subject.

Today, the opportunity to examine the living brain with increasingly accessible new technologies has re-ignited the enthusiasm to identify neuroanatomical differences between the brains of those with and without psychiatric disorders.

It is almost impossible nowadays to pick up a psychiatric journal and not see a study that reports differences in magnetic resonance imaging (MRI) measurements between psychiatric patients and healthy subjects. And, it seems as if all mental disorders—and even behavioral variants within the limits of “normality”—are associated with what appear to be structural changes on MRI.

Unsurprisingly, severe, disabling mental disorders (for example, schizophrenia, autism) have been scrutinized in many studies with various MRI techniques in the hope of finding differences capable of decisively contributing to prevention and early diagnosis. As it happens, schizophrenia, for instance, shows widespread reductions in cortical measurements, which often are found to get worse over time. These various findings are routinely referred to in the literature as “cortical thinning,” “atrophy,” “tissue loss,” or worse, and they are assumed to be insights into the underlying nature of these conditions.

Notwithstanding the likelihood of a biological basis for mental disorders, can we truly conclude that MRI findings are unquestionable reflections of changes in the brain related to pathogenesis?

After a closer analysis of the widespread MRI techniques and several of their limitations, we believe that the answer is no. By perpetuating from study to study the uncritical instantiation of findings potentially representing fallacies of all sorts, there is a serious risk of misinforming our colleagues and our patients about biological abnormalities associated with psychiatric illness.

Here, we offer the inconvenient perspective that various confounders, epiphenomena, and artifacts are equally plausible interpretations of these findings.

Many Factors May Alter MRI Signals

When evaluating claims of anatomical differences in comparison samples based on MRI measurements, you need to recall what MRI actually is.

MRI is not a direct measure of brain structure. MRI is a physical-chemical measure, based on radio-frequency signals emitted from energized hydrogen atoms influenced by the magnetic properties of the microenvironment of surrounding tissue. As such, MRI signals are susceptible to many physical-chemical phenomena not necessarily related to the number or architecture of the cells in the tissue.

Variation in MRI signals and anatomical measurements have been reported for a vast array of nonstructural factors, including common psychotropic drug use, changes in body weight, blood lipid levels, alcohol use, nicotine use, cannabis use, exercise, hydration, pain, cortisol levels, change in brain perfusion associated with acute drug administration, and, finally, an individual’s motion during scanning—even motion that is imperceptible (for example, breathing).

While it is unclear how each of these factors specifically affects the MRI signal, it is likely that they alter the biochemistry and thus the magnetic properties of the tissue rather than the number or basic structure of cells.

Thus, before concluding that MRI differences between a patient sample and a control sample represent microstructural abnormalities of pathogenic significance, one needs to consider also other explanations. While such nonstructural factors may be considered to be “white noise” elements that do not systematically vary from one individual to another in healthy controls, in studies of psychiatric patients, or even in studies of subjects of different ages or other demographic characteristics, these various confounding factors typically vary quite systematically between samples and bias results based on their effects.

For example, patient samples often differ from controls in smoking history, alcohol or cannabis use, exercise, body weight, lipid levels, ongoing stress and thus endogenous corticosteroid levels, medication use, general health, and movement during scanning. Each of these factors will individually and in sum influence the MRI signals and will create differences between groups.

What MRI Can’t Tell You

While we cannot offer a formula for deconvoluting these and other concerns from the existing results of MRI studies in psychiatric patients, we propose instead a change of perspective in future MRI research when patient and control samples are directly compared:

• Researchers using structural MRI techniques should remain highly skeptical of the basis of changes that are found in comparisons of patient and control samples and refer to them as “differences in MRI measurements,” not as “cortical thinning” or “loss.”

• Patient samples should be carefully characterized for potential confounders, especially those mentioned above that tend to be systematically different from controls and that influence MRI measures. These characteristics should be included in a description of the samples.

• Head motion parameters, breathing patterns, and skin conductance measures also should be recorded and included as part of the data of a study so that their potential role can be evaluated.

We have reached a crossroads in neuroimaging studies in psychiatry research. We expect that continuing technological advances based on a more “biological” understanding of the MRI signal will allow a fuller characterization of factors that link MRI signals to brain anatomy and function.

To advance on the path of understanding the pathobiology of mental disorders with these methods, we must be willing to discuss a widely and tacitly recognized—though mostly ignored—“inconvenient” truth: conventional MRI does not allow us to make firm inferences about the primary biology of mental disorders. ■