fMRI: Imaging’s Next Frontier

Behavioral diagnoses, such as autism and attention-deficit hyperactivity disorder (ADHD), are notoriously complex. Observational protocols are subjective, thus diagnostic accuracy remains questionable. Symptoms and behaviors typically persist for years prior to diagnosis, exacerbating the challenges of the disorders. A number of researchers are exploring the diagnostic potential of fMRI in several disorders. 

Autism: New light, but are rads in the dark?

“We need a medical evaluation for autism,” says Joy Hirsch, PhD, director of the Functional MRI (fMRI) Laboratory at Columbia University in New York City. Currently, parents or caregivers complete a subjective rating scale to inform the diagnosis. The ideal protocol, says Hirsch, entails a medical evaluation that examines the child’s anatomy and physiology and provides a level of certainty that data are consistent with an autism diagnosis.

Structural imaging is not up to snuff, as the structure of the autistic brain is indiscriminable from a healthy brain. However, fMRI may fill the gap. Hirsch and colleagues reported that children with autism were not as responsive to passive auditory stimuli as typical children, in a study published August 2011 in Radiology. Specifically, the researchers quantified reduced BOLD (blood-oxygen-level-dependent) activation within the superior temporal gyrus among autistic children compared with healthy children.

The approach offers numerous advantages. “It takes about five minutes to collect the data and requires very little post-processing,” says Hirsch. Statistical parametric mapping, the post-processing technique, is standard and readily available at U.S. medical centers. However, this early research must be repeated and replicated in a larger sample size to determine its sensitivity.

Another challenge with the use of fMRI to diagnose autism, says Nicholas T. Lange, PhD, director of the neurostatistics laboratory at Harvard Medical School in Boston, is the lack of a biological reference point for the disorder. Imaging data cannot be connected to an established physical scale.

Dyslexia: Early identification

Dyslexia presents similar diagnostic challenges. Currently, children with developmental dyslexia are not diagnosed until after a delay in learning to read, says Nadine Gaab, PhD, assistant professor of pediatrics at Boston Children’s Hospital. “It has long-lasting mental health implications. Children with dyslexia are more likely to have depression and low self-esteem.”

She and her colleagues are attempting to determine if fMRI can be employed to identify children at risk for dyslexia several years earlier. Research has indicated that children with a strong family history of dyslexia showed differences in the junction between the parietal and temporal lobe and the cuneiform gyrus compared with children without a family history of the learning disability.  

Gaab and colleagues are at the mid-point of a five-year project. They have imaged 1,000 pre-reading children with a strong family history of dyslexia. During the screening process, they identified children at behavioral risk for dyslexia. They plan to follow children longitudinally and review fMRI exams of children eventually diagnosed with dyslexia to determine if fMRI data could be used to develop a diagnostic tool.

ADHD: A work in progress

ADHD poses many challenges. One of the most significant is an accurate clinical diagnosis, says Xiabo Li, PhD, assistant professor of radiology at the Albert Einstein College of Medicine in New York City. Diagnostic criteria are behavior-based, which can be subjective. The disorder is both under- and over-diagnosed, according to a study published October 2012 in the Journal of Attention Disorders. Results of the 10-year study of more than 10,000 five to 13-year old children found only 39.5 percent of children taking ADHD medication in South Carolina and 28.3 percent in Oklahoma actually met the case definition of ADHD.

In many cases, the hyperactivity or impulsivity component of ADHD is fairly obvious from a behavioral perspective. In contrast, inattention symptoms are quite diverse and can be confused with symptoms of other co-morbid disorders.

Li believes fMRI could help reduce the uncertainty and offer a reliable imaging marker for the disorder to provide an earlier, more definitive diagnosis. She has leveraged fMRI to compare the patterns the brain uses to handle attention tasks in healthy children and compare these with children with ADHD to better understand how the ADHD brain behaves in response to the attention load.

Compared with healthy children, brain activation maps of children with ADHD showed increased involvement of the anterior cingulate cortex and decreased and disrupted functional connectivity between the frontal lobe and parietal lobe.

Li envisions a potential broad role for fMRI as the technology that could inform early diagnosis and perhaps targets for treatment. Although she predicts a role for fMRI in the diagnostic work-up of children suspected of having ADHD, the timeline is uncertain as the technology must be validated.

From structure to function, measurement to treatment

Carrie J. McAdams, MD, PhD, a neuroscientist at University of Texas Southwestern Medical Center in Dallas, and her colleague Dan Krawczyk, PhD, a cognitive neuroscientist at the Center for Brain Health in Dallas, are among the first to apply fMRI to patients with anorexia and bulimia.

The pair has been awarded a National Institutes of Mental Health grant to identify markers for the disorders using fMRI. “We’re interested in how the brain changes when people recover,” says McAdams.

During the study’s first phase, the researchers used fMRI to measure the responses of patients recovering from anorexia to two social cognition tasks. When patients were asked to think about themselves from a social perspective, there was less activation in the precuneous. When they were asked to think about themselves from a physical perspective, there were changes in the dorsal anterior cingulate.

In the next stage, the researchers will compare responses among patients currently struggling with anorexia with responses of patients who have recovered and maintained a healthy weight for one year.

McAdams and Krawczyk hypothesize that there may be changes in blood flow in certain areas of the brain among patients with anorexia. Potential treatments might activate that area. Thus, the model is not diagnostic. Instead, the researchers hope to use fMRI to identify general targets for therapy.

Roles for rads

Radiologists have been slow to wade into the unfamiliar territory of fMRI; most research and applications have been dominated by neurology and psychology. “The radiology profession needs to define the extent to which it wants to become involved in fMRI,” says Thomas T. Liu, PhD, director of the University of California San Diego Center for Functional MRI.  

McAdams and Krawczyk see potential roles in fMRI for radiologists. For example, radiologists could help develop techniques to analyze functional data, or they might offer input into an fMRI checklist that would help researchers gather basic functional data.

One roadblock to greater involvement among radiologists is lack of expertise. Many radiologists don’t know how to complete fMRI post-processing or assess the results. “This is out of the comfort zone for traditional radiologists, who are used to interpreting images rather than signals,” explains Hirsch.

This knowledge gap is tied to a lack of training. fMRI techniques have not been embedded into the mainstream radiology curriculum, so despite interest among residents, fMRI tends to fall under the educational radar, says Hirsch.

Another challenge relates to the difference between fMRI and other advanced imaging modalities, which provide results in units of physical measurement, such as diffusion rates of water, uptake of tracers or concentrations of metabolites. In contrast, fMRI results are based on the percentage difference between an active state and an empirically determined baseline characterized by a lack of activity.

Unlike radiologists, other members of the radiology team have established their expertise. At Boston Children’s, MR technologists play an important role in fMRI research. “It’s challenging because children are not sedated and have to remain still for 30 minutes,” says Gaab. The hospital constructed an MR simulator, a mock spaceship, to help children prepare for the exam. The goal is to help them adjust to the sounds of the scanner and understand the importance of remaining still during the scan. 

It is likely that these research projects will take several years or longer to bear clinical fruit. However, new possibilities will continue to emerge. If and how radiologists are involved remains to be seen. HI