RESEARCH UPDATE

Unlike schizophrenia, in which ventricular enlargement is a well-established anatomic finding, there are no clear anatomic findings in standard brain imaging in bipolar disorder (eg, CT or MRI). But new techniques in neuroimaging are providing clues about what is different in the brains of individuals with bipolar disorder.

Early functional imaging approaches included single photon emission computed tomography (SPECT) scans and positron emission tomography (PET) scans. Then came functional MRI (fMRI). Because increased neuronal activity increases blood flow, that flow rate can be used to reflect which regions of the brain are active, relative to other regions, or relative to a resting state. Functional MRI can quantify and image cerebral blood flow rate in several ways.

Using fMRI, several regions of the brain have been consistently shown to function differently in people with bipolar disorder. In a masterful review, Mary Phillips and Holly Swartz of the University of Pittsburgh and the Western Psychiatric Institute and Clinic summarized the main findings to date (Table).1

But that was 2014. What has happened since? Using a variation on functional MRI that allows the quantification of “functional connectivity,” several new findings have emerged, one of which comes very close to providing a noninvasive “lab test” for bipolar disorder. In this technique, brain activity in different regions of the brain is compared, looking for interactions: eg, when one brain region is active, so is another; or when one region is active, another region decreases its activity.

Several new findings have emerged, one of which comes very close to providing a noninvasive “lab test” for bipolar disorder.

These relationships can be detected through statistical analysis of fMRI data, then quantified and even imaged: not the raw brain activity, but rather the interaction between 2 regions. Effectively, this defines a functional circuit. Activity in these circuits can then be compared between patients with bipolar disorder and healthy controls, or patients with other mental illnesses; or between mood states, within a given patient with bipolar disorder.

This technique has been further refined in a recent study from Dr. Phillips and a team of pediatric bipolar researchers from diverse institutions.2 As always, new findings like these must be interpreted with great caution. Replication is needed before even beginning to consider clinical application. The technique is likely to undergo considerable further refinement. Nevertheless, the results even now are tantalizing.

Clinicians and researchers alike are always looking for a research test that provides a number, a clear objective finding, that goes in one direction (up or down) in patients with bipolar disorder, and in the opposite direction in healthy controls. It would likewise be important that this result also discriminates those with bipolar disorder, and those with similar conditions, such as ADHD.

Functional connectivity studies appear now to have provided such a test, comparing subjects’ response to controls.3 When presented with faces versus simple shapes, in healthy controls activity in the amygdala is generally the inverse of activity in left ventrolateral prefrontal cortex (VLPFC): when the amygdalae are more active, left VLPFC activity goes down.

But in individuals with bipolar disorder, this inverse relationship can be absent, and sometimes goes in the opposite direction: increased activity in the amygdala is associated with increased activity in the VLPFC. Opposite signals with the same lab test-that’s what we need.

Moreover, this study demonstrated large differences in functional connectivity between the amygdalae and left VLPFC not only between subjects with bipolar disorder and healthy controls, but also between those with bipolar disorder and those with ADHD.

For example, functional connectivity between the amygdala and VLPFC in bipolar subjects was +1.1 (don’t sweat the units, it’s complicated, certainly beyond me; but note the positive correlation). By contrast, given the same stimuli, the functional connectivity was negative 0.8 in controls and negative 1.1 in subjects with ADHD (P < .001 and .0001, respectively).

Don’t try this at home

Unfortunately, this kind of neuroimaging and associated data-crunching is complicated. Conducting the research paradigm perfectly is important to be able to see any results at all, because even a simple motion artifact can wipe out real differences and create spurious ones.4 So this approach is not soon going to be a laboratory test that you can order, even if you have a sophisticated MRI team in your hospital.

Why describe it then? Because when a finding is this powerful in its ability to differentiate one diagnosis from another, not just bipolar disorder from healthy controls, we are closer to identifying key brain differences that could shed light on the nature of this paradoxical illness. We can thank Dr. Phillips and her many colleagues for pursuing this work and look forward to further important findings.

ACKNOWLEDGMENTS

Thanks to my hospital (Good Samaritan, in Corvallis, OR), I have the privilege of working with a fantastic librarian, a luxury not often found outside academe. But imagine the privilege of requesting a journal article and receiving it within less than an hour. My continued thanks to Kenneth H. Willer, MLS, for these services, including obtaining the key references cited here, and his remarkable alacrity.

Disclosures:

Dr. Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, Ore. He is the Bipolar Disorder Section Editor for Psychiatric Times. Dr. Phelps stopped accepting honoraria from pharmaceutical companies in 2008 but receives honoraria from McGraw-Hill and W.W. Norton & Co. for his books on bipolar disorders.

References:

1. Phillips ML, Swartz HA. A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. Am J Psychiatry. 2014;171:829-843.

2. Hafeman D, Bebko G, Bertocci MA, et al. Amygdala-prefrontal cortical functional connectivity during implicit emotion processing differentiates youth with bipolar spectrum from youth with externalizing disorders. J Affect Disord. 2016;208:94-100.

3. Manelis A, Ladouceur CD, Graur S, et al. Altered functioning of reward circuitry in youth offspring of parents with bipolar disorder. Psychol Med. 2016;46:197-208.

4. Power JD, Barnes KA, Snyder AZ, et al. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage. 2012;59:2142-2154.