Most clinicians are familiar with the use of brain CT scans in an emergency situation: when a patient has an acute change in mental status, we need to rule out a large stroke, mass, or hemorrhage before assuming the problem is psychiatric. Given the limitations of CT scanning (low resolution, poor visibility of posterior structures, many types of pathology look similar), little more is learned. But what about other imaging modalities? How are they being employed to add to the understanding of mood disorders? And when might they be appropriate for general clinical use?

Magnetic Resonance Imaging (MRI)
Conventional MRI can also be used to help rule out organic causes of mood symptoms. Like CT scanning, you may request an MRI to rule out a tumor or a bleed. In particular, when symptoms develop more slowly, you may find MRI useful to address other types of pathology that can present with apathy or cognitive change, such as subdural hematomas, normal pressure hydrocephalus, white matter disease, edema, or severe atrophy suggestive of dementia.

For anatomical fine-tuning, software can measure volumes of specific brain structures. A recent review of MRI findings in mood disorders observed that major depression is often associated with reduced volumes in brain areas known to be involved in emotional processing, as well as an increase in white matter hyper-intensities that are often frustratingly referred to as “nonspecific white matter changes” in radiology reports (Arnone D et al, Eur Neuropsychopharmacol 2012;22(1):1–16). MRI can also be used to investigate the effects of treatment: repetitive transcranial magnetic stimulation (rTMS), for example, may cause neurogenesis in the amygdala and prevent volume loss in the hippocampus, similar to what is seen with antidepressant use (Furtado CP et al, Brain Stimul 2012; online ahead of print).

Cortical thickness can also be assessed with MRI. Recent studies have shown thinning cortex in patients with schizophrenia (van Haren NEM et al, Arch Gen Psychiatry 2011;68(9):871–880), sometimes made worse with antipsychotics (Ho BC et al, Arch Gen Psychiatry 2011;68(2):128–137). Cortical thinning has been reported in mood disorders as well. Older patients with mild forms of depression—a common clinical presentation—demonstrate greater thinning in the right cingulate gyrus than healthy elderly controls. This MRI observation helps establish that geriatric depression may have similar biology to the more classically described forms of depression (Kumar A et al, Am J Geriatr Psychiatry 2012; online ahead of print). More widespread cortical thinning, particularly in aged individuals, may be a consequence of vascular or neurodegenerative processes, and not reflective of a mood disorder.

Currently, MRI is preferred over CT for imaging of mood disorders, but it’s still primarily a research tool. Moreover, your patient may find it costly if insurance won’t pay, and CT remains a reasonable option for ruling out gross pathology. As with all studies, remember that imaging is only useful if its results would change the management of your patient.

Functional MRI (fMRI)
fMRI is an adaptation of MRI that allows real-time imaging of brain activities. fMRI looks at differences in regional cerebral blood flow or blood oxygenation levels, as proxies for metabolism. Like any functional study, fMRI can be done “at rest” to look for baseline abnormalities or while the patient performs a specific task, eg, cognitive tasks that might be impaired in mood disorders. fMRI has been used to look for changes in the brain with particular treatments, to distinguish among possible subtypes of depression, or to ask broader questions about pathophysiology.

One interesting fMRI study investigates the “hyperconnectivity hypothesis,” which suggests that in depression, areas of the brain are too synchronized in their activity levels. fMRI scans of depressed patients before and after successful treatment confirm that average whole-brain functional connectivity decreased when treatment was successful (Perrin JS et al, Proc Natl Acad Sci USA 2012;109(14):5464–5468). While such findings are intriguing, at present fMRI remains primarily a research tool.

Positron Emission Tomography (PET)
PET generates an image by following a radioactive compound that mimics a naturally occurring one. A radioactive sugar molecule, most commonly FDG (fluorodeoxyglucose), “lights up” areas of the brain that are more metabolically active. This approach can be applied to questions about the areas that correlate with symptoms in mood disorders—such as the well-established phenomenon of hypometabolism in the frontal cortex in depressed patients—or about whether and how treatments are having their effect.

A recent study asked whether metabolic abnormalities in certain brain areas of depressed patients would predict response to vagus nerve stimulation (VNS). The finding that rates of glucose metabolism in two particular regions did, in fact, predict response could provide a way to select patients for VNS who are likely to benefit (Conway CR et al, J Affect Disord 2012;139(3):283–290). Another group is using a ligand to the serotonin transporter to test hypotheses about serotonin firing patterns and how this may predict SSRI effects (Lanzenberger R et al, Neuroimag 2012; online ahead of print).

PET may be part of clinical workup in the elderly where dementia and depression can resemble each other; dementia is characterized by reduced glucose metabolism in widespread cortical areas while depression is characterized by more limited deficits. But even there, clinical judgment ultimately rules your management.

Magnetic Resonance (MR) Spectroscopy
Remember the moment of panic in organic chemistry class when you were asked to assign peaks to a nasty looking spectrum? Relax; software and radiologists do the work for you this time. Like PET, MR spectroscopy can be used to examine alterations in neurotransmitters and their receptors, or alterations in patterns of brain metabolism. Markers for cell death, neuronal integrity, or cell membrane turnover, as well as individual neurotransmitters, show characteristic peaks on the proton spectrum. The relative heights of these peaks allow you to draw inferences about changes in the function of small brain regions.

Numerous MR spectroscopy studies have documented changes in brain metabolism in mood disorders. In bipolar disorder, MR spectroscopy has also shown altered intracellular pH even in euthymic individuals (Wiedemann K, Dialogues Clin Neuroscience 2011;13(2):225–234). A review of studies using MR spectroscopy to look at the biology of mood disorders found that the balance of glutamate and glutamine is altered in major depressive disorder, as compared with bipolar disorder, and differs among mood states in bipolar disorder. This suggests a difference in pathophysiology for the two conditions and could be useful in the future as a diagnostic aide (Yuksel C & Ongur D, Biol Psychiatry 2010;68(9):785–794). At present, MR spectroscopy may be a clinical tool in the oncology world, but it remains a research tool when it comes to mood disorders.

Single Photon Emission Computed Tomography (SPECT)
Like PET, SPECT requires injection of a radioactive isotope to generate an image, although it differs in terms of the radiation emitted and the way the image is acquired. While SPECT scanning has its share of proponents, the technology has limited practical application at this time. One recent study looked at healthy volunteers who took citalopram (Celexa) and escitalopram (Lexapro) and found differences in how these two drugs act at the serotonin transporter, possibly explaining clinical differences between the two medications (Kasper S et al, Int Clin Psychopharmacol 2009;24(3):119–125). Other groups are adapting SPECT to identify cortical areas to target in rTMS (Müller H et al, J Depress Anxiety 2012; online ahead of print).

TCPR Verdict: 
It’s possible that, in the future, neuroimaging will increasingly be used to aid in differential diagnosis, probe for comorbid conditions, customize treatment, and look for treatment effects or penetration of drugs into the brain. However, at the moment, most technologies other than structural MRI are predominantly used in research settings. An important caveat when you request an imaging study: as the ordering physician you are responsible for following up on all results, including those outside the scope of your practice. For example, if an MRI shows white matter disease that suggests past infarctions, refer your patient to a primary care provider or a neurologist.