3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity

Increasing evidence has accumulated for structural brain changes associated with unipolar recurrent major depression. Studies of neuroanatomic structure in early-onset recurrent depression have only recently found evidence for depression-associated structural change. Studies using high-resolution three-dimensional magnetic resonance imaging (MRI) are now available to examine smaller brain structures with precision. Brain changes associated with early-onset major depression have been reported in the hippocampus, amygdala, caudate nucleus, putamen, and frontal cortex, structures that are extensively interconnected. They comprise a neuroanatomic circuit that has been termed the limbic–cortical–striatal–pallidal–thalamic tract. Of these structures, volume loss in the hippocampus is the only consistently observed change to persist past the resolution of the depression. Possible mechanisms for tissue loss include neuronal loss through exposure to repeated episodes of hypercortisolemia; glial cell loss, resulting in increased vulnerability to glutamate neurotoxicity; stress-induced reduction in neurotrophic factors; and stress-induced reduction in neurogenesis. Many depressed patients, particularly those with late-onset depression, have comorbid physical illnesses producing a high rate of hyperintensities in deep white matter and subcortical gray matter and brain damage to key structures involved in the modulation of emotion. Combining MRI studies with functional studies has the potential to localize abnormalities in blood flow, metabolism, and neurotransmitter receptors and provide a better integrated model of depression.