Anterior cingulate cortical volumes and treatment remission of geriatric depression.

Geriatric depression is a syndrome often characterized by a slow response to treatment, a failure to fully remit, and a high propensity for relapse (Dew et al., 2007, Little et al., 1998, Whyte et al., 2004). A number of neurobiological abnormalities, particularly in frontolimbic networks, often are present in the illness; however, the specific contributions of these abnormalities to the clinical presentation and the course of the illness remain unclear. MRI can be used to elucidate the pathophysiology of geriatric depression by identifying structural abnormalities that are not merely present in depressed patients, but are also related to treatment response. Among the frontolimbic networks that are implicated in depressive syndromes in the elderly, the anterior cingulate cortex (ACC) may play a key role (Alexopoulos et al., 2008a). The anterior cingulate appears to be critical in the interaction of dorsal/cortical and ventral/limbic networks that are integral to the experience and regulation of emotion (Phillips et al., 2003, Phillips et al., 2008). Based on convergent data from cytoarchitectural, lesion, and functional connectivity studies, the ACC can be divided into two major subdivisions: the dorsal ACC (BAs 24b’-c’ and 32′) and the perigenual ACC (rostral BAs 24a–c and 32, and subgenual areas BAs 25 and 33) (Devinsky et al., 1995, Vogt et al., 1992). The dorsal ACC subdivision projects to the prefrontal cortex and plays a critical role in executive functions by influencing multiple cognitive processes that include response selection, cognitive inhibition, conflict monitoring and resolution, novelty detection, working memory, and error detection (Botvinick et al., 2004, Bush et al., 2000, Carter et al., 1998, Carter and van Veen, 2007, Drevets, 1998, Stuss et al., 2001). The perigenual ACC subdivision projects directly to the amygdala, periaqueductal gray, nucleus accumbens, hypothalamus, anterior insula, hippocampus and orbitofrontal cortex (Devinsky et al., 1995). The perigenual ACC is involved in assessing the salience of emotional input and the regulation of emotional responses (Drevets, 1998, Etkin et al., 2006, Whalen et al., 1998) Structural MRI studies have revealed volume reductions in the ACC of elderly depressed patients (Ballmaier et al., 2004, Elderkin-Thompson et al., 2008, Lavretsky et al., 2007). In addition to smaller volumes, functional neuroimaging suggests that depression is associated with abnormal activation of the ACC that is characterized by increased metabolism/activation in the subgenual and rostral anterior cingulate and hypometabolism/hypoactivation of the dorsal anterior cingulate (Aizenstein et al., 2008, de Asis et al., 2001, Drevets et al., 2002, Holthoff et al., 2004, Kennedy et al., 2001, Mayberg et al., 1999, Smith et al., 1999, Takami et al., 2007) Neuroimaging studies suggest that the anterior cingulate cortex may play a role in the response of depressive symptoms to treatment. Improvement of depression is often associated with at least partial normalization of abnormal activation of the anterior cingulate (Aizenstein et al., 2008, Drevets et al., 2002, Holthoff et al., 2004, Kennedy et al., 2001, Kennedy et al., 2007, Mayberg et al., 1999, Robertson et al., 2007, Saxena et al., 2002). In young and middle aged adults, smaller volumes of the dorsal and rostral ACC are associated with greater symptom severity during depressive episodes, whereas smaller volumes of the subgenual ACC predict poor treatment response (Chen et al., 2007). Although diffusion tensor imaging (DTI) studies of elderly depressed patients suggest that reduced white matter integrity lateral to the dorsal and rostral ACC is associated with failure to remit with antidepressant treatment (Alexopoulos et al., 2002, Alexopoulos et al., 2008b), studies that examine the relationship between anterior cingulate gray matter volumes and treatment response in geriatric patients are lacking. The rationale for this study is that structural abnormalities of the anterior cingulate may perpetuate depressive symptoms, and, thus, contribute to poor treatment response. Thus, we hypothesized that depressed elders who fail to achieve remission during treatment with escitalopram would have smaller gray matter volumes in the anterior cingulate than those who remit with treatment. Based on the evidence that relatively functionally distinct subregions of the ACC exist, we explored the relationship of treatment response to 4 regions of interest (ROIs); dorsal ACC, rostral ACC, anterior subgenual ACC, and posterior subgenual ACC.