Kaan Yucel

Bilateral Hippocampal Volume Increase in Patients with Bipolar Disorder and Short-term Lithium Treatment

Most previous magnetic resonance imaging (MRI) studies of patients with bipolar disorder (BD) report similar hippocampus (HC) volumes across patients and controls, but because patients studied were heterogeneous with respect to course of illness variables and medication status, the conclusions of these studies remain equivocal. Lithium (Li) is the reference-standard drug for BD and its role as an important agent in neuroprotection and neurogenesis has been documented in human and in animal studies. We compared the volume of the HC, hippocampal head (Hh), and body/tail (Hbt) in three groups with no history of medication use before entry into this study: (a) a group of patients treated with Li for 1–8 weeks and then scanned; (b) a group comprised of patients who were unmedicated at the time of scan; and (c) a group of patients treated with either valproic acid or lamotrigine. Healthy age- and sex-matched comparison subjects were also scanned. HC volumes did not differ between the unmedicated and healthy comparison groups. There was a bilateral increase in volumes of HC and Hh in the Li-treated group compared to the unmedicated group, an effect that was apparent even over a brief treatment period. Our study provides further confirmation that Li can exert structural effects on the HC, which are detectable in vivo. The study emphasizes the need to control for even brief exposure to medication in volumetric studies of the HC.

Anterior Cingulate Volumes in Never-Treated Patients with Major Depressive Disorder

The anterior cingulate cortex (ACC) is implicated in the cognitive and affective abnormalities observed in mood disorders. Bilateral ACC volume reductions have been reported in patients with major depressive disorder (MDD) when compared to healthy controls. We compared regional brain volumes in the subgenual prefrontal cortex (SGPFC; Brodmann area (BA) 24sg), subcallosal gyrus (BA25), and paracingulate gyrus (BA32) in 65 patients receiving a first course of treatment for MDD and 93 healthy control subjects. Patients with more than three episodes of untreated MDD had smaller subcallosal gyrus volumes than healthy controls, while those with three or fewer past untreated episodes did not differ from controls. We also found preliminary evidence that medication-exposed patients had smaller SGPFC volumes than patients with no exposure to medication and healthy controls. There was no evidence that these effects related to mood state, duration of untreated illness, or to patient age. No differences were apparent in paracingulate gyrus volumes between patients and controls. These findings confirm the presence of ACC volume reductions in untreated patients with MDD and suggest that illness burden and short-term medication exposure mediate this change.

Hippocampal metabolic abnormalities at first onset and with recurrent episodes of a major depressive disorder: A proton magnetic resonance spectroscopy study☆

The neural underpinnings of major depressive disorder (MDD) are unknown but there is evidence for structural alteration in the hippocampus that may become more pronounced over the course of illness. The aim of the present study was to examine metabolite levels of N-acetyl-aspartate (NAA), Myo-inositol (MI), Glutamate-glutamine (Glx) and choline-containing compounds (GPC and GPC+PCh) in patients presenting for first treatment of a depressive episode compared to those with multiple past episodes and age and sex matched controls. We used single voxel proton magnetic resonance spectroscopy ((1)H-MRS) centered on the hippocampus. Choline-containing compounds were significantly increased in patients with a high past illness burden relative to controls after controlling for hippocampal volume. The group presenting for first treatment had only increases in MI levels compared with matched controls. These results suggest that abnormal membrane turnover in the hippocampus is greater in patients with highly recurrent illness, and provide support for the hypothesis that there are neuronal changes in this region over the course of illness.

Increased subgenual prefrontal cortex size in remitted patients with major depressive disorder

Bilateral reductions in the volume of the anterior cingulate cortex have been reported in patients with major depressive disorder (MDD) when compared with findings in healthy controls. We compared regional brain volumes in the subgenual prefrontal cortex (SGPFC; Brodmann area (BA) 24(sg)), subcallosal gyrus (BA25) and paracingulate gyrus (BA32) in healthy control subjects and a large and well-characterized sample of patients with recurrent MDD, all of whom had received extensive antidepressant therapy. Patients with a remitted episode of MDD had SGPFC volumes larger than those of healthy controls, while those in an active illness episode did not differ from controls. There were no differences in subcallosal gyrus and paracingulate gyrus volumes between patients with MDD and healthy controls, with the exception that women with MDD had smaller paracingulate volumes than their sex-matched controls. This effect was not related to duration of illness, number of previous episodes, age at illness onset, or age at the time of scanning. Our findings demonstrate SGPFC volume increases in association with long-term antidepressant therapy and suggest that this result may be linked to positive clinical response.

Subgenual anterior cingulate cortex and hippocampal volumes in depressed youth: The role of comorbidity and age

OBJECTIVES Many studies have reported that adults with recurrent major depressive disorder (MDD) have smaller hippocampal volumes than control participants. The data are more variable in youth with MDD, where findings have been inconsistent and the effects of factors such as age and co-morbidity have not been systematically examined. This study therefore assessed hippocampus and subgenual anterior cingulate (sgACC) morphometry in 168 youth, aged 12-25, with or without MDD and comorbid anxiety. METHODS Structural magnetic resonance imaging (MRI) scans and clinical assessments were obtained from 80 participants with MDD (36 with comorbid anxiety disorder) and 88 age-matched control participants. RESULTS Participants with MDD had smaller right hippocampi than controls (p=.013). Older depressed participants (20.1-25 years) had smaller hippocampal volumes than younger ones (<20.1 years; p=.05); this age effect was not apparent in controls (p=.46). Depression scores, indexed by the HAMD17, correlated with hippocampal volumes in older depressed youth. Depressed participants with comorbid anxiety had smaller sgACC, but not hippocampal, volumes than those without anxiety (p=.042). LIMITATIONS Longitudinal, versus cross-sectional, studies can most optimally assess the influence of depression on neurodevelopmental profiles. Though our participants were largely treatment-naïve or in their first week of pharmacotherapy, a handful had extensive treatment histories; thus, treatment history may have influenced brain morphometry. CONCLUSIONS Age effects were apparent when hippocampal volumes of older and younger participants with MDD were compared; such differences were not apparent in healthy participants. Comorbid anxiety was associated with decreased sgACC volumes suggesting delayed or altered neurodevelopment in a key emotion regulation region.

Shift in the brain network of emotional regulation in midlife women: is the menopausal transition the turning point?

Objective:The menopausal transition is marked by hormonal changes and is quite often accompanied by cognitive and emotional complaints. Recent data also suggest a heightened risk for depression. Little is known about the changes in emotional regulation that might contribute to the increased risk of depression in this population. The aim of this study was to examine the brain correlates of emotional regulation in healthy, nondepressed midlife women. Methods:Functional magnetic resonance imaging was obtained in response to a standardized emotional regulation task. Levels of congruency were set and brain activation was measured during high- and low-conflict-resolution trials. Results:Fourteen women aged 40 to 60 years were enrolled into the study, and 11 were included in the final analyses. Activity associated with resolution of emotional conflict was observed in the dorsolateral prefrontal cortex (P < 0.05). No regions were engaged in the generation/monitoring of emotional conflict. Moreover, there was a significant deactivation of the amygdala in response to fearful faces (P < 0.05). Conclusions:Unlike similar studies in younger populations, these results suggest a more significant engagement of the dorsolateral prefrontal cortex and less amygdala activation in emotional regulation in midlife women. These findings are, however, consistent with previous studies in older populations. We hypothesize that a shift in emotional regulation circuitry might therefore occur in women during the menopausal transition and possibly contribute to the occurrence of mood and anxiety symptoms in women during/after this period in life.