Hippocampal shape alterations in healthy young women with familial risk for unipolar depression.

BACKGROUND: Although reduced hippocampal volume (HCV) is a common finding in depression, it is unclear whether the structural alterations leading to reduction of HCV are pre-existing risk factors before the onset of clinical symptoms or a cumulative process that begins with the onset of clinical symptoms. The aim of the present study was to understand the anatomical status of the hippocampus prior to the clinical symptoms in subjects with high familial risk for depression. METHODS: Twenty-seven young women (mean age: 22.3 ±â€¯2.1 years) who were at high risk for familial unipolar depression and 26 age- and gender-matched healthy controls (mean age: 22.1 ±â€¯2.1 years) with low familial risk for depression were included in the study. Total hippocampal volumes were measured by manual tracing. For 3D shape differences, the spherical harmonic basis functions (SPHARM) software was used. The segmented images were parameterized, and the point-to-point based group difference was compared by the Hotelling's T-squared test with total brain volume and Beck Depression Scale as covariates. RESULTS: Although there was no difference in overall HCVs, shape analyses revealed a contracted area on the Cornu Ammonis (CA) 1 region of the right hippocampus head in the high-risk group compared to the low-risk group. Cross-sectional design and small sample size, including only females, were the main limitations of this study. CONCLUSION: This study with shape analyses provided data suggesting that local structural hippocampal alterations in the CA1 region might be associated with depression vulnerability in women at high risk.

Brain regions associated with risk and resistance for bipolar I disorder: a voxel-based MRI study of patients with bipolar disorder and their healthy siblings.

OBJECTIVE: Bipolar I disorder is a highly heritable disorder but not all siblings manifest with the illness, even though they may share similar genetic and environmental risk factors. Thus, sibling studies may help to identify brain structural endophenotypes associated with risk and resistance for the disorder. METHODS: Structural magnetic resonance imaging (MRI) scans were acquired for 28 euthymic patients with bipolar disorder, their healthy siblings, and 30 unrelated healthy controls. Statistical Parametric Mapping 8 (SPM8) was used to identify group differences in regional gray matter volume by voxel-based morphometry (VBM). RESULTS: Using analysis of covariance, gray matter analysis of the groups revealed a group effect indicating that the left orbitofrontal cortex [Brodmann area (BA) 11] was smaller in patients with bipolar disorder than in unrelated healthy controls [F = 14.83, p < 0.05 (family-wise error); 7 mm(3) ]. Paired t-tests indicated that the orbitofrontal cortex of patients with bipolar disorder [t = 5.19, p < 0.05 (family-wise error); 37 mm(3) ] and their healthy siblings [t = 3.89, p < 0.001 (uncorrected); 63 mm(3) ] was smaller than in unrelated healthy controls, and that the left dorsolateral prefrontal cortex was larger in healthy siblings than in patients with bipolar disorder [t = 4.28, p < 0.001 (uncorrected); 323 mm(3) ] and unrelated healthy controls [t = 4.36, p < 0.001 (uncorrected); 245 mm(3) ]. Additional region-of-interest analyses also found volume deficits in the right cerebellum of patients with bipolar disorder [t = 3.92, p < 0.001 (uncorrected); 178 mm(3) ] and their healthy siblings [t = 4.23, p < 0.001 (uncorrected); 489 mm(3) ], and in the left precentral gyrus of patients with bipolar disorder [t = 3.61, p < 0.001 (uncorrected); 115 mm(3) ] compared to unrelated healthy controls. CONCLUSIONS: The results of this study suggest that a reduction in the volume of the orbitofrontal cortex, which plays a role in the automatic regulation of emotions and is a part of the medial prefrontal network, is associated with the heritability of bipolar disorder. Conversely, increased dorsolateral prefrontal cortex volume may be a neural marker of a resistance factor as it is part of a network of voluntary emotion regulation and balances the effects of the disrupted automatic emotion regulation system.

Emotional context effect on recognition of varying facial emotion expression intensities in depression.

BACKGROUND: Previous research has indicated that Major Depressive Disorder (MDD) patients have deficits in the process of facial emotion recognition. In most of these studies, isolated emotional faces were used, and the effect of the surrounding context of the face was neglected. We aimed to investigate how context emotion (sad or happy) affects facial emotion recognition and whether this effect is different in depressive individuals compared to the control group. METHODS: Happy, sad, neutral facial expressions with congruent and incongruent visual contexts were presented to 51 MDD patients and 42 matched healthy controls. Emotional facial expressions are presented as morphs gradually expressing happiness or sadness with 40% and 80% intensity levels. Mean reaction time, mean accuracy rate, and mean emotion intensity rating score was calculated for each condition. RESULTS: The performances on facial emotion intensity rating and accuracy rate were similar between MDD patients and controls. MDD patients were slower to recognize all facial emotions and to recognize facial emotions with emotionally incongruent backgrounds compared to congruent ones. LIMITATIONS: Antidepressant therapy of patients might have affected our results. CONCLUSIONS: Emotional contextual features have an important role in facial emotion recognition but this effect is independent of depression. Longer reaction time in depression may be related to some cognitive impairments.

Correlation of serum BDNF levels with hippocampal volumes in first episode, medication-free depressed patients.

The hippocampus seems to be affected in MDD, and brain-derived neurotrophic factor (BDNF) has positive effects on neurogenesis within the hippocampus. Although there are inconsistencies among study results, a smaller hippocampal volume in depressed patients is thought to be related to the pathophysiology of the disease. We looked at the correlation between serum BDNF (sBDNF) levels and hippocampal volumes (HCV) of first-episode MDD patients (18 female, 7 male; mean age = 32.1 ± 9.3) and healthy controls (17 female, 5 male; mean age = 29.7 ± 6.4). Region of interest analysis was conducted on the images acquired via MRI. sBDNF levels and HCV correlated only in the MDD group (right: r = 0.46, P = 0.02; left: r = 0.47, P = 0.02); however, HCV did not differ between MDD patients and healthy controls (right: F = 2.45, df = 1.46, P > 0.05; left: F = 0.05, df = 1.46, P > 0.05). BDNF may be a factor underlying HCV differences between MDD and healthy control subjects, which become apparent as severe and multiple episodes are experienced.

No pituitary gland volume change in medication-free depressed patients.

Increased serum cortisol levels and a hyperactive hypothalamo-pituitary-adrenal (HPA) axis have been proposed to play an important role in the pathophysiology of Major Depressive Disorder (MDD). However, there are inconsistent results regarding pituitary gland volume (PGV), which is one of the key elements of the HPA axis evaluated by MRI in depressed patients. In this study, we analyzed the PGV of medication-free moderately depressed MDD patients (N=34) and age and sex matched healthy controls (N=39). PGV did not differ between MDD patients and healthy controls [mean volume+/-S.D.; 0.76+/-0.17 cm3 and 0.75+/-0.14 cm3; ANCOVA, F1,69=1.25 p>0.05; respectively]. Our results confirm that volumetric PGV changes are not crucial for depression pathophysiology among unmedicated, moderately depressed adults.

The effect of antidepressant treatment on N-acetyl aspartate levels of medial frontal cortex in drug-free depressed patients.

The medial frontal cortex has been shown to modulate emotional behavior and stress responses, suggesting that the dysfunction of this region may be involved in the pathogenesis of depressive symptoms. The present study was performed to determine whether there was any effect of antidepressant treatment on the metabolite levels in the left medial frontal cortex as measured by proton magnetic resonance spectroscopy in depressed patients. Twenty patients diagnosed as having major depressive disorder according to DSM-IV and 18 healthy volunteer subjects were included in the study. Twelve of patients had their first episode and were drug-naïve. Other depressed patients were drug-free for at least 4 weeks. The severity of depression was assessed by HAM-D and Clinical Global Impression Scale-Severity (CGI-S). Single voxel, 8 cm(3), 1H MR spectra of left medial frontal cortex was acquired both before and following antidepressant treatment. The concentrations and ratios of N-acetyl aspartate (NAA), Creatine+Phosphocreatine (Cr+PCr) and Choline (Cho) were measured. Pretreatment NAA/Cr values of patients were lower than those of healthy controls, but this difference did not reach to statistically significant levels (t=1.83, df=36, p=0.07). However, antidepressant treatment had significant effect on NAA/Cr ratios (groupxtreatment interaction: F=9.93 df=1,36, p=0.03). After the treatment, NAA/Cr values of patients increased significantly compared to pretreatment values (t=3.32, df=19, p=0.004). No significant difference was observed between the post-treatment NAA/Cr values of patients and those of controls (t=1.64, df=36, p=0.19). Correlation analysis detected negative correlation between pretreatment CGI-S scores and NAA/Cr ratios (r=-0.51, p=0.02). This preliminary result suggests that there might be a possible defect in the neuronal integrity in the left medial frontal cortex (mainly left anterior cingulate cortex) of depressed patients. Antidepressant treatment with its neurotrophic effects might play a positive role in restoring the neuronal integrity. Further studies are needed to support these initial findings.

Cortical thickness and VBM in young women at risk for familial depression and their depressed mothers with positive family history.

It has been demonstrated that compared to low-risk subjects, high-risk subjects for depression have structural and functional alterations in their brain scans even before the disease onset. However, it is not known if these alterations are related to vulnerability to depression or epiphenomena. One way to resolve this ambiguity is to detect the structural alterations in the high-risk subjects and determine if the same alterations are present in the probands. In this study, we recruited 24 women with the diagnosis of Major Depressive Disorder (MDD) with recurrent episodes and their healthy daughters (the high-risk for familial depression group; HRFD). We compared structural brain scans of the patients and HRFG group with those of 24 age-matched healthy mothers and their healthy daughters at similar ages to the HRFD group; respectively. Both cortical gray matter (GM) volume and thickness analyses revealed that HRFD daughters and their MDD mothers had similar GM differences in two regions: the right temporoparietal region and the dorsomedial prefrontal cortex. These results suggested that the observed alterations may be related to trait clinical and neurophysiological characteristics of MDD and may present before the onset of illness.

Altered hippocampal formation shape in first-episode depressed patients at 5-year follow-up.

It is generally accepted that patients with major depressive disorder have smaller hippocampus size compared to healthy people. However, it is still not known if this situation exists before the onset of the disease or is a result of the toxic mechanism created by the depression itself. The findings of the long-term follow-up studies of first-episode depressed patients might contribute to solve the ongoing problem. In this study, the hippocampus of 18 first-episode patients who were followed-up for 5 years, were compared with those of healthy controls. There were no volumetric differences among groups neither at the baseline nor after 5 years of follow-up. However, shape analyses, using high dimensional mapping methods, revealed regional structural changes in the head and tail of the hippocampal formation in CA1 and subiculum regions in patients at the follow-up. Furthermore, a significant negative correlation was found with the number of days in depression without antidepressant treatment in the CA1 region in the head and tail of the hippocampal formation bilaterally. The findings of this study support the hypothesis that pathophysiological processes of depression induce structural alterations in depressed patients.

Volumetric MRI studies of the hippocampus in major depressive disorder: Meanings of inconsistency and directions for future research.

There are numerous magnetic resonance imaging (MRI) studies investigating the hippocampal volumetric differences between depressed and healthy subjects. Although there are inconsistencies among study results, a smaller hippocampal volume in depressed patients is thought to be related to the pathophysiology of the disease. Many factors appear to affect hippocampal volumes in major depressive disorder patients. Among these factors, recurrency, severity and the individual patient are the most pronounced. Patient groups with a mean age older than 40 years, or samples consisting of patients who have had severe or multiple episodes are more likely to demonstrate smaller hippocampal volumes. The possible causes of this relationship are discussed to give new perspectives to future research.

The effect of depression, BDNF gene val66met polymorphism and gender on serum BDNF levels.

OBJECTIVE: To determine the effect of BDNF gene val66met polymorphism on serum BDNF levels in drug-free patients with major depressive disorder (MDD) and healthy subjects, that differ by gender. METHODS: Sixty-six drug-free patients (19 males+47 females) with non-psychotic MDD and fifty-six healthy controls (18 males+38 females) were recruited. Three-way ANOVA was employed to analyze the effect of mental health status, met-carriage and gender on Hamilton Depression Rating Scale (HDRS) scores and serum BDNF levels, by using the MIXED Procedure (SAS). RESULTS: Patients had a lower serum BDNF level than healthy subjects (22.47 vs. 27.49; p<0.0001). Met-carrier patients had a higher HDRS score than Val homozygote's (25.99 vs. 22.99, p<0.02). Serum BDNF level for met-carrier subjects (patients+controls) was lower than Val homozygote subjects (23.08 vs. 26.87; p<0.002). However, there were no effects of two-way interactions of met-carriage and mental health status on HDRS scores and serum BDNF levels. There was no gender effect on HDRS scores in the patients. Overall, male subjects (patients+controls) had a higher serum BDNF level than female subjects (26.87 vs. 23.08; p<0.002). However, there were no effects of two-way interactions of gender with mental health status and met-carriage on serum BDNF levels. CONCLUSIONS: We replicated the previous findings of lower serum BDNF levels during depression and in females. In addition, we found that met-carriage had an effect in reducing serum BDNF levels, regardless of gender and depression. Further animal and human studies with a larger sample size should investigate whether BDNF val66met polymorphism could alter brain and serum BDNF levels.

Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients.

Researchers have reported that serum brain-derived neurotrophic factor (sBDNF) of drug-free depressed patients are lower than those of healthy controls and proposed that low sBDNF levels might reflect failure of neuronal plasticity in depression. In this study, we compared sBDNF levels of depressed patients (n = 28) before and after 8 weeks of antidepressant treatment, with those of healthy controls (n = 18) to test the hypothesis that initially low sBDNF levels of drug-free depressed patients will increase parallel with their clinical response to antidepressant treatment. The severity of depression and response to treatment were assessed with Hamilton Rating Scale for Depression (HAM-D). sBDNF was assayed with the sandwich ELISA method. Baseline sBDNF levels of patients (mean, 20.8 ng/ml; [S.D., 6.7]) were significantly lower than those of controls (mean, 26.8 ng/ml; [S.D., 9.3]; p = 0.015), and were negatively correlated with HAM-D scores (r = -0.49, p = 0.007). After 8 weeks of treatment, sBDNF levels of patients had increased significantly (mean, 33.3 ng/ml; [S.D., 9.9]; p < 0.001) and no longer differed from those of controls. These results support the hypothesis that BDNF might play a critical role in the pathophysiology of major depressive disorder and successful antidepressant treatment increases the attenuated BDNF levels in depressed patients.