Abnormal Functional Connectivity of Amygdala in Late-Onset Depression Was Associated with Cognitive Deficits

<div><p>Background</p><p>Major depressive disorder (MDD) is associated with decreased function of cortico-limbic circuits, which play important roles in the pathogenesis of MDD. Abnormal functional connectivity (FC) with the amygdala, which is involved in cortico-limbic circuits, has also been observed in MDD. However, little is known about connectivity alterations in late-onset depression (LOD) or whether disrupted connectivity is correlated with cognitive impairment in LOD.</p><p>Methods and Results</p><p>A total of twenty-two LOD patients and twenty-two matched healthy controls (HC) underwent neuropsychological tests and resting state functional magnetic resonance imaging (rs-fMRI). Regional homogeneity (ReHo) and FC with bilateral amygdala seeds were used to analyze blood oxygen level-dependent fMRI data between two groups. Compared with HC, LOD patients showed decreased ReHo in the right middle frontal gyrus and left superior frontal gyrus. In the LOD group, the left amygdala had decreased FC with the right middle frontal gyrus and the left superior frontal gyrus in the amygdala positive network, and it had increased FC with the right post-central gyrus in the amygdala negative network. However, significantly reduced FC with the right amygdala was observed in the right middle occipital gyrus in the amygdala negative network. Further correlative analyses revealed that decreased FC between the amygdala and the right middle occipital gyrus was negatively correlated with the verbal fluency test (VFT, <i>r</i> = −0.485, <i>P</i> = 0.022) and the digit span test (DST, <i>r</i> = −0.561, <i>P</i> = 0.007).</p><p>Conclusions</p><p>Our findings of reduced activity of the prefrontal gyrus and abnormal FC with the bilateral amygdala may be key markers of cognitive dysfunction in LOD patients.</p></div

Maps of functional connectivity with Amygdala in the results of one sample t-test.

<p>Resting state left amygdala FC pattern for (a) LOD group, (b) HC group. Resting state right amygdala FC pattern for (c) LOD group, (d) HC group. Corrected with Monte Carlo simulation, P<0.05, Cluster size is more than 119 voxels.</p

Maps of functional connectivity of Amygdala.

<p>(a) Decreased functional connectivity of left amygdala positive network in LOD compared with HC with a corrected threshold of <i>P</i><0.05, determined by Monte Carlo simulation. Cluster size is more than 119 voxels. (b) Increased functional connectivity of left amygdala negative network in LOD compared with HC with a corrected threshold of <i>P</i><0.05, determined by Monte Carlo simulation. Cluster size is more than 77 voxels. (c) Decreased functional connectivity of right amygdala negative network in LOD compared with HC with a corrected threshold of <i>P</i><0.05, determined by Monte Carlo simulation. Cluster size is more than 86 voxels. (d) − (e) Significant negative correlation between FC with right amygdala and VFT/DST. VFT: Verbal fluency test; DST: digit span test; <i>r</i> = spearman’s correlation coefficient.</p

Demographic and neuropsychological data between LOD group and HC group.

<p>LOD: late-onset depression; HC: healthy controls; MMSE: Mini mental state exam; HAMA: Hamilton Anxiety Scale; HAMD: Hamilton Depression Scale; AVLT-delayed recall: Auditory Verbal Learning Test-delayed recall; SDMT: Symbol digit modalities test; DST: Digit span test-forward and backward; VFT: Verbal fluency test-animal and verb; TMT-A: Trail making test-A; TMT- B: Trail making test- B.</p>a<p>Independent-samples t-test.</p>b<p>Chi square test.</p>c<p>Analysis of covariance.</p

Reduced ReHo in late onset depression compared with healthy controls with voxels with <i>P</i><0.05 and cluster size is more than 148 voxels, determined by Monte Carlo simulation,age, gender and education level as covariates.

<p>Reduced ReHo in late onset depression compared with healthy controls with voxels with <i>P</i><0.05 and cluster size is more than 148 voxels, determined by Monte Carlo simulation,age, gender and education level as covariates.</p

The result of one sample t-test in amygdala functional connectivity for LOD group and HC group.

<p><b>Note:</b> A corrected threshold of p<0.05 determined by Monte Carlo simulation was taken as meaning there was a significantly difference. Cluster size is more than 389 voxels. R  =  right; L  =  left; cluster size is in mm³.</p

Significant Correlations between Neuropsychological Measurements and ReHo/FC with Amygdala in HC group.

<p>Note: this table only showed the significant correlations by Spearman's correlation. *: <i>P<</i>0.05.</p

Reduced ReHo in LOD group compared with HC group.

<p><b>Note:</b> A corrected threshold of p<0.05 determined by Monte Carlo simulation was taken as meaning there was a significantly difference between groups. R  =  right; L  =  left; cluster size is in mm³.</p

Abnormal functional connectivity of bilateral amygdala in LOD group compared with HC group.

<p><b>Note:</b> A corrected threshold of p<0.05 determined by Monte Carlo simulation was taken as meaning there was a significantly difference between groups. R  =  right; L  =  left; cluster size is in mm³.</p

Data_Sheet_1_Distinct Features of Cerebral Blood Flow and Spontaneous Neural Activity as Integrated Predictors of Early Response to Antidepressants.docx

AimsThe purpose of this study is to explore whether pre-treatment features of brain function can discriminate non-responders to antidepressant medication in the early phase.MethodsForty-four treatment-responsive depressed (RD) patients, 36 non-responsive depressed (NRD) patients, and 42 healthy controls (HCs) were recruited. Regional cerebral blood flow (CBF) and amplitude of low-frequency fluctuation (ALFF) values were calculated for all subjects. Correlation analyses were used to explore the relationship between symptom improvement and CBF/ALFF. Receiver operating characteristics (ROC) and the 10-fold cross-validation support vector machine (SVM) classifier were applied for the discrimination of treatment response.ResultsCompared with the HCs, the RD and NRD groups exhibited lower CBF and ALFF in the right posterior lobe of the cerebellum. Compared with the NRD group, the RD group showed distinct CBF patterns in the left frontal striatal regions and right frontal cerebellar regions, as well as distinct ALFF features in the left frontoparietal striatum and right frontotemporal striatal cerebellar regions. The ROC and SVM classifier revealed the optimal power to distinguish the RD and NRD groups based on the combined measures (i.e., CBF and ALFF).ConclusionDistinct features of CBF and ALFF in the frontal striatal network may serve as promising neuroimaging predictors for identifying patients with blunted responsiveness, which may facilitate personalized antidepressant treatment.</p