Impaired Prefronto-Thalamic Functional Connectivity as a Key Feature of Treatment-Resistant Depression: A Combined MEG, PET and rTMS Study

<div><p>Prefrontal left-right functional imbalance and disrupted prefronto-thalamic circuitry are plausible mechanisms for treatment-resistant depression (TRD). Add-on repetitive transcranial magnetic stimulation (rTMS), effective in treating antidepressant-refractory TRD, was administered to verify the core mechanisms underlying the refractoriness to antidepressants. Thirty TRD patients received a 2-week course of 10-Hz rTMS to the left dorsolateral prefrontal cortex (DLPFC). Depression scores were evaluated at baseline (W0), and the ends of weeks 1, 2, and 14 (W14). Responders were defined as those who showed an objective improvement in depression scores ≥50% after rTMS. Left-right frontal alpha asymmetry (FAA) was measured by magnetoencephalography at each time point as a proxy for left-right functional imbalance. Prefronto-thalamic connections at W0 and W14 were assessed by studying couplings between prefrontal alpha waves and thalamic glucose metabolism (PWTMC, reflecting intact thalamo-prefrontal connectivity). A group of healthy control subjects received magnetoencephalography at W0 (N = 50) to study whether FAA could have a diagnostic value for TRD, or received both magnetoencephalography and positron-emission-tomography at W0 (N = 10) to confirm the existence of PWTMC in the depression-free state. We found that FAA changes cannot differentiate between TRD and healthy subjects or between responders and non-responders. No PWTMC were found in the TRD group at W0, whereas restitution of the PWTMC was demonstrated only in the sustained responders at W14 and euthymic healthy controls. In conclusion, we affirmed impaired prefronto-thalamic functional connections, but not frontal functional imbalance, as a core deficit in TRD.</p></div

Selection of frontal sensors (all colored squares).

<p>Green: left frontal sensors; Orange: right frontal sensors.</p

Demographic data and clinical variables between rTMS responders and non-responders.

<p>Note: MDE, major depressive episode; HDRS-17, 17-item Hamilton depression rating scales; BDI, Beck depression index; <b>^#</b> Significant decreases (pair-<i>t</i> test, p<0.05) as compared to baseline values; *p<0.05, **p<0.005.</p

Correlations between MEG frontal alpha activity and PET glucose metabolism in healthy controls and in depression before and after successful rTMS treatment.

<p>(A) <i>In healthy subjects</i>. Frontal alpha activity correlated well with glucose metabolism in the thalamus (circled in yellow). (B) <i>Before rTMS.</i> Frontal alpha activity correlated well with glucose metabolism in various parts of the prefrontal cortex, but did not correlate with thalamic activity. (C) <i>After successful rTMS treatment</i>. Frontal alpha activity correlated well with glucose metabolism in the thalamus (circled in yellow), brainstem, precuneus, and cingulate cortices. mPFC, medial prefrontal cortex; dACC, dorsal anterior cingulate cortex; MCC, middle cingulate cortex; SMA, supplementary motor area. Brain regions showing significant negative correlations (cluster-level corrected P<0.001) in each condition are shown in red color.</p

rTMS-related metabolic change in responders (<i>3-month vs. baseline</i>).

<p>Responders demonstrated significantly decreased metabolism in the thalamus, midbrain, cerebellum, posterior cingulate cortex (PCC), basal ganglia, occipital cortex, parahippocampus and subgenual anterior cingulate cortex (sgACC). Contrast bar denotes <i>t</i> values. The significance was set at a cluster-level corrected P<0.001 by paired-<i>t</i> tests.</p

rTMS’s cumulative effects on reversing frontal alpha asymmetry (FAA).

<p>FAA of rTMS responders (in red color) and non-responders (in blue color) showed no difference from baseline (W0) to the end of the 1^st week (W1) and the 2^nd week (W2) after initiation of rTMS. In both groups, rTMS decreased FAA in a dose-dependent manner from W0 to W2, despite lack of statistical significance. During the follow-up period from the end of W2 to the 14^th week (W14), no active rTMS was used, and we observed a gradual rebound of FAA to its baseline value in both groups.</p

Altered Resting-State Functional Connectivity of Striatal-Thalamic Circuit in Bipolar Disorder

<div><p>Bipolar disorder is characterized by internally affective fluctuations. The abnormality of inherently mental state can be assessed using resting-state fMRI data without producing task-induced biases. In this study, we hypothesized that the resting-state connectivity related to the frontal, striatal, and thalamic regions, which were associated with mood regulations and cognitive functions, can be altered for bipolar disorder. We used the Pearson's correlation coefficients to estimate functional connectivity followed by the hierarchical modular analysis to categorize the resting-state functional regions of interest (ROIs). The selected functional connectivities associated with the striatal-thalamic circuit and default mode network (DMN) were compared between bipolar patients and healthy controls. Significantly decreased connectivity in the striatal-thalamic circuit and between the striatal regions and the middle and posterior cingulate cortex was observed in the bipolar patients. We also observed that the bipolar patients exhibited significantly increased connectivity between the thalamic regions and the parahippocampus. No significant changes of connectivity related to the frontal regions in the DMN were observed. The changed resting-state connectivity related to the striatal-thalamic circuit might be an inherent basis for the altered emotional and cognitive processing in the bipolar patients.</p></div

The mean functional connectivity across all participants.

<p>(a) The mean 90 90 correlation matrix across all participants. The anatomical locations of 90 ROIs are listed in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096422#pone.0096422.s001" target="_blank">Table S1</a>. The warm colors represent the positive correlations whereas the cool colors represent the negative correlations between ROIs. (b) The modular structure of brain functional connectivity across all participants. This modular pattern is obtained by reordering regions in the mean correlation matrix according to maximizing the strength of connectivity close to the main diagonal of the matrix. Module 6 consisted of 3 striatal regions and 8 thalamus subregions forming the striatal-thalamic circuit. Module 3 consisted of 9 medial frontal regions, 1 temporal region, 7 parietal regions, 1 posterior cingulate cortex and 1 occipital region forming the DMN. The details of the modular structure are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096422#pone.0096422.s002" target="_blank">Table S2</a>.</p

Clinical correlations between the altered functional connectivity and the clinical rating scales.

<p>Clinical correlations between the altered functional connectivity and the clinical rating scales.</p

Significantly changed connectivity related to the striatal-thalamic circuit in bipolar patients.

<p>Significantly changed connectivity related to the striatal-thalamic circuit in bipolar patients.</p