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

Abstract

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.

EEG alpha asymmetry as a gender-specific predictor of outcome to acute treatment with different antidepressant medications in the randomized iSPOT-D study

“…Some studies have looked at alpha asymmetry in relation to antidepressant treatment outcome and reported differences between responders and non-responders in mostly non-frontal areas (e.g., occipital sites: Bruder et al, 2008;Ulrich et al, 1986; right greater than left hemisphere alpha: Bruder et al, 2001, but differences were not specific to FAA). Tenke and colleagues conducted a larger study that used current source density measures (Tenke et al, 2011) and did not replicate their earlier alpha asymmetry findings in relation to treatment outcome (Bruder et al, 2008) and a similar null finding was reported by Li et al (2013), for response to rTMS. Interestingly, gender differences have been reported for this measure e.g.…”

A Resting-State Brain Functional Network Study in MDD Based on Minimum Spanning Tree Analysis and the Hierarchical Clustering

“…The asymmetric frontal cortical activity in the MDD group had been widely presented not only in alpha band but also in the theta band [24,77]. Besides EEG study, a combined MEG, PET, and rTMS Study also pointed out that prefrontal left-right functional imbalance and disrupted prefrontothalamic circuitry were plausible mechanisms for the depression [78]. Hierarchical clustering was a useful method to divide the brain functional network into several submodules.…”

Modulation of Intrinsic Brain Activity by Electroconvulsive Therapy in Major Depression

“…Our current results extend these findings by highlighting the importance of dorsal ACC in relation to the thalamus. Indeed, mediodorsal thalamus serves a role in depression (49; 50), perhaps particularly as a major interface between the hippocampus and mPFC mediating regulatory control of emotional and cognitive aspects of behavior and depression (51; 52). Future research cutting across imaging modalities and model systems will be most helpful in integrating these and other findings to inform and improve hippocampal neurotrophic theories (53; 54) and other models (41; 42) of ECT and of depression.…”

“…The mPFC may play a particular role in depression and treatment response (3); the sgACC exhibits volume loss and hyperconnectivity in MD (36; 58; 59), and BA 25 is a current target of deep brain stimulation (DBS) in clinical trials (60). The vmPFC is also modulated by pharmacological treatment of MDD (60; 61), and the ventral striatal loop and mesolimbic reward pathway are implicated in depression (37; 49; 50; 62), including ECT response (42; 62). …”