Fronto-insular network and prefrontal GABA levels following targeted transcranial theta-burst magnetic stimulation

Abstract

Background and Aims: Recent neuroimaging studies have identified the insula as a key brain region in the pathophysiology of depression and may be a crucial target for the treatment of depression [1]. The modulation of insular networks may have widespread effects on the connectivity of other disrupted networks, and ultimately reduce symptom burden in depression. In addition, patients with depression have also shown to have altered neurochemistry (e.g. glutamate and GABA) [2]. Neurostimulation approaches have demonstrated that modulation of both cortical connectivity [3] and neurochemistry [4] is possible, though the precise nature of these effects is uncertain. Using a connectivitybased approach, we sought proof of concept for the neuromodulation of the insula through transcranial magnetic stimulation (TMS) and how these effects may be related to GABA changes in the frontal cortex. Our aim was to develop a connectivityinformed neuromodulation approach for TMS to reduce depressive symptom burden. To this end, we report a proof of concept study in healthy controls. Methods: In a sample of 27 healthy controls, we investigated the effects of intermittent theta-burst TMS (iTBS) on frontoinsular effective connectivity using resting-state functional MRI and Granger causal analysis (GCA). We also measured GABA levels in a voxel placed in the left dorsolateral prefrontal cortex (DLPFC) using magnetic resonance spectroscopy. Images were acquired on a GE 3T MR750 scanner and preprocessed using standard procedures. For each subject, GCA was seeded from the right anterior insula (rAI) to locate the highest peak intensity within the left DLPFC, which was used as the neuronavigation target location for iTBS. We also ran an inverse GCA from each individual's DLPFC target region to the rAI to form a reciprocal fronto-insula network. The Granger coefficients were extracted from 6mm spherical regions of interest from both rAI and DLPFC target regions and compared between placebo and real iTBS. GABA (relative to creatine) levels were also compared between placebo and real iTBS and correlated with changes in Granger coefficients. Results: Results showed significant dampening of the putative negative influence of the DLPFC on the rAI following iTBS (p = 0.043). Levels of GABA were also significantly reduced following iTBS (p = 0.041). Furthermore, absolute changes in frontoinsular connectivity induced by iTBS were significantly correlated with absolute changes in GABA (p = 0.002). This suggests that iTBS has a direct effect on the effective connectivity between the DLPFC and rAI via an inhibitory mechanism on the influence of the DLPFC on the rAI, and this functional change may be mediated by changes in GABA levels in frontal regions. Conclusions: Our results demonstrate that the application of a single session of targeted iTBS on the frontal cortex can modulate the effective connectivity of the rAI, a key target region in depression, and additionally produce changes in frontal GABA levels. Moreover, we showed that these changes were inter-related, suggesting that changes in both the fronto-insular circuitry and neurochemistry may underlie the therapeutic effects of iTBS. These findings raise the possibility of targeted Brain Network Modulation to optimise the outcomes of TMS treatment in patients with depression.