Intermittent Theta-Burst Stimulation Transcranial Magnetic Stimulation Increases GABA in the Medial Prefrontal Cortex: A Preliminary Sham-Controlled Magnetic Resonance Spectroscopy Study in Acute Bipolar Depression

Abstract

Background: Magnetic resonance spectroscopy (MRS) has been used to identify gamma-aminobutyric acid (GABA) alterations in mood disorders, particularly in the medial prefrontal cortex (mPFC) where decreased concentrations have been associated with anhedonia. In major depressive disorder (MDD), prior work suggests that repetitive transcranial magnetic stimulation (rTMS) increases mPFC GABA concentrations proportional to antidepressant response. To our knowledge, this has not been examined in acute bipolar depression.Methods: As part of a multicentre 4-week randomized, double-blind, sham-controlled trial using intermittent theta-burst stimulation (iTBS) of the left dorsolateral prefrontal cortex (DLPFC) in individuals with acute bipolar depression, we quantified mPFC GABA and Glx (glutamate+glutamine) concentrations using a 3T MRS scan at baseline and after the intervention. Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale-17 (HRDS-17), and anhedonia was measured using the Snaith-Hamilton Pleasure Scale (SHAPS).Results: The trial was terminated for futility and magnetic resonance spectroscopy data was acquired for 18 participants. At baseline, there were no associations between GABA or Glx concentrations and anhedonia, however GABA was negative correlated with depressive symptom severity on the HRDS-17. Compared to the sham-iTBS group, participants receiving active-iTBS had a significant increase in mPFC GABA concentrations. This was unrelated to antidepressant outcomes or improvements in anhedonia.Conclusion: Our data suggests that iTBS targeting the DLPFC is associated with physiological changes in the mPFC. In acute bipolar depression, our preliminary data suggests that mPFC GABA is dissociated from antidepressant iTBS treatment outcomes and anhedonia.

Are we really targeting and stimulating DLPFC by placing transcranial electrical stimulation (tES) electrodes over F3/F4?

“…Based on the analysis of both normal and tangential components of the EFs in modulating prefrontal cortex, Csifcsak et al reported that strong stimulation can be found not only in DLPFC but also in the medial prefrontal cortex (MPFC) in bipolar montages which are commonly used for depression [21]. Their study supported previous modeling studies that have suggested the medial prefrontal cortex as a new target for depression in TMS studies [22,23]. In another example of atlas-based parcellation of the computational head models, four different electrode arrangements were simulated for a single standard subject (ICBME152) and 22 cortical areas were extracted per hemisphere [22].…”

Integrated analysis of the chemical-material basis and molecular mechanisms for the classic herbal formula of Lily Bulb and Rehmannia Decoction in alleviating depression

“…As of now, multiple studies allowed the formulation of several theories attempting to elucidate the pathogenesis of depression, including the monoamine [ 50 ], cytokine [ 51 ], HPA hyperactivity [ 52 ], neuroinflammation and neuroplasticity [ 53 ], GABA-glutamate-mediated depression [ 54 ], and circadian hypotheses [ 55 ]. These theoretical studies show that depression is a complex mental disorder involving a variety of neurotransmitters, brain regions, circuits and various biochemical substances or/and systems.…”

“…Importantly, both GABAergic synapse and neurotrophic signaling pathways (BDNF-Ntrk2) were involved in the antidepressant and anti-anxiety effects of the LBRD standard decoction in both in vitro and in vivo models. Reduction in BDNF and GABA neurotransmission co-occur in the mPFC tissues and has been repeatedly seen in animal models and human subjects, and this has been associated with anhedonia and anxiety [ 54 , 79 – 82 ]. In addition, treatment with antidepressants and anti-anxiety agents, as well as repetitive transcranial magnetic stimulation treatment has been shown to enhance GABA and BDNF expression in depression [ 83 , 84 ].…”

Neurostimulation as a treatment for mood disorders in patients: recent findings

“…The authors attempted to determine the efficacy of iTBS to treat acute BD using an antimanic drug combined with iTBS in the left dlPFC but found that this method was ineffective [9]. Interestingly, another study pointed out an increase in mPFC GABA levels after left dlPFC iTBS treatment, but this was not associated with improvement in depression symptoms in BD [10]. Thus, a different mechanism could exist in BD.…”